Evidence that thrombocytopenia observed in humans treated with orally bioavailable glycoprotein IIb/IIIa antagonists is immune mediated

Glycoprotein (GP) IIb/IIIa antagonists are effective therapeutic agents, but elicit thrombocytopenia with a frequency that approaches 2%. Here, we provide evidence that thrombocytopenia in humans treated with the GP IIb/IIIa antagonist roxifiban is immune mediated. Two patients underwent conversion to a highly positive drug-dependent antibody (DDAB) status temporally associated with thrombocytopenia. Despite the continued presence of DDABs, the fall in platelet count was reversed by discontinuation of drug treatment, pointing to the exquisite drug dependency of the immune response. DDABs appear to bind to neoepitopes in GP IIb/IIIa elicited on antagonist binding. This information was used to develop an enzyme-linked immunosorbent assay (ELISA) for DDAB using solid-phase GP IIb/IIIa. A high level of specificity is indicated by the observation that DDAB binding is dependent on the chemical structure of the GP IIb/IIIa antagonist and that only 2% to 5% of human blood donors and 5% of chimpanzees present with pre-existing DDABs. Furthermore, none of 108 nonthrombocytopenic patients from the phase II roxifiban study showed an increase in antibody titer. Absorption of thrombocytopenia plasma with platelets reduced the DDAB ELISA signal, indicating that the test detects physiologically relevant antibodies. Screening patients for pre-existing or increasing DDAB titer during treatment with GP IIb/IIIa antagonists may reduce the incidence of drug-induced thrombocytopenia.     

Rapid Detection of Rare Deleterious Variants by Next Generation Sequencing with Optional Microarray SNP Genotype Data

Autozygosity mapping is a powerful technique for the identification of rare, autosomal recessive, disease‐causing genes. The ease with which this category of disease gene can be identified has greatly increased through the availability of genome‐wide SNP genotyping microarrays and subsequently of exome sequencing. Although these methods have simplified the generation of experimental data, its analysis, particularly when disparate data types must be integrated, remains time consuming. Moreover, the huge volume of sequence variant data generated from next generation sequencing experiments opens up the possibility of using these data instead of microarray genotype data to identify disease loci. To allow these two types of data to be used in an integrated fashion, we have developed AgileVCFMapper, a program that performs both the mapping of disease loci by SNP genotyping and the analysis of potentially deleterious variants using exome sequence variant data, in a single step. This method does not require microarray SNP genotype data, although analysis with a combination of microarray and exome genotype data enables more precise delineation of disease loci, due to superior marker density and distribution.     

A concise guide to clinical reasoning

What constitutes clinical reasoning is a disputed subject regarding the processes underlying accurate diagnosis, the importance of patient‐specific versus population‐based data, and the relation between virtue and expertise in clinical practice. In this paper, I present a model of clinical reasoning that identifies and integrates the processes of diagnosis, prognosis, and therapeutic decision making. The model is based on the generalized empirical method of Bernard Lonergan, which approaches inquiry with equal attention to the subject who investigates and the object under investigation. After identifying the structured operations of knowing and doing and relating these to a self‐correcting cycle of learning, I correlate levels of inquiry regarding what‐is‐going‐on and what‐to‐do to the practical and theoretical elements of clinical reasoning. I conclude that this model provides a methodical way to study questions regarding the operations of clinical reasoning as well as what constitute significant clinical data, clinical expertise, and virtuous health care practice.     

System Strategies for Colorectal Cancer Screening at Federally Qualified Health Centers

Objectives. We assessed the protocols and system processes for colorectal cancer (CRC) screening at federally qualified health centers (FQHCs) in 4 midwestern states.Methods. We identified 49 FQHCs in 4 states. In January 2013, we mailed their medical directors a 49-item questionnaire about policies on CRC screening, use of electronic medical records, types of CRC screening recommended, clinic tracking systems, referrals for colonoscopy, and barriers to providing CRC.Results. Forty-four questionnaires (90%) were returned. Thirty-three of the respondents (75%) estimated the proportion of their patients up-to-date with CRC screening, with a mean of 35%. One major barrier to screening was inability to provide colonoscopy for patients with a positive fecal occult blood test (59%). The correlation of system strategies and estimated percentage of patients up-to-date with CRC screening was 0.43 (P = .01).Conclusions. CRC system strategies were associated with higher CRC screening rates. Implementing system strategies for CRC screening takes time and effort and is important to maintain, to help prevent, or to cure many cases of CRC, the second leading cause of cancer in the United States.Federally qualified health centers (FQHCs) attempt to provide comprehensive, quality primary health care services to medically underserved communities and vulnerable populations. Approximately 1198 centers receive operating grants from the Public Health Service Act and thus qualify for reimbursement from Medicare and Medicaid.1 FQHCs served 21 million patients in 2012, of whom 36% were uninsured and 92% were living below the 200% poverty level.1 One of the services provided by FQHCs is colorectal cancer (CRC) screening through stool testing for occult blood.2 This service is covered under the Medicare FQHC benefit for persons aged 65 years and older and for those who qualify for the Medicaid program.3CRC is the second leading cause of cancer deaths in the United States.4 Only 63% of US adults report being up-to-date with CRC screening.5 CRC is a disease that is largely preventable; colonoscopy, through detection of early tumors and removal of precancerous polyps, could prevent 65% of CRC cases.6,7 Several national organizations have guidelines for CRC screening.8,9 National guidelines promote any of several tests for CRC screening: tests that pick up occult bleeding and endoscopic tests that visualize all or part of the colon.8–10Clinical tests to directly visualize colorectal cancer and precancerous polyps are colonoscopy, flexible sigmoidoscopy, double-contrast barium enema, and computed tomographic colonography (virtual colonoscopy). Fecal occult blood tests (FOBTs), which detect blood in the stool that is not visible and that indicates possible cancer, are the guaiac-based test and the fecal immunochemical test (FIT). FOBTs are recommended annually, and colonoscopy is recommended every 10 years, if no polyps are found.8–10 FOBTs are much less expensive than colonoscopy and are often preferred by patients. In many safety net settings, FOBTs are the initial option for patients, because of the prohibitive cost and limited availability of colonoscopy.11,12Through an infrastructure grant to enhance community-based cancer control in Iowa, we visited 4 FQHCs in Iowa and learned that FOBTs were available for use, but were for the most part not given to patients to avoid having to arrange and pay for a follow-up colonoscopy if FOBT results were positive. One FQHC director explained that the annual budget included a fund for extra tests that might be needed for any medical reason, and once these funds were exhausted, no more funding was available in that year. Thus, CRC screening was not a top priority, because of many other competing health care needs.To enhance CRC screening, system strategies are appropriate. A system strategy is a group of interrelated items that are part of a plan of action to accomplish a specific goal, such as improving CRC screening. Many different system strategies have been identified for improving CRC screening, such as physician recommendation,13,14 mailed patient reminders,15–17 and electronic medical record (EMR) physician reminders.18,19Patients at greatest risk for not receiving CRC screening are racial and ethnic minorities, Asians and Hispanics, and individuals who lack a usual source of health care or health insurance.20 Underuse of CRC screening is frequently associated with socioeconomic disadvantage21 and is associated with higher late-stage CRC rates.22 Because many of our nation’s most disadvantaged individuals make use of FQHCs, we assessed the protocols and system processes in place for CRC screening at FQHCs in 4 midwestern states and estimated rates of CRC screening in these FQHCs.     

Interleukin 10 promoter region polymorphisms and susceptibility to advanced alcoholic liver disease

BACKGROUND: The factors determining why less than 10% of heavy drinkers develop advanced alcoholic liver disease (ALD) remain elusive, although genetic factors may be important. Interleukin 10 (IL-10) is an important cytokine with anti-inflammatory, anti-immune, and antifibrotic functions. Several polymorphisms have been identified in the IL-10 promoter and recent evidence suggests that some of these may have functional effects on IL-10 secretion. AIMS: To test the hypothesis that IL-10 promoter region polymorphisms are associated with susceptibility to ALD. METHODS: The allele frequencies for the two single base pair substitutions at positions -627 (C-->A) and -1117 (A-->G) in the IL-10 promoter were determined in 287 heavy drinkers with biopsy proved advanced ALD, 107 heavy drinkers with no evidence of liver disease or steatosis only on biopsy, and 227 local healthy volunteers. RESULTS: At position -627, 50% of patients with advanced ALD had a least one A allele compared with 33% of controls (p<0.0001) and 34% of drinkers with no or mild disease (p=0.017). At position -1117, the slight excess of the A allele in drinkers with advanced disease was because of linkage disequilibrium between the A alleles at the two sites. CONCLUSIONS: Among heavy drinkers, possession of the A allele at position -627 in the IL-10 promoter is associated with an increased risk of advanced liver disease. This is consistent with recent functional data that the -627*A allele is associated with low IL-10 expression which will favour inflammatory, immune mediated, and profibrotic mechanisms of alcohol related liver injury.     

Bone marrow aspirates as part of routine donor assessment for allogeneic blood and marrow transplantation can reveal presence of occult hematological malignancies in otherwise asymptomatic individuals

Pre transplant screening work-up of donors for allogeneic blood and marrow transplantation is essential in an effort to minimize risks to the recipient and protect the donor. At Princess Margaret Hospital, every potential donor is screened with a bone marrow aspirate. The case histories of three asymptomatic potential donors who presented within 1 year with normal complete blood counts, history and physical examination are presented. A 65-year-old male patient was diagnosed with smouldering multiple myeloma, a 72-year-old male patient with chronic lymphocytic leukemia and a 42-year-old male patient with myelodysplastic syndrome. Bone marrow examination led to the diagnosis in each one of these cases. Of note is that each of the potential donors was discovered to have the same disease as the transplant recipient. In vitro clonogenic hemopoietic progenitor assays were compared to those of 20 normal volunteers. Inferior growth of hemopoietic progenitor colonies in all three was noted. In conclusion, particularly in older donors and donors with potential for familial malignancies, more screening investigations including bone marrow aspiration may be reasonable to investigate for occult hematological malignancies prior to stem cell donation. Clonogenic assays can contribute to detect hemopoietic abnormalities pre transplant.     

Cigar and pipe smoking related to four year survival of coronary patients.

Six hundred and thirty-four male patients under 60 years who survived a first attack of unstable angina or myocardial infarction were followed for a period of four years. Details of initial and follow-up smoking habits were examined. Patients who continued to smoke cigarettes or cigars had an excess mortality compared with non-smokers, with those who stopped smoking, and with cigarette smokers who changed to pipe smoking. Pipe smokers who continued smoking the pipe had an observed mortality which was greater than that of the non-smokers, but the numbers were small and the results were not statistically significant. The effect of smoking habit on mortality was not influenced by two other determinants of prognosis: age and severity of initial attack. These results confirm that the long-term prognosis of patients after unstable angina or myocardial infarction may be significantly influenced by smoking habits. They are consistent with the hypothesis that cigar and pipe smoking may have an adverse effect after myocardial infarction but further studies are needed to corroborate the association between cigar and pipe smoking and prognosis of coronary heart disease.     

Natriuretic peptides in the diagnosis of heart disease--first amongst equals?

The natriuretic peptides and their role in neurohumoral regulation of the cardiovascular system have become the focus of considerable interest from the scientific and clinical community in recent years. BNP in particular has been shown to be an important diagnostic and prognostic marker of use in a wide range of applications. As measurement techniques develop and are refined, routine evaluation of serum levels of these markers is expected to become more widespread. We have reviewed the biochemistry of the natriuretic peptide family, their role in cardiovascular pathophysiology and the evidence supporting their use in the clinical setting.     

Lanreotide Autogel® for Acromegaly

Since their introduction into clinical practice, somatostatin analogs have been the pharmacological therapy of choice for the treatment of acromegaly. The first preparations of somatostatin analogs available for clinical use were administered subcutaneously two or three times daily, which was not optimal with respect to patient compliance. The introduction of long-acting formulations of somatostatin analogs has overcome this inconvenience. Lanreotide Autogel, a new viscous, supersaturated, aqueous solution of lanreotide, is available in a prefilled syringe and administered by deep subcutaneous injection every 28 days. Lanreotide Autogel has different pharmacokinetic properties from the earlier lanreotide slow-release (SR) formulation, which may account for its better tolerability. Furthermore, lanreotide Autogel is at least as efficacious as the other somatostatin analogs in lowering growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels in the majority and in restoring safe GH and age-normalized IGF-1 levels in about 50-60% of patients with acromegaly. In conclusion, lanreotide Autogel is a valuable new addition to the acromegaly treatment armamentarium. Patients receiving intramuscular lanreotide SR injections every 7-14 days can be switched to an appropriate dose of deep subcutaneous lanreotide Autogel every 28 days, without any impact on safety or loss of efficacy.