Main clinical manifestations of a bleeding diathesis: an often disregarded aspect of medical and surgical history taking

Summary.  A suitable clinical evaluation of a bleeding diathesis is often forgone. The young doctor is often unprepared to describe in an accurate way the different types of bleeding. An adequate classification and adequate clinical information about a bleeding diathesis are instead of paramount importance. Bleeding may be cutaneous, mucous, articular, muscular, parenchymal, intracavitary, orificial. Each of these sites and forms may have diagnostic implications. An accurate description of the several forms of cutaneous bleeding (petechiae, purpuric spots, ecchymosis, haematomas, etc.) is needed for referrals and for controls. The correct evaluation of cutaneous bleeding manifestations of children (battered child syndrome) is absolutely important for clinical and medico‐legal purposes. The same is true for the battering syndrome seen in women abused by their spouses. The grading of haemarthrosis in haemophilia patients is important for the follow‐up. A proper description of haematuria is essential in suggesting the probable site of bleeding (kidney or bladder or urethra). A proper evaluation of bleeding may give also useful information on the general health status of the patients (presence of anaemia, poor nutrition, renal insufficiency, etc.). The combination of bleeding and thrombosis in the same patient is also a clinical challenge. The relationship between haemorrhage and thrombosis may be sequential or concomitant. Sequential thrombosis may occur in a patient confined in bed for a brain haemorrhage. Concomitant thrombosis and bleeding occur in DIC and in patients with thrombosis being treated with anticoagulants. Finally, it should be kept in mind that a proper evaluation of the bleeding diathesis of a given patient may help the caring doctor in ordering appropriate laboratory tests (e.g. a platelet count for petechiae, a PTT for a patient with haemarthrosis, etc.)

Genetic predisposition to hemophagocytic lymphohistiocytosis: report on 500 patients from the Italian registry

Background Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease affecting mostly children but also adults and characterized by hyperinflammatory features. A subset of patients, referred to as having familial hemophagocytic lymphohistiocytosis (FHL), have various underlying genetic abnormalities, the frequencies of which have not been systematically determined previously. Objective This work aims to further our understanding of the pathogenic bases of this rare condition based on an analysis of our 25 years of experience. Methods From our registry, we have analyzed a total of 500 unselected patients with HLH. Results Biallelic pathogenic mutations defining FHL were found in 171 (34%) patients; the proportion of FHL was much higher (64%) in patients given a diagnosis during the first year of life. Taken together, mutations of the genes PRF1 (FHL2) and UNC13D (FHL3) accounted for 70% of cases of FHL. Overall, a genetic diagnosis was possible in more than 90% of our patients with FHL. Perforin expression and the extent of degranulation have been more useful for diagnosing FHL than hemophagocytosis and the cytotoxicity assay. Of 281 (56%) patients classified as having "sporadic" HLH, 43 had monoallelic mutations in one of the FHL-defining genes. Given this gene dosage effect, FHL is not strictly recessive. Conclusion We suggest that the clinical syndrome HLH generally results from the combined effects of an exogenous trigger and genetic predisposition. Within this combination, different weights of exogenous and genetic factors account for the wide disease spectrum that ranges from HLH secondary to severe infection to FHL

Robust exponential decay of correlations for singular-flows

We construct open sets of Ck (k bigger or equal to 2) vector fields with singularities that have robust exponential decay of correlations with respect to the unique physical measure. In particular we prove that the geometric Lorenz attractor has exponential decay of correlations with respect to the unique physical measure.Comment: Final version accepted for publication with added corrections (not in official published version) after O. Butterley pointed out to the authors that the last estimate in the argument in Subsection 4.2.3 of the previous version is not enough to guarantee the uniform non-integrability condition claimed. We have modified the argument and present it here in the same Subsection. 3 figures, 34 page

Large deviations for non-uniformly expanding maps

We obtain large deviation results for non-uniformly expanding maps with non-flat singularities or criticalities and for partially hyperbolic non-uniformly expanding attracting sets. That is, given a continuous function we consider its space average with respect to a physical measure and compare this with the time averages along orbits of the map, showing that the Lebesgue measure of the set of points whose time averages stay away from the space average decays to zero exponentially fast with the number of iterates involved. As easy by-products we deduce escape rates from subsets of the basins of physical measures for these types of maps. The rates of decay are naturally related to the metric entropy and pressure function of the system with respect to a family of equilibrium states. The corrections added to the published version of this text appear in bold; see last section for a list of changesComment: 36 pages, 1 figure. After many PhD students and colleagues having pointed several errors in the statements and proofs, this is a correction to published article answering those comments. List of main changes in a new last sectio

A ten year review of the sickle cell program in Muhimbili National Hospital, Tanzania

Background: Africa has the highest burden of Sickle cell disease (SCD) but there are few large, systematic studies providing reliable descriptions of the disease spectrum. Tanzania, with 11,000 SCD births annually, established the Muhimbili Sickle Cell program aiming to improve understanding of SCD in Africa. We report the profile of SCD seen in the first 10 years at Muhimbili National Hospital (MNH). Methods: Individuals seen at MNH known or suspected to have SCD were enrolled at clinic and laboratory testing for SCD, haematological and biochemical analyses done. Ethnicity was self-reported. Clinical and laboratory features of SCD were documented. Comparison was made with non-SCD population as well as within 3 different age groups (< 5, 5-17 and ≥ 18 years) within the SCD population. Results: From 2004 to 2013, 6397 individuals, 3751 (58.6%) SCD patients, were enrolled, the majority (47.4%) in age group 5-17 years. There was variation in the geographical distribution of SCD. Individuals with SCD compared to non-SCD, had significantly lower blood pressure and peripheral oxygen saturation (SpO2). SCD patients had higher prevalence of severe anemia, jaundice and desaturation (SpO2 < 95%) as well as higher levels of reticulocytes, white blood cells, platelets and fetal hemoglobin. The main causes of hospitalization for SCD within a 12-month period preceding enrolment were pain (adults), and fever and severe anemia (children). When clinical and laboratory features were compared in SCD within 3 age groups, there was a progressive decrease in the prevalence of splenic enlargement and an increase in prevalence of jaundice. Furthermore, there were significant differences with monotonic trends across age groups in SpO2, hematological and biochemical parameters. Conclusion: This report confirms that the wide spectrum of clinical expression of SCD observed elsewhere is also present in Tanzania, with non-uniform geographical distribution across the country. Age-specific analysis is consistent with different disease-patterns across the lifespan

The European Cancer Patient’s Bill of Rights, update and implementation 2016

In this implementation phase of the European Cancer Patient’s Bill of Rights (BoR), we confirm the following three patient-centred principles that underpin this initiative: 1: The right of every European citizen to receive the most accurate information and to be proactively involved in his/her care. 2: The right of every European citizen to optimal and timely access to a diagnosis and to appropriate specialised care, underpinned by research and innovation. 3: The right of every European citizen to receive care in health systems that ensure the best possible cancer prevention, the earliest possible diagnosis of their cancer, improved outcomes, patient rehabilitation, best quality of life and affordable health care. The key aspects of working towards implementing the BoR are: - Agree our high-level goal. The vision of 70% long-term survival for patients with cancer in 2035, promoting cancer prevention and cancer control and the associated progress in ensuring good patient experience and quality of life. - Establish the major mechanisms to underpin its delivery. (1) The systematic and rigorous sharing of best practice between and across European cancer healthcare systems and (2) the active promotion of Research and Innovation focused on improving outcomes; (3) Improving access to new and established cancer care by sharing best practice in the development, approval, procurement and reimbursement of cancer diagnostic tests and treatments. - Work with other organisations to bring into being a Europe based centre that will (1) systematically identify, evaluate and validate and disseminate best practice in cancer management for the different countries and regions and (2) promote Research and Innovation and its translation to maximise its impact to improve outcomes

Fitness Trade-Offs in the Evolution of Dihydrofolate Reductase and Drug Resistance in Plasmodium falciparum

Background: Patterns of emerging drug resistance reflect the underlying adaptive landscapes for specific drugs. In Plasmodium falciparum, the parasite that causes the most serious form of malaria, antifolate drugs inhibit the function of essential enzymes in the folate pathway. However, a handful of mutations in the gene coding for one such enzyme, dihydrofolate reductase, confer drug resistance. Understanding how evolution proceeds from drug susceptibility to drug resistance is critical if new antifolate treatments are to have sustained usefulness. Methodology/Principal Findings: We use a transgenic yeast expression system to build on previous studies that described the adaptive landscape for the antifolate drug pyrimethamine, and we describe the most likely evolutionary trajectories for the evolution of drug resistance to the antifolate chlorcycloguanil. We find that the adaptive landscape for chlorcycloguanil is multi-peaked, not all highly resistant alleles are equally accessible by evolution, and there are both commonalities and differences in adaptive landscapes for chlorcycloguanil and pyrimethamine. Conclusions/Significance: Our findings suggest that cross-resistance between drugs targeting the same enzyme reflect the fitness landscapes associated with each particular drug and the position of the genotype on both landscapes. The possibl

Impact of the Method of G6PD Deficiency Assessment on Genetic Association Studies of Malaria Susceptibility

BACKGROUND:Clinical association studies have yielded varied results regarding the impact of glucose-6-phosphate dehydrogenase (G6PD) deficiency upon susceptibility to malaria. Analyses have been complicated by varied methods used to diagnose G6PD deficiency. METHODOLOGY/PRINCIPAL FINDINGS:We compared the association between uncomplicated malaria incidence and G6PD deficiency in a cohort of 601 Ugandan children using two different diagnostic methods, enzyme activity and G6PD genotype (G202A, the predominant East African allele). Although roughly the same percentage of males were identified as deficient using enzyme activity (12%) and genotype (14%), nearly 30% of males who were enzymatically deficient were wild-type at G202A. The number of deficient females was three-fold higher with assessment by genotype (21%) compared to enzyme activity (7%). Heterozygous females accounted for the majority (46/54) of children with a mutant genotype but normal enzyme activity. G6PD deficiency, as determined by G6PD enzyme activity, conferred a 52% (relative risk [RR] 0.48, 95% CI 0.31-0.75) reduced risk of uncomplicated malaria in females. In contrast, when G6PD deficiency was defined based on genotype, the protective association for females was no longer seen (RR = 0.99, 95% CI 0.70-1.39). Notably, restricting the analysis to those females who were both genotypically and enzymatically deficient, the association of deficiency and protection from uncomplicated malaria was again demonstrated in females, but not in males (RR = 0.57, 95% CI 0.37-0.88 for females). CONCLUSIONS/SIGNIFICANCE:This study underscores the impact that the method of identifying G6PD deficient individuals has upon association studies of G6PD deficiency and uncomplicated malaria. We found that G6PD-deficient females were significantly protected against uncomplicated malaria, but this protection was only seen when G6PD deficiency is described using enzyme activity. These observations may help to explain the discrepancy in some published association studies involving G6PD deficiency and uncomplicated malaria