A specific time course for mobilization of peripheral blood CD34+ cells after plerixafor injection in very poor mobilizer patients: impact on the timing of the apheresis procedure

BACKGROUND: This report describes the specific kinetics of the peripheral blood (PB) CD34+ cell concentration in a selected group of very poor stem cell mobilizer patients treated with granulocyte–colony‐stimulating factor (G‐CSF) and plerixafor and determines the kinetics' impact on apheresis. STUDY DESIGN AND METHODS: All patients had previously experienced at least two failures of mobilization (without use of plerixafor). The present salvage therapy consisted in the administration of 10 µg/kg/day G‐CSF for 5 days added to a dose of plerixafor administered at between 5 a.m. and 6 a.m. on Day 5. The PB CD34+ cell counts were tested every 3 hours thereafter. Apheresis was initiated as soon as the PB CD34+ cell count reached 10 × 10⁶/L. RESULTS: A PB CD34+ cell count higher than 10 × 10⁶/L was observed as soon as 3 hours after plerixafor administration in 10 of the 11 patients who reached this threshold at some point in the monitoring process. Interestingly, all patients presented an early decrease in the PB CD34+ cell count 8 to 12 hours after plerixafor administration (below 10 × 10⁶/L for seven patients). CONCLUSION: Had such patients been tested for PB CD34+ cell mobilization according to conventional criteria (i.e., 11 hr after plerixafor administration), apheresis would not have been performed at the optimal timing. For very poor stem cell mobilizer patients, early monitoring of PB CD34+ cell count may be required for the optimal initiation of apheresis.     

Effects of chronic inhibition of converting enzyme on mechanical and structural properties of arteries in rat renovascular hypertension

The effect of hypertension and of therapy by converting enzyme inhibitor (S 9490-3, perindopril) on the function and structure of large arteries has been studied in two-kidney, one-clip Goldblatt hypertensive rats. After one month without treatment, clipped hypertensive rats (n = 24) and sham-operated rats (n = 24) were randomly allocated to treatment by S 9490, 1 mg/kg once a day (n = 24) or to placebo (n = 24) and pursued for 4 weeks. Hemodynamic parameters, including instantaneous pressure and aortic velocity measured by D?ppler, were recorded under anesthesia at the end of the treatment period. Passive mechanical properties of carotid arteries were recorded in situ in the presence or the absence of smooth muscle cell activity (potassium cyanide poisoning). Morphological parameters of the aortic media, including medial thickness, nucleus density, and cross sectional area and relative density in proteins of interstitial matrix, were recorded by an automated morphometrical system. Hypertension was associated with an increase in characteristic impedance of the aorta and a decrease in compliance of the arterial system. Treatment with converting enzyme inhibitors completely reversed these in vivo markers of the rigidity of large arteries. Hypertension was associated with a shift of the passive pressure-volume relation in the carotid. Treatment with converting enzyme inhibitors normalized the carotid pressure-volume relation, whereas poisoning smooth muscle cells induced a disappearance of the curve differences between hypertensive and normotensive animals. Morphometric analysis of aortic walls permits us to report this functional change to structural modification of the arterial wall. Aortic media thickness was increased by hypertension; this phenomenon was reversed by treatment. Modification of aortic thickness was due to hypertrophy of smooth muscle cells with parallel modifications of absolute amount of collagen, whereas absolute amount of elastin did not change in this early phase of renovascular hypertension in young rats. Treatment with converting enzyme inhibitors reversed the thickness of aortic media without regression of the increase in absolute amount of collagen content whereas absolute amount of elastin content did not change.     

Bcl-2 protein expression is the strongest independent prognostic factor of survival in primary cutaneous large B-cell lymphomas

Bcl-2 protein expression has been associated with poor prognosis in patients with noncutaneous diffuse large B-cell lymphomas. In primary cutaneous large B-cell lymphomas, the location on the leg, the round-cell morphology defined as the predominance of centroblasts and immunoblasts over large centrocytes, and multiple skin lesions were identified as adverse prognostic factors. The prognostic value of bcl-2 protein expression has not been studied in large series of patients. We evaluated 80 primary cutaneous large B-cell lymphomas collected by the French Study Group on Cutaneous Lymphomas. The prognostic value of age, sex, number of lesions, cutaneous extent, location, serum lactate dehydrogenase (LDH) level, B symptoms, morphology, and bcl-2 protein expression was studied. The overall 5-year specific survival rate was 65%. In univariate analysis, advanced age, multiple skin lesions (n = 48), location on the leg (n = 25), round-cell morphology (n = 32), and bcl-2 expression (n = 39) were significantly related to death from lymphoma. In multivariate analysis, bcl-2 expression (P =.0003), multiple skin lesions (P =.004), and age remained independent prognostic factors. The 5-year specific survival rates in bcl-2-positive and bcl-2-negative patients were 41% and 89%, respectively (P <.0001). A new prognostic classification of primary cutaneous B-cell lymphoma should be based primarily on bcl-2 protein expression rather than the location of skin lesions.     

Association between smoking and outcomes in older adults with atrial fibrillation

Tobacco smoking is a risk factor for atrial fibrillation (AF), but little is known about the impact of smoking in patients with AF. Of the 4060 patients with recurrent AF in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, 496 (12%) reported having smoked during the past two years. Propensity scores for smoking were estimated for each of the 4060 patients using a multivariable logistic regression model and were used to assemble a matched cohort of 487 pairs of smokers and nonsmokers, who were balanced on 46 baseline characteristics. Cox and logistic regression models were used to estimate the associations of smoking with all-cause mortality and all-cause hospitalization, respectively, during over 5 years of follow-up. Matched participants had a mean age of 70 ± 9 years (± S.D.), 39% were women, and 11% were non-white. All-cause mortality occurred in 21% and 16% of matched smokers and nonsmokers, respectively (when smokers were compared with nonsmokers, hazard ratio=HR=1.35; 95% confidence interval=95%CI=1.01-1.81; p=0.046). Unadjusted, multivariable-adjusted and propensity-adjusted HR (95% CI) for all-cause mortality associated with smoking in the pre-match cohort were: 1.40 (1.13-1.72; p=0.002), 1.45 (1.16-1.81; p=0.001), and 1.39 (1.12-1.74; p=0.003), respectively. Smoking had no association with all-cause hospitalization (when smokers were compared with nonsmokers, odds ratio=OR=1.21; 95%CI=0.94-1.57, p=0.146). Among patients with AF, a recent history of smoking was associated with an increased risk of all-cause mortality, but had no association with all-cause hospitalization.     

Multiple forms of chromosome I, II and V in a restricted population of Leishmania infantum contrasting with monomorphism in individual strains suggest haploidy or automixy.

We have resolved the molecular karyotypes of 22 Leishmania infantum strains isolated between 1980 and 1988 in a restricted geographic area and belonging to zymodemes MON-11, −29 and −33. Three strains were isolated from sandflies and all the others from human cutaneous lesions. A high degree of karyotypic homology is observed among these strains, contrasting with the highly polymorphic MON-1 strains isolated in the same area. We have analysed the time-dependent evolution of size variants of chromosomes I to V, each identified by chromosome-specific DNA probes. More evidence is given for the role of subtelomeric regions in chromosomal size variation in Leishmania for both chromosomes I and II. At the population level, the chromosomes I, II and V are present in respectively 8, 4 and 3 distinct sizes. Furthermore, and despite the small size of the sample, various combinations were observed among these different chromosomal forms. These results could be explained by the occurrence of a high rate of recurrent mutations or of genetic exchange. In contrast, only one chromosomal form was observed in individual karyotypes for the chromosomes I V. These results could tally with the hypothesis of a haploid organisation for these chromosomes and strains, or, in the frame of a diploid organisation, with the hypothesis of a predominantly automictic sexuality giving rise to 2 identical forms of the homologues in the same strain.     

Identification of the Ca2+ current activated by vasoconstrictors in vascular smooth muscle cells

The noncontractile aortic cell line A7r5 was chosen to study the effect of the vasoconstrictor peptide vasopressin on transmembrane Ca²⁺ movements, using conventional whole-cell patch recording techniques. Conditions in which previously characterised vasoconstrictor-modulated currents were suppressed revealed a tiny inward current component (−18±2 pA,n=50, at -61 mV in 110 mM CaCl₂). The vasopressin-activated inward current was absent when Ca²⁺ was absent from the extracellular solution, and the current amplitude increased with [Ca²⁺] (0.01–110 mM), with an apparent dissociation constant for Ca²⁺ of 9.7 mM. It was highly selective for Ca²⁺ over monovalent cations (permeability ratio Ca/Cs greater than 17). It was not voltage gated, except that the current/potential characteristic showed some inwards rectification. Amplitudes of the evoked inward currents had the same order of magnitude in Sr²⁺ and Ca²⁺, whereas they were much smaller in Mn²⁺, suggesting that this pathway is highly permeable to Sr²⁺ but poorly permeable to Mn²⁺. Inward currents evoked in Ca²⁺ were inhibited by other cations with the following order of potency: La³⁺>Cd²⁺>Co²⁺∼Ni²⁺∼Mn²⁺. The channel producing this current corresponds most probably to the ionic pathway originally called the receptor-operated calcium channel, which produces a long-lasting, constrictor-induced plateau of increased intracellular free calcium concentration in smooth muscle. Dedicated by Catherine Van Renterghem to her father, Jacques Van Renterghem     

CR1(CD35) and CR2(CD21) complement C3 receptors are expressed on normal human thymocytes and mediate infection of thymocytes with opsonized human immunodeficiency virus

The present study demonstrates that the C3b receptor CR1 (CD35) and the C3dg/Epstein-Barr virus receptor CR2 (CD21) are expressed by 25% and 70% of normal human thymocytes, respectively. The expression of CR2 extends to both CD1⁺ and CD1^? cells in the thymus. Two subsets of CR2⁺ thymocytes were defined expressing low and high density of the receptor. The CR2⁺⁺ subset represented 20% of CR2⁺ thymocytes and co-expressed the CR1 receptor. CR2⁺⁺ thymocytes expressed an immature CD1^dull, CD3^?, CD4^dull, CD8^?, CD7⁺⁺ phenotype and included a subpopulation of large cells expressing CD34. Twenty percent of thymocytes expressed the CD21 epitope defined by monoclonal antibody BU32, which is involved in the binding of CD23 to CD21. These observations provide a basis for a role for CD21 in the proliferation and differentiation of thymocytes at early stages of maturation. The functionality of CR1 and CR2 on thymocytes was evidenced by the ability of the receptors to mediate infection of cells with complement-opsonized human immunodeficiency virus (HIV). The results may be relevant to the immunopathogenesis of HIV infection.