Blood dendritic cells in patients with acute lymphoblastic leukaemia

Myeloid and plasmacytoid dendritic cells (MDCs, PDCs) play a key role in the initiation of immune responses. In this study, we show a severe reduction of MDCs and PDCs in patients with B lineage acute lymphoblastic leukaemia (B-ALL; P = 0.01 vs. controls). DCs from patients with T lineage ALL (T-ALL) were quantitatively and functionally comparable to healthy donors, as demonstrated by secretion of interleukin (IL)-12p70 and interferon-alpha. In vitro, the circulating CD34(+) fraction of B-ALL cases did not generate either CD1a(+) MDCs or PDCs, suggesting that DC development is probably affected in B-ALL, but not in T-ALL.     

Fibroblast growth factor-23 mutants causing familial tumoral calcinosis are differentially processed

Familial tumoral calcinosis (TC, OMIM 211900) is a heritable disorder characterized by hyperphosphatemia, normal or elevated serum 1,25-dihydroxyvitamin D, and often severe ectopic calcifications. Two recessive mutations in fibroblast growth factor-23 (FGF23), serine 71/glycine (S71G) and serine 129/phenylalanine (S129F), were identified as causing TC. Herein, we undertook comprehensive biochemical analyses of an extended TC family carrying the S71G FGF23 mutation, which revealed that heterozygous (serine/glycine, S/G) individuals had elevated serum FGF23 C-terminal fragments compared with wild-type (serine/serine, S/S) family members (P < 0.025). To understand the differential processing of FGF23 in TC patients, we transiently expressed S71G as well as S129F FGF23. FGF23 ELISA in tandem with Western analyses revealed increased proteolytic cleavage of mutant FGF23 and a limited secretion of intact protein. Furthermore, S71G and S129F FGF23 carrying mutations that disrupt the furin-like protease RXXR motif in FGF23 rescued the secretion of the intact protein, and both TC mutant proteins harboring the R176Q mutation revealed no altered sensitivity to trypsin compared with the native (R176Q)FGF23. Finally, S71G, but not S129F mutant FGF23, is rescued by temperature. In summary, FGF23 mutations causing TC lead to increased intracellular proteolysis of FGF23, most likely by furin-like proteases, due to conformational changes of the mutant protein. The destabilizing nature of these mutations provides new insight into the pathophysiology of TC and exemplifies the physiological importance of FGF23 in phosphate and vitamin D metabolism.     

A novel recessive mutation in fibroblast growth factor-23 causes familial tumoral calcinosis

Gain-of-function mutations in fibroblast growth factor-23 (FGF23) are responsible for autosomal dominant hypophosphatemic rickets, a disorder of isolated renal phosphate wasting. Patients with the disorder display hypophosphatemia with normocalcemia as well as inappropriately normal 1,25-dihydroxyvitamin D [1,25(OH)2D3] concentrations. Reciprocally tumoral calcinosis (TC) patients are often hyperphosphatemic with inappropriately normal or elevated serum 1,25(OH)2D3 levels and have ectopic and vascular calcifications, a phenotype similar to that of Fgf23 null mice. Therefore, the goal of the present studies was to test whether FGF23 was a candidate gene for TC. Two sisters in a consanguineous TC family had hyperphosphatemia and normal 1,25(OH)2D3 levels with characteristic ectopic and vascular calcifications. Interestingly, these patients had low-normal intact serum FGF23 levels but demonstrated FGF23 concentrations approximately 40 times normal when assessed with a C-terminal FGF23 serum assay. Mutational analyses identified a homozygous S71G mutation in FGF23 in the TC patients, which was not found in control alleles. Finally, modeling demonstrated that the S71G mutation most likely destabilizes full-length FGF23. In summary, recessive FGF23 mutations can lead to TC. Additionally, our findings indicate that FGF23 may adopt an unstable conformation in some TC patients, possibly leading to nonfunctional FGF23 protein.     

Medical therapy of a left-sided native valve endocarditis with neurologic sequela

Infective endocarditis could present with a plethora of signs and symptoms. Among the rarity of its presentation is acute confusion associated with neurological deficits, mimicking stroke especially in the young population. We report a case of a 33-year-old young man with acute right-sided hemiparesis and confusion 2 weeks after tooth extraction. The brain CT and MRI was consistent with new infarction on the left middle and anterior cerebral arteries’ territory. Echocardiography unveiled the existence of posterior mitral valve leaflet vegetation. Blood culture grew Group B beta-haemolytic Streptococcus, sensitive to penicillin. Two weeks of intravenous gentamicin with 6 weeks of intravenous benzylpenicillin were administered. In this case report, we highlight the importance of recognition of infective endocarditis in a young patient presenting with cerebrovascular accident following tooth extraction.A wide variety of organisms have been attributed to infections of native heart valves. Among them are staphylococci, streptococci, and the group of Haemophilus, Aggregatibacter (previously Actinobacillus), Cardiobacterium, Eikenella corrodens, Kingella (HACEK) organisms. Aortic or mitral valves (left-sided) accounts for the vast majority of endocarditis cases in non-intravenous drug users. Right sided infective endocarditis contributes 5-10% of all cases of endocarditis, usually among intravenous drug users.1 Emboli from left-sided valvular vegetation can become dislodged or fragmented into the brain via systemic circulation, resulting in neurological complications. In contrast with the right sided embolus, the right sided infective endocarditis may cause embolic phenomenon due to preexisting congenital heart diseases such as patent foramen ovale, atrial septal defect, or ventricular septal defect. In this case report, we highlight the importance of recognition of infective endocarditis with an embolic stroke in a young confused patient with normal cardiac valve following a simple dental extraction procedure.     

Pretransplant hepatitis C virus infection and its effect on the post-transplant course of living renal allograft recipients

BACKGROUND: Hepatitis C virus infection (HCV) is a main health problem in end-stage renal disease (ESRD) patients. The effect of pretransplant HCV infection on survival among ESRD patients who have undergone renal transplantation is controversial. We report the results of a large monocenter study that evaluated the effect of hepatitis C on the patient, and on graft survival in renal-transplanted patients who received living donated allograft. METHODS: A historical cohort study, we investigated all 1006 patients who received a living kidney transplant at Baghiatollah Medical Center in Tehran, Iran, between March 1995 and October 2001 (up to 85 months follow up). Patients' sera had been routinely assayed for anti-HCV antibodies and hepatitis B surface antigen (HBsAg) at the time of transplantation. The HBsAg-positive patients were excluded from the survival analysis. Survivals were examined using Kaplan-Meier analysis and compared using the log-rank test. Multivariate analysis was performed using Cox's model. RESULTS: Forty-five patients (4.5%) were anti-HCV-antibody positive. Anti-HCV-antibody-positive patients spent a longer time on dialysis and had a higher rate of retransplantation. There were no differences in recipients' sex and age and donors' age between the two groups. The 7-year patient survival rate was 89.9% in the anti-HCV-antibody-positive group and 95.5% in the HCV-negative group (P = 0.74). Seven-year graft survival was 82.0% and 75.0% in the anti-HCV-antibody-positive and HCV-negative groups, respectively (P = 0.39). In the multivariate analysis, age was the only significant parameter correlated with patient survival (P = 0.02). CONCLUSIONS: HCV infection does not seem to influence patient and graft survival within a medium-time follow up in living allograft recipients, and anti-HCV-antibody positive status (alone) is not a contraindication for renal transplantation. However, further studies are needed to better define the role of HCV infection in long-term prognosis.     

Association between BMI-1 expression, acute graft-versus-host disease, and outcome following allogeneic stem cell transplantation from HLA-identical siblings in chronic myeloid leukemia

Expression of CD7, ELA-2, PR-3, and the polycomb group gene BMI-1 reflects the intrinsic heterogeneity and predicts prognosis of patients with chronic myeloid leukemia (CML) who were not treated with allogeneic stem cell transplantation (allo-SCT). This study investigated whether expression of these genes determined outcome following allo-SCT in a cohort of 84 patients with chronic-phase (CP) CML. We found that patients expressing BMI-1 at a "high" level before allo-SCT had an improved overall survival (P = .005) related to a reduced transplantation-related mortality. In multivariate analysis, when adjusted for the European Group for Blood and Marrow Transplantation (EBMT)-Gratwohl score and other prog-nostic factors, there was an independent association between BMI-1 expression and grades 2 to 4 acute graft-versus-host disease (relative risk [RR] = 2.85; 95% confidence interval [CI], 1.3-6.4; P = .011), suggesting that BMI-1 measured prior to allo-SCT can serve as a biomarker for predicting outcome in patients with CP-CML receiving allo-SCT, and may thus contribute to better therapeutic decisions.     

Infantile pyknocytosis,a rare cause of hemolytic anemia in newborns: report of two cases in twin girls and literature overview

Infantile pyknocytosis is a rare cause of neonatal jaundice and hemolytic anemia. We report on two cases in twin girls that were diagnosed on peripheral blood smear reading. Pyknocytosis should be considered in cases of early unexplained severe hemolytic anemia, and systematic peripheral smear review performed. Its management consists of phototherapy and RBC transfusion.     

Outcome of colonic fistula surgery in the modern surgical era

Background

Various conditions lead to the development of colonic fistulas. Contemporary surgical data is scarce and it is unclear whether advances in surgical care have impacted outcome. The aim of the present study was to review the short- and long-term outcome of patients treated surgically for colonic fistula over an 8-year period at a tertiary institution.

Methods

A retrospective review was performed, focusing on the type of operative interventions, short- and long-term complications, length of hospital stay, readmission rate, mortality rate, and fistula recurrence.

Results

Forty-five patients were treated for colonic fistula. The most common etiology was diverticulitis (74 %). Fistula type was colovesical (58 %), colocutaneous (18 %) and colovaginal (15 %). Laparoscopic resection was performed in 42 % of cases. An intraoperative complication occurred in 4 %. A primary anastomosis was performed in 96 % of patients and 10 (23 %) had a temporary stoma. Median length of hospital stay was 6 days. Postoperative complications were common (47 %) and wound infection was noted in 20 % of patients. The readmission rate was 29 % and the 90-day mortality was 4 %. All patients healed their fistula with no recurrences noted during a median follow-up of 37 months.

Conclusions

Surgical intervention healed the majority of patients with colonic fistula. However postoperative complications were common and readmission occurred in one-third of the cases. Laparoscopic excision was feasible in nearly half of the patients.