Dilated cardiomyopathy and limb-girdle muscular dystrophy-dystroglycanopathy due to novel pathogenic variants in the DPM3 gene.

Deficiency of Dolichol-P-mannose synthase subunit 3 (DPM3) affects the N-glycosylation and O-mannosylation pathways that are respectively involved in congenital disorders of glycosylation (CDG) and alpha-dystroglycanopathies. Herein, we describe novel pathogenic variants in the DPM3 gene in two unrelated male patients. They developed dilated cardiomyopathy in their late teens, limb-girdle muscular dystrophy - one patient in childhood and the other in adulthood. In both patients, next generation sequencing found in the DPM3 gene a heterozygous deletion and a heterozygous pathogenic missense mutation in exon 2 (c.41T>C, p.Leu14Pro). Electrophoresis of serum transferrin found an abnormal N-glycosylation profile suggestive of CDG type 1 (decreased tetrasialotransferrin, increased disialo- and asialotransferrin). Only two cases of DPM3 gene mutations with limb-girdle muscular dystrophy-dystroglycanopathy have been reported previously. The present study highlights several aspects related to DPM3 gene mutations such as mild to moderately severe limb-girdle muscular dystrophy, dilated cardiomyopathy, and abnormal N-glycosylation profile suggestive of CDG type 1.

Venous thrombosis in children and adolescents with Hodgkin lymphoma in Sweden.

INTRODUCTION: Pediatric patients with Hodgkin lymphoma (HL) have several risk factors for venous thromboembolism (VTE). Although these patients are occasionally treated with thromboprophylaxis, no guidelines are implemented in Sweden. Scarce data from adult patients indicate an increased risk of VTE, but pediatric data is largely missing. Given the favorable overall survival of HL, there should reasonably be more focus on preventing complications. MATERIALS AND METHODS: We conducted a retrospective cohort study, including all patients registered in the Childhood Cancer Registry under the age of 18years diagnosed with HL between January 2005 and December 2015 in Sweden. RESULTS: Data was retrieved from the medical records of all 163 patients (100%) at six Swedish pediatric cancer centers. The incidence of VTE was 7.7% (symptomatic VTE 3.9%). The median follow-up was 3.4years (range 0.3-10.5). Only five patients (3.1%) were treated with thromboprophylaxis. All VTE events occurred in the older age category (11-17years) and all but one (92.7%) had a mediastinal mass. While the VTE did not significantly affect the treatment of HL, it caused increased morbidity and 2/12 developed a post-thrombotic syndrome. No significant risk factors for VTE were identified. CONCLUSIONS: VTE is a relatively common complication of HL and its treatment, causing increased acute and long-term morbidity. However, due to limited number of events we could not demonstrate risk-factors for VTE that would identify patients who might benefit from thromboprophylaxis.

Significant response to immune therapies in a case of subacute necrotizing myopathy and FKRP mutations.

Necrotizing myopathies can be encountered in various conditions as acquired myopathies (toxic or autoimmune) or muscular dystrophies. We report a twenty-year-old Caucasian woman who presented with clinical findings suggestive of an inflammatory myopathy: subacute onset of lower limb muscle weakness, myalgia, weight loss and absence of family history. The serum creatine kinase level was elevated at 4738 IU/L (normal range, 25-175 IU/L). Muscle biopsy was consistent with necrotizing myopathy. The patient showed significant clinical improvement following corticosteroid, azathioprine and intravenous immunoglobulin treatments. Biological tests revealed no specific autoantibodies associated with necrotizing autoimmune myopathies. Immunohistochemical staining for sarcolemmal proteins in muscle biopsy samples finally led to a diagnosis of limb-girdle muscular dystrophy 2I (fukutin-related protein gene mutations). The response to immune therapies suggested a possible inflammatory component associated with the muscular dystrophy and highlighted the potential benefit of corticosteroid treatment in patients with LGMD2I and subacute onset.

Pathophysiology and biomarkers in chronic inflammatory demyelinating polyradiculoneuropathies.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired dysimmune disorder characterized by strong heterogeneity in terms of clinical manifestations, prognostic and response to treatment. To date, its pathophysiology and potential target antigens are not totally identified despite substantial progress in the understanding of the involved molecular mechanisms. Recent researches in the field have underlined the importance of cell-mediated immunity (lymphocytesT CD4+, CD8+ and macrophages), the breakdown of blood-nerve barrier, a failure of T-cell regulation, and the disruption of nodal and paranodal organization at the node of Ranvier. This last point is possibly mediated by autoantibodies towards axoglial adhesion molecules which may disrupt sodium and potassium voltage-gated channels clustering leading to a failure of saltatory conduction and the apparition of conduction blocks. The purpose of this article is to overview the main pathophysiologic mechanisms and biomarkers identified in CIDP.

[Subarachnoidal hemorrhage and multiple vascular cerebral abnormalities in ß-thalassemia major]. / Hémorragie sous-arachnoïdienne et anomalies vasculaires cérébrales multiples au cours d'une ß-thalassémie majeure.

ß-thalassemia is a genetic hemoglobinopathy, which can cause hypercoagulability, vessel wall damages and thromboembolic events. Spontaneous subarachnoidal hemorrhages are not commonly described in this affection. We report subarachnoidal hemorrhage, observed during the post-partum period in a 27-year-old woman suffering from ß-thalassemia major. Brain MRI revealed complex vascular abnormalities: intracranial carotid occlusion, carotid micro-aneurisms, abnormally developed deep perforators and cortical arteries.

Front-line immunosuppressive treatment of acquired aplastic anemia.

In this article, front-line immunosuppressive therapy (IST) for acquired plastic anemia (AA) is illustrated and discussed. Also second-line and salvage options are briefly illustrated. First-line IST should consist of horse anti-thymocyte globulin (ATG) and CsA that has been shown to result in response rates between 60 and 80%. CsA should be given for 12 months until transfusion independence is achieved and then tapered very slowly in the presence of a CR. Patients with a partial response are usually continued on CsA. Tight monitoring of the blood count during CsA tapering is necessary to identify early loss of response. G-CSF 5 µg/kg/day s.c. in the first 30 days has been shown to reduce infections and hospitalization and to identify early responders, as those who achieve neutrophils count of0.5 × 10(9)/L by day +30. This schedule is recommended in the first month of therapy. Afterward, G-CSF can be considered in neutropenic febrile episodes. Patients not achieving transfusion independence after a first course of IST may be considered for second-line IST, or for an allogeneic hematopoietic SCT depending on patient age, ongoing infection, neutrophil count and transfusion requirements. Third-line IST is rarely given, but some options are discussed.

Changes in health complaints after removal of amalgam fillings.

The aim of the present study was to investigate whether removal of all amalgam fillings was associated with long-term changes in health complaints in a group of patients who attributed subjective health complaints to amalgam fillings. Patients previously examined at the Norwegian Dental Biomaterials Adverse Reaction Unit were included in the study and assigned to a treatment group (n = 20) and a reference group (n = 20). Participants in the treatment group had all amalgam fillings replaced with other restorative materials. Follow-ups took place 3 months, 1 and 3 years after removal of all amalgam fillings. There was no intervention in the reference group. Subjective health complaints were measured by numeric rating scales in both groups. Analysis of covariance was used to compare changes in health complaints over time in the two groups. In the treatment group, there were significant reductions in intra-oral and general health complaints from inclusion into study to the 3-year follow-up. In the reference group, changes in the same period were not significant. Comparisons between the groups showed that reductions in intra-oral and general health complaints in the treatment group were significantly different from the changes in the reference group. The mechanisms behind this remain to be identified. Reduced exposure to dental amalgam, patient-centred treatment and follow-ups, and elimination of worry are factors that may have influenced the results.

Fanconi anaemia: new strategies.

Fanconi anaemia (FA) is a rare genetic disease characterized by chromosomal instability, somatic abnormalities, marrow failure and cancer proness. The main cause of morbidity and mortality is bone marrow failure, which typically arises in the first decade of life and progresses to full-blown transfusion dependence and severe neutropenia in a variable number of years. Myelodysplastic syndrome (MDS) and AML may arise on the background of marrow failure, although cases of patients diagnosed with MDS or overt leukaemia before the full appearance of marrow aplasia are reported. This article reviews the current options for treatment of bone marrow failure in FA and provides an algorithm for supporting decisions on treatment. The use of androgens, corticosteroids and growth factors is reviewed, as well as the results in recent cohorts of matched sibling donor haematopoietic stem cell (HSC) transplants and unrelated donor HSC transplants, including cord blood graft. The conditioning regimens used are analysed and commented. Up-to-date information on second tumours after HSC transplant and on experimental treatments such as gene therapy, prenatal and preimplantation diagnosis and inhibition of pro-inflammatory cytokines is provided.

The polymorphisms -318C>T in the promoter and 49A>G in exon 1 of CTLA4 and the risk of aplastic anemia in a Caucasian population.

Aplastic anemia (AA) is a rare disease with a major autoimmune pathogenetic component. CTLA4 is a T-lymphocyte surface molecule involved in the maintenance of immune tolerance. Some polymorphisms associated with a reduced expression of CTLA4, and thus presumably with increased tendency to autoimmunity, have been associated with various autoimmune diseases. In this study, we evaluated the distribution of the low expression polymorphisms -318C > T and 49A > G of CTLA4 in a population of 67 patients with acquired AA and in 100 normal controls. There was no difference in the distribution of the tested polymorphism between patients and controls and, within the patient group, between those who responded to immunosuppression vs those who did not respond. This study indicates that the polymorphisms -318C > T and 49A > G of CTLA4 do not affect the risk of developing AA and do not influence the response to immunosuppression.

Different quantities and quality of fat in milk products given to young children: effects on long chain polyunsaturated fatty acids and trans fatty acids in plasma.

UNLABELLED: In this study we compared plasma contents of long-chain polyunsaturated fatty acids (LC-PUFAs) and trans fatty acids in triglycerides (TG), phospholipids (PL) and cholesterolesters (CE) in young children fed milk diets containing different amounts of linoleic (LA) and alpha-linolenic acid (ALA). Because the diets differed in vitamin A and E content, plasma concentrations of vitamin A and E were also studied. Thirty-seven 1-y-old children were randomly assigned to one of four feeding groups: (1) low-fat milk (LF) (1.0 g cow's milk fat/dL); (2) standard-fat milk (SF) (3.5 g cow's milk fat/dL); (3) partially vegetable fat milk (PVF) (3.5 g fat/dL; 50% vegetable fat from rapeseed oil, 50% milk fat); and (4) full vegetable fat milk (FVF) (3.5 g fat/dL; 100% vegetable fat from palm-, coconut- and soybean oil). We found higher amounts of plasma LA in the FVF group than in the LF and SF groups (p < 0.001) and higher amounts of ALA in the PVF group than in the SF (p < 0.001 in TGs, p < 0.05 in CEs) and LF (p < 0.01 in PLs and CEs, p < 0.05 in TGs) groups. However, amounts of plasma arachidonic acid (AA) were similar between groups as well as the amounts of docosahexaenoic acid (DHA) in CEs and PLs. Total trans FAs were lower in CEs in the PVF and FVF groups than in the SF group (p < 0.05 SF vs PVF; p < 0.01 SF vs FVF). Plasma concentrations of alpha-tocopherol were higher in the FVF group than in the other groups (p < 0.05 FVF vs SF, p < 0.01 FVF vs SF and PVF). CONCLUSION: Children consuming milk diets containing high amounts of vegetable fat present with higher plasma LA and ALA without any effects on amounts of plasma LC-PUFA. The plasma LC-PUFA status is not adversely affected by a low-fat milk diet. AHA and DHA in plasma are not affected by the diets studied, presumably because 15-mo-old children may be able to compensate for dietary influences through endogenous LC-PUFA metabolism.

Carotid endarterectomy in patients 55 years of age and younger.

Prior studies have suggested that young patients may be more prone to recurrent disease after carotid endarterectomy (CEA). The goal of this study was to review a series of CEAs performed on younger patients (< or = 55 years) and to determine if these patients are more likely to develop recurrent stenosis. A review was conducted of CEAs performed from 1985 through 1994. Analysis was performed on a study group of 94 young patients who underwent 109 CEAs during this time. A control group of 222 patients older than 55 years who underwent 256 CEAs during the years 1991 through 1993 was selected for comparison. During a mean of nearly 4 years of follow-up, younger patients were significantly more likely to experience a late failure of CEA, including total occlusion of the operated artery, or recurrent stenosis requiring redo surgery. Careful patient evaluation is important in choosing younger patients who require CEA. Implications of these data include mandating careful noninvasive follow-up examinations for younger patients undergoing CEA.

Interferon gamma and tumour necrosis factor alpha are overexpressed in bone marrow T lymphocytes from paediatric patients with aplastic anaemia.

Twelve paediatric patients with aplastic anaemia and two groups of normal control subjects underwent flow cytometric analysis for intracytoplasmic expression of gamma interferon (gamma-IFN) and tumour necrosis factor alpha (TNF-alpha) in bone marrow and peripheral blood CD4+ and CD8+ cells. The same cytokines were tested, by immunoassay, in culture supernatants from unstimulated bone marrow mononuclear cells (MNCs). Marrow CD4+ and CD8+ cells expressing gamma-IFN and TNF-alpha were significantly increased in the patients in comparison with normal control subjects (P from < 0.05 to < 0.0001 in the different cellular subsets). Patients' marrow CD4+ and CD8+ cells containing gamma-IFN and TNF-alpha were significantly increased when compared with the same cell fractions from paired peripheral blood samples (P from < 0.05 to < 0.0001 in the various cellular subsets). In the supernatant of marrow MNCs, gamma-IFN and TNF-alpha were detected in four out of eight and five out of eight cases, respectively, whereas neither cytokine was traceable in the control subjects. Patients' peripheral blood CD4+ and CD8+ cells containing gamma-IFN and TNF-alpha were not significantly increased in comparison with those from normal control subjects. Whereas patients with favourable and unfavourable outcomes had no significantly different proportions of marrow gamma-IFN+/CD4+ and gamma-IFN+/CD8+ cells, the percentages of marrow CD4+ and CD8+ cells containing TNF-alpha were significantly lower in subjects with favourable than in those with unfavourable outcome. Overall, these findings show that, in aplastic patients, T cells overexpressing gamma-IFN and TNF-alpha concentrate in the bone marrow and that intracytoplasmic expression of TNF-alpha in marrow CD4+ and CD8+ cells is associated with an unfavourable clinical course.

Fatty acid content of plasma lipid fractions, blood lipids, and apolipoproteins in children fed milk products containing different quantity and quality of fat.

BACKGROUND: Differences in fatty acid content of plasma lipid fractions and serum lipid concentrations were investigated among young children fed different milk diets composed to achieve a recommended saturated fat intake. METHODS: Thirty-eight healthy children were randomly assigned to one of four feeding groups at 12 months: 1) low-fat milk (1.0 g/dL cow's milk fat); 2) standard-fat milk (3.5 g/dL cow's milk fat); 3) partially vegetable fat milk (3.5 gtat/dL fat; 50% vegetable fat: rapeseed oil); and 4) full vegetable-fat milk (3.5 gtat/dL fat; 100% vegetable fat: palm, coconut, and soy oil). Plasma fatty acids, blood lipids, and apolipoproteins were analyzed at 15 months, and dietary intakes at 12, 15, and 18 months. RESULTS: There were significantly lower percentage contributions of saturated fatty acids in plasma triglycerides in children fed low-fat milk or milk with 50% or 100% vegetable fat than in children fed standard-fat milk. Plasma polyunsaturated fatty acid levels were significantly higher in children fed milks with vegetable fat than in children fed standard-fat milk. Plasma saturated and polyunsaturated fatty acids in triglycerides most closely reflected dietary intake. Blood lipid concentrations were lower in children fed milk with 50% vegetable fat. CONCLUSIONS: Children fed milk with 50% or 100% vegetable fat, together with high vegetable-fat and low milk-fat dairy products have lower percentages of plasma saturated fatty acids and higher percentages of polyunsaturated fatty acids than children fed standard- or low-fat milk and dairy products.

Macronutrient and energy intakes in young children fed milk products containing different quantities and qualities of fat and protein.

BACKGROUND: Milk is the major source of protein and saturated fats in the diet after infancy. In the present study, the effects of different fat and protein quantity as well as fat quality in milk and dairy products on nutrient intake and growth in young children were determined. METHODS: Thirty-eight healthy children were randomly assigned to one of four feeding groups at 12 months of age: 1) Low-fat milk (1.0 g fat/dl, 3.3 g protein/dl); 2) standard-fat milk (3.5 g fat/dl, 3.3 g protein/dl); 3) partially vegetable fat and protein-reduced milk (3.5 g fat/dl, 50% vegetable; 2.2 g protein/dl); and 4) full-vegetable-fat milk (3.5 g fat/dl, 100% vegetable; 3.0 g protein/dl). Nutrient intake and growth were measured at 12, 15, and 18 months. RESULTS: The protein intake was significantly reduced with the protein-reduced milks. The intake of saturated fat was significantly lower with low-fat milk (11% of energy) or milks containing vegetable fat (13%) than in standard-fat milk (19.6%). However, the total fat intake was below 30% of energy in low-fat milk, whereas the total fat intake remained more than 30% in the other groups. Energy intake and growth were similar in all groups. CONCLUSIONS: A modified milk with reduced protein content for young children results in protein intakes closer to recommendations. A modified milk with either 50% or 100% vegetable fat and dairy products with low milk fat and high vegetable fat content results in intakes of total and saturated fats closer to international recommendations, compared with standard or low-fat milk and dairy products.

Higher concentrations of serum transferrin receptor in children than in adults.

BACKGROUND: The serum transferrin receptor (TfR) concentration in adults is suggested to provide a sensitive measure of iron depletion and together with the serum ferritin concentration to indicate the entire range of iron status, from iron deficiency to iron overload. However, little is known about TfR concentrations in children. OBJECTIVE: Our objective was to compare serum TfR and ferritin concentrations and their ratios in children and adults and look for correlations between TfR concentrations and other measures of iron status. DESIGN: Our study groups were healthy 1-y-old infants (n = 36), 11-12-y-old prepubertal boys (n = 35), and 20-39-y-old men (n = 40). RESULTS: TfR concentrations were higher in infants (x; 95% reference interval: 7.8 mg/L; 4.5, 11.1) than in prepubertal boys (7.0 mg/L; 4.7, 9.2) and higher in prepubertal boys than in men (5.8 mg/L; 3.1, 8.5). Geometric mean TfR-ferritin ratios were higher in infants (316; 95% reference interval: 94, 1059) than in prepubertal boys (219; 78, 614) and higher in prepubertal boys than in men (72; 23, 223). By multiple linear regression analysis, the best predictors of TfR concentration were serum iron (P = 0.004) and log serum ferritin (P < 0.0001), both being inverse correlations (R2 = 0.32). Mean corpuscular volume, blood hemoglobin, transferrin iron saturation, transferrin, and even age seemed to not have an influence on the TfR concentration and erythropoiesis was not a determinant of TfR concentration. CONCLUSIONS: Low serum ferritin and iron concentrations, even within the normal physiologic range, result in high TfR concentrations. The lower the iron stores, the stronger the influence of ferritin on TfR. A high TfR concentration in children, especially in infants, is a response to physiologically low iron stores. Age-specific reference concentrations for TfR are needed.

Outcome of mammary prostheses explantation: a patient perspective.

A retrospective study to characterize determinants of subjective outcome following removal of silicone gel-filled mammary implants was undertaken. One hundred consecutive female patients (aged 24 to 69 years, mean 46 years) who underwent removal of implants were surveyed. Eighty-two patients had mammary implants for cosmetic indications, 17 for postmastectomy reconstruction, and 1 for correction of congenital breast absence. The survey was conducted 6 to 12 months after explantation. Sixty-three patients (63%) returned questionnaires. Fifty-one patients were satisfied with the overall outcome of explantation (81% of respondees). Quality of life, as measured by self-assessed physical and cognitive functions, and improvement of symptoms attributed by the patients to the presence of implants, improved in 49 patients (78%), worsened in 2 patients (3%), and has not changed in 12 patients (19%). Twenty-one patients (33%) judged postexplantation and/or breast recontouring surgery aesthetic outcome as expected, 26 (41%) as an improvement better than expected, 9 (14%) judged their appearance as worse than expected, and 7 have not responded. Twenty-three patients (37%) perceived their postoperative course as "complicated" (scarring, inflammation, infection, seroma, asymmetry, distortion of breast contour, among those items listed). Five patients (8%) complained of mastalgia (not present prior to explantation). However, only 1 patient stated that the "complications" changed her opinion about "benefits" of this procedure. Sixty respondents (95%) indicated that comprehensive informed consent prior to explantation was instrumental in their acceptance of the outcome. If convinced that implants are safe, fifteen patients (24%) would and 41 patients (65%) would not like implants "back," and 7 patients (11%) gave no answer. Analysis of the patients' perspective should help to care for patients who contemplate or have undergone surgery with mammary implants.

Expression of vascular cell adhesion molecule-1 by follicular dendritic cells.

Follicular dendritic cells are the major supporting cell of the germinal center microenvironment. The major function of follicular dendritic cells is to present antigen to B cells in secondary lymphoid tissues. Through cell-cell interactions, FDCs are hypothesized to be central to the regulation of normal B cell growth and differentiation. The major receptor-ligand pair which mediates B cell-FDC adhesion is the beta 1 integrin VLA-4, present on B cells and VCAM-1 expressed on FDCs. Follicular non-Hodgkin's lymphomas similarly employ this mechanism to bind to neoplastic germinal centers. The VCAM-1 molecule can exist as a 6 or 7 immunoglobulin domain form. The major form of VCAM-1 on activated endothelium is the 7 domain form. In this report we have determined by polymerase chain reaction of purified FDCs that they express predominantly mRNA for 7 domain VCAM-1. It is likely that the two forms of VCAM-1 are associated with distinct functions, therefore the expression of 7 domain VCAM-1 may be important in normal and neoplastic B cell-FDC interactions.

Characterization of microbial presence at the surface of silicone mammary implants.

The purpose of this project was to examine the incidence of microbial presence on the surface of mammary implants and its correlation with clinical presentation. The significance of microbial presence without signs of overt infection is questioned. Several issues are raised, including whether the presence of micro-organisms may immunize the host, trigger autoimmune reactions, or locally change the course of healing (resulting in capsular contracture). A total of 150 explanted silicone mammary implants from 87 patients were cultured. Cultures of 81 devices were positive (54%); the predominant isolate was Staphylococcus epidermidis (found on 68 implants, or 84%). Bacteria were detected on 76% (62 of 82) of implants surrounded by contracted capsules and on 28% (19 of 68) of those without capsular contracture (p < 0.05). Among 40 patients (46%) who had no general health problems, 11 (28%) had positive cultures of explanted devices (15 of 62 explants, or 24%). In the remaining 47 patients (54%) who complained of myalgia (77%), arthralgia (68%), chronic fatigue (38%), skin rashes (21%), cognitive problems (19%), dry mucosal membranes (19%), episodes of low-grade fever (17%), and hair loss (13%), 38 (81%) had positive cultures (66 of 88 explants, or 75%) (p < 0.05). The hypothesis that capsular contracture or problems that might be related to chronic infection and immunization are associated with subclinical infection is supported by this study.

Stimulation of protein tyrosine phosphorylation in human B cells after ligation of the beta 1 integrin VLA-4.

B lymphocytes express several adhesion molecules that are involved in cell-cell and cell-extracellular matrix interactions. The alpha 4 beta 1 integrin VLA-4, expressed on pre-B and mature/activated B cells, mediates adhesion of these cells to its two ligands, VCAM-1 and fibronectin. Recent evidence suggests that VLA-4 is involved in T lymphocyte activation; however, relatively little is known of the role of VLA-4 in B cell differentiation. To begin to assess the potential involvement of VLA-4 in B cell activation, we have examined the effect of ligation of VLA-4 on protein tyrosine phosphorylation in B cells. We found that cross-linking of VLA-4 by either mAb or natural ligands (i.e., VCAM-1 and the FN-40 cleavage fragment of fibronectin) induced the tyrosine phosphorylation of a 110-kDa protein in a human pre-B cell line (Nalm-6), an EBV-transformed B cell line (SB), and normal tonsillar B cells. These findings suggest that VLA-4 can activate a tyrosine kinase in B cells and B cell lines. These signals may be involved in the subsequent differentiation of pre-B and mature B cells within specific microenvironments where VLA-4 mediated adhesion is operational.