Is there a ‘Basque’ profile regarding autosomal recessive deficiencies of coagulation factors?*

When excluding haemophilia and von Willebrand disease, coagulation factors deficiencies constitute rare autosomal recessive disorders (<1 in 500,000) of less precisely defined epidemiology. We have reported herein the distribution of these entities in the French Basque Country, a genetic isolate of very old individualization with peculiar biological specificities. The prevalence of these disorders was markedly high, especially, as already shown, factor XI deficiency. This unusual profile needs to be discussed in the view of population genetics.     

Gastrointestinal motility problems in the elderly patient

Statistics abound demonstrating the aging of the population, and this comes as no news to physicians caring for an increasing number of elderly patients. This group experiences the expected age-related physiologic declines, including systems critical to integrative functions such as immunologic, neurologic, and metabolic systems. Although an increased prevalence of several common gastrointestinal disorders occurs in the elderly person, aging per se appears to have less direct effect on most gastrointestinal functions, in large part because of the functional reserve of the gastrointestinal tract. Although irritable bowel symptoms decrease with aging, there seems to be an increase in many gastrointestinal disorders of function and motility. The gastroenterologist will frequently encounter elderly patients with complaints of dysphagia, anorexia, dyspepsia, and disorders of colonic function. Understanding age-related changes in gastrointestinal physiology and effects of common comorbid illnesses enhances the ability to evaluate and treat these common, troublesome symptoms.     

Factor VII deficiency: A cause of (or risk factor for) bleeding?

Among the rare bleeding disorders factor VII deficiency is the most common, but correlating deficiency with bleeding phenotype is challenging. In their study Lou and colleagues investigate a large cohort of unrelated factor VII deficient patients providing a further perspective on the link between genotype and phenotype in this disorder. Commentary on: Lou et al. Structural and functional characterization of novel F7 mutations identified in Chinese factor VII deficient patients. Br J Haematol. 2023;202:623–635.     

Congenital combined deficiency of coagulation factors VII and X – different genetic mechanisms

Combined coagulation factor VII (FVII) and factor X (FX) deficiency (combined FVII/FX deficiency) belongs to the group of bleeding disorders in which both factors show reduced plasma activity. It may arise from coincidental inheritance of separate coagulation factor deficiencies or a common cause as large deletions comprising both gene loci. The F7 and F10 genes are located on the long arm of chromosome 13. Here, we describe 10 cases with combined FVII/FX deficiency representing both genetic mechanisms of occurrence. Genetic analyses included direct sequencing of the F7 and F10 genes and MLPA (multiplex ligation‐dependent probe amplification) for detection of heterozygous large deletions. In four patients, the combined deficiency was due to a large deletion within the terminal end of chromosome 13. In the remaining six cases the deficiency resulted from coincidental inheritance of different genetic alterations affecting both genes independently. In most cases, the genetic defects were heterozygous, presenting with prolonged PT, normal aPTT and mild or no bleeding symptoms. Only in one case compound heterozygous mutations were detected in the F10, resulting in prolonged aPTT and a more severe bleeding phenotype. To avoid a misdiagnosis of combined FVII/FX deficiency, analyses of single factor activities have to be performed in all cases with prolonged PT even if aPTT is normal. Genetic analyses are substantial for correct prediction of an inheritance pattern and a proper genetic counselling.     

Familial multiple coagulation factor deficiencies – chance associations and distinct clinical disorders

Summary.  The familial multiple coagulation factor deficiencies (FMCFDs) are a group of rare haemostatic disorders of genetic origin in which there is reduced plasma activity of more than one coagulation factor. FMCFDs may arise from co-incidental inheritance of separate coagulation factor deficiencies or from a single genetic or cytogenetic defect. All the FMCFDs present significant challenges in diagnosis and management yet there is little systematic evidence with which to guide clinical practice. This review summarizes the historical literature that describes the FMCFDs and introduces a refined classification of these disorders. The clinical and laboratory characteristics of the most common FMCFDs are considered in detail.     

Retrospective analysis of 1312 patients with haemophilia and related disorders in a single Chinese institute

With 1.3 billion people, China has the largest population in the world, and therefore has the largest population of persons with haemophilia (PWH). As there is no national registry for haemophilia, it is difficult to ascertain how many PWH have actually been diagnosed. Between January 1983 and June 2002, 1312 patients with coagulation disorders were referred to our hospital, and 1190 patients were evaluable. Among them, 1069 (89.8%) patients had haemophilia, 68 had vWD, 20 had factor XI deficiency, 10 had acquired factor VIII inhibitor and 23 had other coagulation disorders. Of the 1069 PWH, 14.7% were unclassified, 38.4% severe, 35.7% moderate and 11.1% mild. If the unclassified cases were excluded, 45.1% were severe, 41.9% moderate and 13.0% mild. Twenty-nine of the 68 vWD patients had vWF:Ag <5%, and subcategorized as type 3 vWD. Because vWF multimer analysis was not performed in our centre, the remaining vWD patients were not subdivided.     

贵州省碘缺乏病和地方性氟中毒的地理分布差异及影响因素

研究了贵州碘缺乏病和地方性氟中毒的地理分布及其影响因素。结果发现：贵州外环境缺碘、饮水氟含量低，有较大面积的碘缺乏病和地方性氟中毒流行，前者主要分布在东南部烧柴区，后者主要分布于西北部燃煤区。这种分布与燃料结构和燃烧方式有关。在烧柴区，木柴中碘和氟含量甚低，外环境缺碘和低氟状态没有改变，形成了碘缺乏病区，在燃煤区，煤燃烧释放的碘和氟改善了第一环境的碘不足，避免了碘缺乏病流行，同时环境中过量氟导致地方性氟中毒发生。     

The investigation of a prolonged APTT with specific clotting factor assays is unnecessary if an APTT with Actin FS is normal

Introduction: An isolated prolongation to the activated partial thromboplastin time (APTT) can be caused by the presence of the lupus anticoagulant or an intrinsic or contact factor deficiency, of which only deficiencies of factors VIII, IX or XI are associated with bleeding. Our local protocol states that further investigation of a prolonged APTT by specific assays of FVIII, FIX and FXI should only be undertaken where the APTT with one reagent (Synthasil) is more than 3 s prolonged, and further investigation by an APTT with a second reagent (Actin FS) is also prolonged, unless there is a history of bleeding in the patient, in which case assays are indicated irrespective of the APTT. Methods: We retrospectively reviewed the results of all APTTs performed over a 36 ‐month period to evaluate whether strictly applying our protocol would reduce the number of unnecessary clotting factor assays performed, without leaving patients with potentially significant bleeding disorders undiagnosed. Results: Of a total number of 587 samples tested for coagulation factors VIII, IX and XI, only 117 samples yielded an abnormal result. Thus, 80% of all the assays requested in the 3 ‐year period audited gave a result within the reference range for factors VIII, FIX and XI. Three quarters of the abnormal results revealed mild FXI deficiency. Conclusion: This review has demonstrated that no significant coagulation factor deficiency would be left undiagnosed if the protocol was followed. This would have considerably reduced the cost and time spent performing these assays.     

Hepatitis C virus and non-Hodgkin's lymphomas:Metaanalysis of epidemiology data and therapy options

Hepatitis C virus(HCV) is a global health problem affecting a large fraction of the world's population: This virus is able to determine both hepatic and extrahepatic diseases. Mixed cryoglobulinemia, a B-cell "benign" lymphoproliferative disorders, represents the most closely related as well as the most investigated HCVrelated extrahepatic disorder. Since this virus is able to determine extrahepatic [non-Hodgkin's lymphoma(NHL)] as well as hepatic malignancies(hepatocellular carcinoma), HCV has been included among human cancer viruses. The most common histological types of HCV-associated NHL are the marginal zone, the lymphoplasmacytic and diffuse large cell lymphomas. The role of the HCV in the pathogenesis of the B-cell lymphoproliferative disorders is confirmed also by the responsiveness of the NHL to antiviral therapy. The purpose of this review is to provide an overview of the recent literature and a meta analysis of the epidemiology data, to explain the role of HCV in the development of NHL's lymphoma. Furthermore, the possibility to treat these HCV-related NHL with the antiviral therapy or with other therapeutic options, like chemotherapy, is also discussed.     

Gastrointestinal motility disorders in inflammatory bowel diseases

The relationship between motility and inflammatory gastrointestinal disorders is at the same time complex and intriguing since these conditions might share some genetic,environmental,immunological and microbial predisposing factors.In addition,significant symptom overlapping may occur,muddling the waters within the clinical context.Although on one hand this represents a challenge for the clinician for a potential under-or over-treatment and diagnostic delay,on the other hand it possibly represents an opportunity for the researcher to better disclose the intimate relationship between chronic(often low-grade)inflammation,motor disorders and deranged sensory function.The best example is probably represented by Crohn’s disease and ulcerative colitis.In fact,a number of gastrointestinal motor disorders have been described in association with these diseases,disorders which span from the esophagus to the anorectum,and which will be extensively covered in this review.It is conceivable that at least part of this derangement is strictly related to inflammatory cytokine trafficking and neuromuscular changes;however,given the high prevalence of functional gastrointestinal disorders in the general population,this overlap might also be serendipitous.However,it is worth noting that literature data on this topic are relatively scarce,sometimes quite outdated,and mostly focused on the interplay between irritable bowel syndrome and inflammatory bowel disease.Nevertheless,both researchers and clinicians must be aware that symptoms related to gastrointestinal motility disorders may be highly prevalent in both active and inactive inflammatory bowel disease,correlate with greater psychological comorbidity and poorer quality of life,and may negatively influence the therapeutic approaches.     

Environmental exposure to carcinogens causing lung cancer: epidemiological evidence from the medical literature

OBJECTIVE: In 2000 there were 1.1 million lung or bronchial cancer deaths worldwide, with relatively limited evidence of causation other than for smoking. We aimed to search and appraise the literature regarding evidence for a causal relationship between air pollution and lung cancer according to the 10 Bradford Hill criteria for causality. METHODOLOGY: A MEDLINE search was performed using the following key words: 'lung neoplasm', 'epidemiology', 'human', 'air pollution'and 'not molec*'. The criteria for inclusion was: cited original research that described the study population, measured environmental factors, was of case control or cohort design, and was undertaken after 1982. RESULTS: Fourteen papers (10 case control, four cohort studies) fulfilled the search criteria, with a sample size ranging from 101 cases and 89 controls, to a cohort of 552 cases and 138 controls. Of the 14 papers that fulfilled the search criteria the number of papers addressing each of the Bradford Hill criteria were as follows: Strength of association: eight studies demonstrated significant positive associations between environmental exposure and lung cancer with a relative risk range of 1.14-5.2. One study found a negative association with relative risk 0.28. Consistency: eight of 14 studies found significant positive associations and one of 14 a significant negative association. Specificity: tobacco smoking and occupational exposure were addressed in all studies (often crudely with misclassification). Temporality: exposure prior to diagnosis was demonstrated in nine studies. Dose-response relationship: evident in three studies. Coherence, analogy: not addressed in any study. CONCLUSION: Evidence for causality is modest, with intermediate consistency of findings, limited dose-response evidence and crude adjustment for important potential confounders. Large studies with comprehensive risk factor quantification are required to clarify the potentially small effect of air pollution given the relatively large effects of tobacco smoking and occupational carcinogen exposure.     

Clonal interference in large populations

Clonal interference, the competition between lineages arising from different beneficial mutations in an asexually reproducing population, is an important factor determining the tempo and mode of microbial adaptation. The standard theory of this phenomenon neglects the occurrence of multiple mutations as well as the correlation between loss by genetic drift and clonal competition, which is questionable in large populations. Working within the Wright-Fisher model with multiplicative fitness (no epistasis), we determine the rate of adaptation asymptotically for very large population sizes and show that the standard theory fails in this regime. Our study also explains the success of the standard theory in predicting the rate of adaptation for moderately large populations. Furthermore, we show that the nature of the substitution process changes qualitatively when multiple mutations are allowed for, because several mutations can be fixed in a single fixation event. As a consequence, the index of dispersion for counts of the fixation process displays a minimum as a function of population size, whereas the origination process of fixed mutations becomes completely regular for very large populations. We find that the number of mutations fixed in a single event is geometrically distributed as in the neutral case. These conclusions are based on extensive simulations combined with analytic results for the limit of infinite population size.     

Candida vertebra osteomyelitis in a girl with factor X deficiency

Candidal vertebra osteomyelitis is a rare condition which occurs primarily in immunocompromised patients. We report a 14-year-old girl with factor X deficiency who developed candida vertebra osteomyelitis during home therapy. The microorganism was probably from a contaminated peripheral cannula used for infusion of factor concentrate. This is the first such case in bleeding disorders to our knowledge.     

Long-term extensive expansion of mouse hepatic stem/progenitor cells in a novel serum-free culture system

BACKGROUND & AIMS: The liver has high regenerative potential. We attempted to establish a novel culture system for extensive expansion of fetal mouse hepatic stem/progenitor cells and to characterize cultured cells. METHODS: Hepatic spheroids collected from 6-day floating cultures were cultured on collagen-coated dishes in serum-free conditions in medium containing growth factors. Cultured cells were mainly characterized by immunocytochemistry and flow cytometry or transplanted into adult mice. RESULTS: Approximately 400 expanding hepatic spheroids were generated from every 1 x 10(6) fetal liver cells. Subsequently, highly replicative colonies were subcultured with maintaining colony formation on collagen-coated dishes. These colonies consisted of small immature alpha-fetoprotein-positive cells and hepatocytic and cholangiocytic lineage-committed cells. The immature alpha-fetoprotein-positive cells could be expanded in a reproducible manner at least 5 x 10(5)-fold (which involved at least 30 passages over >6 months) without losing differentiation potential. Flow cytometric analysis showed that all cultured cells expressed CD49f, but not CD34, Thy-1, c-kit, or CD45. Nearly 15% of the cells expressed Sca-1, and approximately 5%-20% of the cells were side population cells. Both sorted side population cells and Sca-1-positive cells (especially side population cells) produced a large number of alpha-fetoprotein-positive cells and lineage-committed cells. Expanded cells had bidirectional differentiation potential and improved serum albumin levels in mice with severe liver damage. CONCLUSIONS: Long-term extensive expansion of transplantable hepatic stem/progenitor cells was reproducibly achieved in a novel serum-free culture system. Moreover, this culture system yielded side population and Sca-1-positive cell populations that included hepatic stem/progenitor cells with differentiation and proliferation properties.     

Prevalence of polycythemia vera and essential thrombocythemia

Polycythemia vera (PV) and essential thrombocythemia (ET) are common types of myeloproliferative disorders (MPD), the prevalence of which has not been well documented in the United States. Recent breakthroughs in the molecular etiology of these disorders and the accelerated development of targeted pharmacotherapeutics to treat them underscore the need to define the affected population. In this study, we obtained health claims data from major commercial insurance payers in Connecticut and the Center for Medicare and Medicaid Services to estimate the prevalence of PV and ET. Specifically, logistic regression was utilized to develop algorithms to predict the probability that an individual with claims suggestive of MPD truly has PV or ET, and the algorithms were then applied to health claims to estimate the number of PV and ET patients in Connecticut. As of 2003, the age-standardized prevalence was 22 per 100,000 and 24 per 100,000 for PV and ET, respectively, in Connecticut. Applying the age-specific prevalence of PV and ET to the entire US population resulted in an estimated total of 65,243 patients with PV and 71,078 patients with ET in the United States in 2003. This study is the first to assess the prevalence of PV and ET in a large US population. Given the large number of individuals afflicted with these diseases and the fact that demographic changes alone will further increase the burden of     

老年人血镁水平降低与血糖代谢异常的关系

目的 探讨老年人血镁水平降低与血糖代谢异常的关系.方法 收集我院门诊126例老年人的查体资料,其中2型糖尿病患者50例,糖调节异常者35例,血糖正常者41例,对3组老年人临床资料进行比较分析.结果 (1)3组的年龄、体质指数、血脂水平差异均无统计学意义,糖尿病组和糖调节异常组血清镁明显低于血糖正常组,分别为(0.75±0.11)mmol/L和(0.78±0.12)mmol/L对(0.84±0.1)mmol/L,差异有统计学意义(P＜0.01、＜0.05);(2)低血镁发病率在2型糖尿病和糖调节异常组明显高于血糖正常组,分别为24.0%和28.6%对7.3%(均为P＜0.01);(3)相关分析结果显示,血镁水平与空腹血糖及糖化血红蛋白水平呈明显负相关(r=-0.343、-0.271,均为P＜0.01),与年龄及体质指数无相关.结论 老年人血清镁水平降低与血糖代谢异常有关.

Abstract：

Objective To explore the relationship between serum magnesium (Mg) levels and glucose metabolism disorders in the elderly.Methods The data of health examination of 126 elderly people were collected in our hospital.There were 50 patients with type 2 diabetes,35 patients with impaired glucose regulation (IGR) and 41 people with normal glucose.The clinical data of the three groups were compared and analyzed.Results (1)There were no significant differences in age,body mass index (BMI) and blood lipid level among the three groups.The mean serum Mg level was lower in normal glucose group [(0.84±0.1) mmol/L] than in diabetic group [(0.75±0.11) mmol/L,P＜0.01] and IGR group [(0.78±0.12) mmol/L,P＜0.05].(2)The prevalence of hypomagnesemia was higher in diabetic group and IGR group than in normal glucose group (24%,28.6% vs.7.3%,P＜ 0.01 ).(3)The correlation study showed that the serum magnesium level was negatively associated with fasting plasma glucose and HbA1c (r= - 0.343,- 0.271,P＜0.01 ),but not associated with age and BMI.Conclusions The low serum magnesium level is associated with glucose metabolism disorders in the elderly.     

Arterial structure and function in inflammatory bowel disease

Inflammatory bowel disease(IBD) is the result of a combination of environmental,genetic and immunologic factors that trigger an uncontrolled immune response within the intestine,which results in inflammation among genetically predisposed individuals. Several studies have reported that the prevalence of classic cardiovascular risk factors is lower among subjects with IBD than in the general population,including obesity,dyslipidaemia,diabetes and hypertension. Therefore,given the risk profile of IBD subjects,the expected cardiovascular morbidity and mortality should be lower in these patients than in the general population. However,this is not the case because the standardized mortality ratio is not reduced and the risk of coronary heart disease is increased in patients with IBD. It is reasonable to hypothesize that other factors not considered in the classical stratification of cardiovascular risk may be involved in these subjects. Therefore,IBD may be a useful model with which to evaluate the effects of chronic low-grade inflammation in the development of cardiovascular diseases. Arterial stiffness is both a marker of subclinical target organ damage and a cardiovascular risk factor. In diseases characterized by chronic systemic inflammation,there is evidence that the inflammation affects arterial properties and induces both endothelial dysfunction and arterial stiffening. It has been reported that decreasing inflammation viaanti tumor necrosis factor alpha therapy decreases arterial stiffness and restores endothelial function in patients with chronic inflammatory disorders. Consistent with these results,several recent studies have been conducted to determine whether arterial properties are altered among patients with IBD. In this review,we discuss the evidence pertaining to arterial structure and function and present the available data regarding arterial stiffness and endothelial function in patients with IBD.     

An illustrative case and a review on the dosing of recombinant factor VIIa in congenital factor XI deficiency

Recombinant activated factor VII (rFVIIa) has been used in a very limited number of patients with severe factor XI (FXI) deficiency. The dose and duration of treatment has varied greatly between these case reports. In a few of these cases there was also evidence of thrombotic complications. We present here a report on one additional patient with congenital FXI deficiency. For two major orthopaedic procedures in this patient we used rFVIIa as a single bolus dose followed by continuous infusion at a low rate. The data from these treatment episodes, together with those from a review of the published cases, lend support to the concept of using much lower doses than in haemophilia with inhibitors. A bolus dose of 20 microg kg(-1) and thereafter maintenance of the FVII activity at approximately 3 IU mL(-1) appears effective and safe.     

Large scale screening for haemoglobin disorders in southern Vietnam: implications for avoidance and management

In order to obtain an approximate assessment of the public health burden that will be posed by the inherited disorders of haemoglobin in southern Vietnam, several thousand individuals were screened for these conditions. A smaller sample was screened for glucose‐6‐phosphate dehydrogenase (G6PD) deficiency. The important haemoglobin disorders identified were β thalassaemia, haemoglobin E and a variety of different forms of α thalassaemia. There were sufficient G6PD‐deficient individuals to materially affect malaria control programme design. The most remarkable finding was wide variation in the gene frequencies of these conditions among the ethnic groups sampled. The approximate number of babies expected to be born with clinically significant haemoglobin disorders in Vietnam was estimated from the gene‐frequency data. This study emphasizes the importance of wide‐scale population screening, including ethnic subgroups, to establish the requirements for inherited haemoglobin disorder programmes in resource‐limited settings.