Ectopic expression of Delta4 impairs hematopoietic development and leads to lymphoproliferative disease

Notch signaling plays a critical role in cell fate determination in many developmental systems, including the hematopoietic system. We and others have recently cloned a novel Notch ligand called Delta4. In this study, we show the effect of retrovirus-mediated ectopic expression of Delta4 in hematopoietic cells. Lethally irradiated mice transplanted with bone marrow cells expressing Delta4 initially suffered from leukopenia and thrombocytopenia. Although all lineages were affected, the deficit in B cells and platelets was the most durable and profound. A rapid expansion of CD4(+)CD8(+) cells occurred shortly after transplantation. CD4(+)CD8(+) cells progressively invaded all tissues analyzed except the thymus, which surprisingly was atrophic. CD4(+)CD8(+) cells were mainly non-Delta4-transduced cells, strongly suggesting that the disease was not cell autonomous. Around 15 weeks after transplantation, mice died from this severe lymphoproliferative disorder, which was not transplantable in late-stage disease into secondary recipients. Mice transduced with a soluble form of Delta4 behaved like control mice. Characterization of early hematopoietic development revealed that Delta4 expression impaired formation of day-12 spleen colony-forming units (CFU-Ss) and, to a greater extent, pre-CFU-Ss. No effect was observed on myeloid colony-forming cells (CFU-Cs), indicating that Delta4 specifically acted on the earliest hematopoietic stem cell compartment. These results show that constitutive expression of Delta4 in hematopoietic cells impairs the development of B cells, platelets, and early stem cells and induces a lethal lymphoproliferative disease.     

CD221 (IGF-1R) is aberrantly expressed in multiple myeloma, in relation to disease severity

We investigated the expression of insulin-like growth factor-1 receptor (CD221) in normal, reactive and malignant plasma cells. We show that CD221 is aberrantly expressed on human myeloma cells, that higher levels of CD221 are observed in patients and human myeloma cell lines with the most aggressive 14q32 translocations, and that CD221 expression has a negative prognostic impact in patients with multiple myeloma.     

Thyroid-stimulating hormone-stimulated fused positron emission tomography/computed tomography in the evaluation of recurrence in 131I-negative papillary thyroid carcinoma.

Fluorine-18 2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) detects recurrence of papillary thyroid carcinoma (PTC) in thyroidectomized patients with elevated thyroglobulin (Tg) levels and negative (131)I-whole-body scans. This paper describes the utility of thyroid-stimulating hormone (TSH)-stimulated fused FDG-PET/computed tomography (CT) scanning on our first 15 patients of this population. METHODS: Patients were prepared for PET/CT imaging with thyroid hormone withdrawal (n = 7) or recombinant human TSH (n = 8). All other imaging before the PET/CT did not demonstrate evidence of recurrence. RESULTS: PET/CT scans revealed active foci in 9 patients, 4 prepared with hypothyroidism, and 5 with exogenous TSH. Positive results were demonstrated even in those with relatively low stimulated-TSH Tg values (13 and 14 microg/L). Six patients with positive PET/CT scans were treated surgically, yielding malignant tissue for 5 of those patients. CONCLUSION: PET/CT scans performed under TSH stimulation are an effective method of detecting of recurrence of PTC and direct surgical interventions, even in those with persistently elevated but relatively low Tg levels.     

The etiologic diagnosis of infectious discitis is improved by amplification-based DNA analysis

OBJECTIVE: Blood cultures and cultures of disc material are required to identify and treat bacterial agents responsible for septic spondylodiscitis, but these methods have limited sensitivities. We undertook this study to compare nonculture amplification-based DNA analysis with conventional culture of disc aspirate. METHODS: Nineteen patients with spondylodiscitis, including 11 with a history of spinal surgery, presented with negative blood cultures and underwent percutaneous disc or epidural abscess puncture for bacterial diagnosis. Amplification by polymerase chain reaction was performed on 16S ribosomal DNA universal target genes and femA staphylococci-specific target genes in all patients, and on the upstream p34 mycobacterial gene in 1 patient. Species identification relied on amplicon sequencing and comparison with templates from GenBank. Amplification of the femA gene led to subsequent testing for methicillin resistance by amplification of the mecA gene. Further assessment using a staphylococci- and methicillin resistance-specific DNA array was performed on 3 samples. RESULTS: Microbiologic and molecular assays identified the causative organism in 14 of 19 patients (74%) and 19 of 19 patients (100%), respectively. In culture-positive patients, DNA-based and microbiologic results were highly correlated. Five agents (Staphylococcus simulans, Staphylococcus sciuri, Brucella species, Actinomyces israelii, and Mycobacterium tuberculosis complex) were identified only by DNA-based methods. In 1 sample, Corynebacterium jeikeium and coagulase-negative Staphylococcus were both cultured, whereas DNA analysis identified only Staphylococcus hominis. CONCLUSION: DNA-based methods are highly sensitive and specific. They can usefully complement standard microbiologic methods for identifying the cause of infectious spondylodiscitis and contribute to species-specific therapeutic orientation in patients with negative blood and disc aspirate cultures.     

A 5' splice region G → C mutation in exon 3 of the human β-spectrin gene leads to decreased levels of β-spectrin mRNA and is responsible for dominant hereditary spherocytosis (spectrin Guemene-Penfao)

We studied a family with autosomal dominant hereditary spherocytosis (HS) associated with a mild spectrin deficiency. Linkage analysis using two microsatellite markers (D14S63 and D14S271) very close to the β-spectrin gene (SPTB) showed that HS co-segregated with alleles of these microsatellite markers and the linkage between the marker and HS was statistically significant. The presence of a β-spectrin protein polymorphism (β-spectrin Vay; A1880V) in trans of the HS allele was not itself deleterious, but allowed the detection of decreased membrane expression of the spherocytic β-spectrin allele in two HS-affected subjects. Direct sequencing of the coding exons of the β-spectrin gene in one affected subject showed the presence of a G → C transversion at the terminal nucleotide of exon 3, which did not change the leucine codon 100 (CTG → CTC). The presence of the mutation was confirmed by restriction enzyme digestion at the DNA level in all affected SH members of the family. The G → C mutation severely reduced the utilization of the 5' splice site and resulted in aberrant mRNA splicing with intron 3 retention.     

Deep vein thrombosis in elderly patients hospitalized in subacute care facilities: a multicenter cross-sectional study of risk factors, prophylaxis, and prevalence

BACKGROUND: The efficacy of venous thromboembolism prophylaxis has not been established, to our knowledge, in elderly patients hospitalized in subacute care facilities. OBJECTIVES: To describe risk factors and physician practices in the prevention of venous thromboembolism and to estimate the prevalence of deep vein thrombosis. METHODS: A multicenter cross-sectional study was conducted in the subacute care departments of 36 French hospitals. The study population included 852 inpatients older than 64 years. Systematic ultrasound examination was performed by angiologists. RESULTS: Of the 852 inpatients, 178 (20.9%; 95% confidence interval [CI], 18.2%-23.8%) had 3 or more risk factors other than age, while 144 patients (16.9%; 95% CI, 14.4%-19.6%) had none. The rate of prophylactic anticoagulant treatment was 56.1%, ranging from 20.0% to 86.9%, depending on the department. In multivariate analysis, prophylaxis use was associated with acute immobilization (odds ratio [OR], 4.17; 95% CI, 2.48-7.01), chronic immobilization (OR, 3.19; 95% CI, 2.22-4.60), major surgical procedure (OR, 6.81; 95% CI, 4.26-10.88), and congestive heart failure (OR, 1.65; 95% CI, 1.02-2.67). Prophylaxis use was low in patients who had cancer (OR, 0.49; 95% CI, 0.29-0.84) or myocardial infarction (OR, 0.39; 95% CI, 0.14-1.00). It was not significantly associated with paralytic stroke or history of venous thromboembolism. Deep vein thrombosis was detected in 135 patients (15.8%; 95% CI, 13.4%-18.5%): 50 (5.9%; 95% CI, 4.4%-7.7%) had proximal vein thrombosis and 85 (10.0%; 95% CI, 8.0%-12.2%) had calf vein thrombosis. CONCLUSIONS: The prevalence of deep venous thrombosis is high in these patients, despite wide use of prophylaxis. Further prospective studies assessing the clinical benefit of extended duration prophylaxis are needed in elderly patients hospitalized in subacute care settings.     

Feasibility of routine pulmonary arterial impedance measurements in pulmonary hypertension

OBJECTIVES: Right ventricular (RV) afterload is best described by a pulmonary arterial impedance (PVZ) spectrum, which integrates pulmonary vascular resistance (PVR), elastance, and wave reflection. We evaluated the feasibility of PVZ determinations in patients with pulmonary arterial hypertension (PAH) during routine right heart catheterization and Doppler echocardiography. DESIGN: Prospective study. SETTING: Academic hospital. PATIENTS: Twenty-two patients with PAH. INTERVENTIONS: Right heart catheterization with a fluid-filled Swan-Ganz catheter, Doppler echocardiography, and administration of inhaled nitric oxide (NO) [10 to 20 ppm; 17 patients], maximum tolerated dose of IV epoprostenol (average, 8.5 ng/kg/min; 5 patients), and IV dobutamine (8 micro g/kg/min; 8 patients). MEASUREMENTS AND RESULTS: PVZ was calculated from the spectral analysis of synchronized pulmonary artery pressure (Ppa) and flow waves. The mean (+/- SE) Ppa was 63 +/- 3 mm Hg, and the mean PVR was 16 +/- 2 Wood units. The PVZ spectrum was markedly shifted to higher than normal pressures and frequencies, with a mean 0-Hz impedance (Z(0)) of 1,506 +/- 138 dyne. s. cm(-5), and a mean characteristic impedance (Zc) of 124 +/- 11 dyne. s. cm(-5), which are in keeping with data from previous studies. Inhaled NO levels decreased Ppa, PVR, Z(0), and Zc without a change in cardiac output. Epoprostenol administration did not affect Ppa, increased cardiac output, and decreased Z(0) and Zc. Dobutamine administration increased cardiac output and Ppa, and decreased PVR and Z(0), without changing Zc. CONCLUSIONS: The determination of PVZ to quantify RV afterload is feasible during routine right heart catheterization and Doppler echocardiography. The measurement is sensitive to pharmacologic interventions.     

Amorphous mesostructured zirconia with high (hydro)thermal stability

Here, combining the evaporation-induced self-assembly (EISA) method and the liquid crystal templating pathway, mesostructured amorphous zirconium oxides have been prepared by a soft templating method without addition of any heteroelement to stabilize the mesopore framework. The recovered materials have been characterized by SAXS measurements, nitrogen adsorption–desorption analysis and X-ray diffraction (XRD). The obtained mesostructured zirconia exhibits a high thermal stability. An in situ XRD study performed as a function of temperature shows that the amorphous ZrO₂, obtained after removal of the pore templating agent (pluronic P123), begins to crystallize in air from 420 °C. Amorphous mesostructured ZrO₂ also presents a high hydrothermal stability; these materials are not degraded after 72 hours in boiling water.

Amorphous mesostructured zirconia with high thermal stability and hydrothermal stability in boiling water has been obtained without addition of stabilizer.