Contribution of cellular HIV-1 DNA quantification to the efficacy analysis of antiretroviral therapy: a randomized comparison of 2 regimens, including 3 drugs from 2 or 3 classes (TRIANON, ANRS 081)

Cellular HIV-1 DNA level was sequentially measured by quantitative polymerase chain reaction in 141 patients not previously treated with highly active antiretroviral therapy (HAART), who were enrolled in a 72-week randomized trial (ANRS 081 "Trianon") comparing 2 regimens, including 3 drugs from 2 classes (indinavir + stavudine + lamivudine, group 1) or 3 classes (indinavir + stavudine + nevirapine, group 2). The median decrease from baseline to week 72 in cellular HIV-1 DNA level was not significantly different between the 2 groups (0.54 and 0.45 log10 copies/10 peripheral blood mononuclear cells [PBMCs] in groups 1 and 2, respectively), whereas a higher proportion of patients maintained a plasma HIV-1 RNA level less than 20 copies/mL at week 72 in group 1 than in group 2 (79% and 52%; P = 0.0009). Furthermore, the difference in cellular HIV-1 DNA decrease from baseline to week 72 between patients who achieved a plasma HIV-1 RNA level less than 20 copies/mL at week 72 and those who did not was not statistically significant (0.54 and 0.45 log10 copies/10 PBMCs, respectively; P = 0.14). The decay in cellular HIV-1 DNA from baseline to week 72 was higher in antiretroviral-naive patients than in pretreated patients (0.55 and 0.23 log10 copies/10 PBMCs, respectively; P = 0.0008). The cellular HIV-1 DNA level change under therapy was best fitted to a 2-phase decay model with a junction point at week 16, from which its half-life was estimated at 18 weeks during the initial phase and at 104 weeks thereafter. In conclusion, the changes under therapy in cellular HIV-1 DNA level, which were mostly coincident to those of plasma HIV-1 RNA, did not add significant information to the comparison of the viral efficacy of the 2 studied regimens.     

Effect of IgA on respiratory burst and cytokine release by human alveolar macrophages: role of ERK1/2 mitogen-activated protein kinases and NF-kappaB

Human alveolar macrophages (HAM) express FcalphaR receptors for immunoglobulin (Ig)A which could link humoral and cellular branches of lung immunity. Here, we investigate the effects of polymeric (p-IgA) and secretory (S-IgA) IgA interaction with Fc(alpha)R on lipopolysaccharide (LPS)- and phorbol myristate acetate (PMA)-activated respiratory burst and TNF-alpha release by HAM. Activation of HAM with LPS and PMA increases the respiratory burst and TNF-alpha release through activation of the extracellular signal-related protein kinases 1 and 2 (ERK1/2) pathway, because these effects are inhibited by treatment of HAM with PD98059, a selective inhibitor of mitogen-activated protein (MAP)/ERK kinases (MEK) pathway. S-IgA and p-IgA downregulate the LPS-increased respiratory burst in HAM through an inhibition of ERK1/2 activity. In contrast, p- and S-IgA induce an increase in the respiratory burst of PMA-treated HAM. This effect is associated with an upregulation by IgA of the PMA-induced phosphorylation of ERK1/2 and is also inhibited by PD98059. Moreover, p-IgA and S-IgA enhance TNF-alpha release by HAM through an alternative pathway distinct from ERK1/2. Because LPS is known to activate nuclear factor-kappaB (NF-kappaB) in HAM, we evaluate the effect of IgA on NF-kappaB. Treatment of HAM with LPS, p- and S-IgA, but not PMA, induces NF-kappaB activation through IkappaBalpha phosphorylation and subsequent proteolysis. Antioxidants, namely N-acetylcysteine (NAC) and glutathione (GSH), have no effects on IgA-mediated NF-kappaB nuclear translocation and only a minor and late effect on that of LPS, suggesting that reactive oxygen intermediates (ROI) play a minor role in HAM activation through NF-kappaB. TNF-alpha release by LPS-activated HAM is sensitive to NF-kappaB inhibition and only partly to oxidant scavenging. In contrast, TNF-alpha release by IgA-treated HAM is not dependent on oxidants and only partly dependent on NF-kappaB. Our results show a differential HAM regulation by IgA through both dependent and independent modulation of ERK pathway. In addition, IgA activates NF-kappaB and this effect was independent on oxidants. These data may help to understand the role of IgA in both lung protection and inflammation.     

Kallmann syndrome: 14 novel mutations in KAL1 and FGFR1 (KAL2)

Kallmann syndrome (KAL) combines hypogonadotropic hypogonadism and anosmia. Hypogonadism is due to Gonadotropin Releasing Hormone (GnRH) deficiency and anosmia is related to hypoplasia of the olfactory bulbs. Occasional symptoms include renal agenesis, bimanual synkinesia, cleft lip palate, dental agenesis. KAL is genetically heterogeneous and two genes have so far been identified, namely KAL1 (Xp22.3) and FGFR1/KAL2 (8p12), which underlie the X chromosome‐linked form and an autosomal dominant form of the disease, respectively. We studied a cohort of 98 unrelated Caucasian KAL patients. We identified KAL1 mutations in 14 patients, of which 7 (c.3G>A (p.M1?), g.IVS1+1G>T, c.570_571insA (p.R191fsX14), c.784G>C (p.R262P), c.958G>T (p.E320X), c.1651_1654delinsAGCT (p.P551_E552delinsSX), c.1711T>A (p.W571R)) have not been previously reported. In addition, we found FGFR1 mutations in 7 patients, namely c.303G>A (p.V102I), C.385A>C (p.D129A), c.810G>A (p.V273M), c.1093_1094delAG (p.R365fsX41), c.1561G>A (p.A520T), c.1836_1837insT (p.Y613fsX42), c.2190C>G (p.Y730X), all of which were novel mutations. In this study, unilateral renal agenesis and bimanual synkinesia were exclusively found associated with KAL1mutations, cleft palate and dental agenesia with FGFR1mutations. © 2004 Wiley‐Liss, Inc.     

Recombination pattern of the TCR γ locus in human peripheral T-cell lymphomas

The recombination events of the γ and β T-cell receptor (TCR) loci were analysed in a series of 39 peripheral T-cell lymphomas (PTCLs) in association with the expression of TCR chains. In TCR αβ PTCLs, 22/23 cases showed a γ-gene rearrangement while only 18/23 showed a concomitant β-gene rearrangement. The germline configuration of the β locus was found in angioimmunoblastic lymphadenopathy and lymphoepithelioid lymphomas. Three γδ PTCLs rearranged both γ and β genes. TCR silent PTCLs showed three different patterns of γ- and β-gene rearrangements. Three cases were in germline configuration for both loci; five cases had a rearranged γ and a germline β locus; and five cases had the two loci rearranged. Regarding the variable genes in the γ-rearranged alleles, members of the VγI subgroup were the most frequently presented (39/50), followed by VγII, VγIII, and VγIV (9/50, 1/50, and 1/50, respectively). Joining segment usage was as follows: J1 or J2 (32/50), JP1 or JP2 (17/50), and JP (1/50). Taken together, these data demonstrate that the γ locus is more frequently rearranged whatever the TCR expression. The γ-locus analysis provides a better diagnostic yield than the β locus in the study of PTCL clonality.     

Eutopic endometrium and peritoneal,ovarian and bowel endometriotic tissues express a different profile of matrix metalloproteinases-2, -3 and -11, and of tissue inhibitor metalloproteinases-1 and -2

Endometriosis is subsequent to the ability of endometrial glands to invade normal tissues. Matrix metalloproteinases (MMPs)—enzymes that mediate normal tissue turnover, including endometrial breakdown during menstruation—appear to be involved in this invasive process. Here, we examined the immunohistochemical expression of MMP-2, MMP-3, MMP-11, tissue inhibitor metalloproteinase (TIMP)-1 and TIMP-2 in endometrium from women with (n=9) or without endometriosis (n=18) in comparison with peritoneal (n=20), ovarian (n=20) and colorectal endometriosis (n=20). Women with endometriosis showed decreased endometrial MMP-2 expression compared with women without endometriosis (mean±SD positive cells: 24.3±28.3% and 69.3±12.1%), together with loss of MMP-3 expression (0 versus 17.5%±20.2). MMP-11, TIMP-1 and TIMP-2 expression was similar in the two groups. Endometrial MMP-2, -3 and -11 expression and TIMP-1 and -2 expression were similar in women with endometriosis and in those with peritoneal endometriosis. MMP-2, -3 and -11 expression was higher in colorectal endometriosis than in ovarian and peritoneal endometriosis. TIMP-2 expression was lower in colorectal endometriosis (P=0.0002) and ovarian endometriotic cysts (P=0.003) than in peritoneal endometriosis. TIMP-1 expression did not vary according to the location of endometriotic lesions. These results suggest that MMP-2 and -3 and TIMP-2 may be involved in the pathogenesis of endometriosis. Interestingly, MMP-2 and -3 overexpression was related to the infiltrative nature of endometriotic lesions, with possible sequential expression from peritoneal to colorectal endometriosis.     

Télomérisation radicalarie de monomères N-acryloyl-N-alkylamino esters d'intXérêt biologique

Three methyl 11-(N-acryloyl-N-alkylamino)undecanoates were synthesized from acryloyl chloride and amino-or alkylaminoundecanoic acid esters. These compounds were telomerized in the presence of 1-dodecanethiol as telogen to yield telomers with molecular weight lower than 5000. These telomers are likely to generate HIV inhibitor polyanions with good biocompatibility. The K/K_t value was assessed from a kinetic study of the telomerization reaction. NMR spectroscopy analysis indicates that the polymerization degree DP _n are in good agreement with expectation for methyl 11-(N-acryloylamino)undecanoate. However, they were lower than expected for methyl 11-(N-acryloyl-N-alkylamino)undecanoate.     

Variability versus heterogeneity in syndromal hypothalamic hamartoblastoma and related disorders: Review and delineation of the Cerebro-Acro-Visceral Early lethality (CAVE) multiplex syndrome

We report on a case of neonatal hypothalamic hamartoblastoma with holoprosencephaly, Hirschsprung disease, and tetramelic postaxial polydactyly. Twenty-seven previous cases of congenital hypothalamic embryonic tumours with associated congenital defects are reviewed. A classification in isolated, associated, and syndromal forms is proposed. The difficulties encountered in differential diagnosis between the syndromal form (mainly represented by the Pallister-Hall syndrome) and related diseases as Smith-Lemli-Opitz type II, holoprosencephaly-polydactyly, orofaciodigital type VI and hydrolethalus syndromes are outlined. Two pathogenic mechanisms are discussed: a classical pleiotropic model and single sequence model. The latter is sufficient to delineate syndromal hypothalamic hamartoblastoma. With the former, syndromal hypothalamic hamartoblastoma cannot be clearly recognized in the absence of a CNS tumour, a child with syndromal hypothalamic hamartoblastoma cannot be reliably diagnosed as Pallister-Hall rather than another MCA syndrome, and, ultimately, the existence of Pallister-Hall syndrome could be questioned, as it could only be the extreme expression of one or several other syndromes. As this hypothesis cannot be proven or disproven at this point, the authors suggest creating the concept of multiplex phenotype. “Cerebro-Acro-Visceral Early lethality multiplex syndrome” is suggested to encompass all the ambiguous cases. Within this complex, an operative classification key is proposed. © 1992 Wiley-Liss, Inc.     

Dry heat loss in incubator: comparison of two premature newborn sized manikins

Keeping premature newborns warm is crucial for their survival. Their ability to prevent excessive heat loss to the environment and to control their body temperature is limited. The risk of hypothermia is particularly important for low-birth-weight newborns with a large body surface area in relation to their mass of heat-producing tissues. The present study was performed to assess the body heat loss difference between small and large body-size premature newborns using two anthropomorphic thermal manikins of premature newborns of 900 g and 1,800 g (respective body surface areas of 0.086 and 0.150 m²). The dry heat loss from the six body segments of the small manikin (S) was measured and compared with that of the large manikin (L). The two manikins were exposed to five different environmental temperatures ranging between 29 and 35°C in a single-walled, air-heated closed incubator. The magnitudes of heat loss decreased significantly by 20.4% between the two manikins [small manikin 110.1 (44.3) W/m² vs large manikin 87.6 (25.8) W/m², mean values with one standard deviation]. The results obtained from the comparison of the heat loss measures from the two manikins confirm the fact that the heat loss increases with an increase in the ratio of the body surface area to body mass. The thermal manikin appears to provide an accurate method for the assessment of thermal conditions in neonatal care.     

Structures et propriétés diélectriques des poly(α-acétoxystyréne)s parasubstitués

The relations between structure and isothermal, dielectric properties of poly(α-acetoxystyrene)s substituted in para position by ? OCOCH₃ ( 1a ), ? OCOCH₂CH₃ ( 1b ), ? OCOCH₂CH₂CH₃ ( 1c ), ? OCOC₆H₅ ( 1d ), ? OCOCH₂CH₂Cl ( 1f ) and ? OCOOCH₃ ( 1g ) were studied. The dielectric constants, at 10⁵ Hz and 20 ± 2°C, were found to be: 3,79 ( 1a ), 3,36 ( 1b ), 3,18 ( 1c ), 3,51 ( 1d ), 3,36 ( 1e ), 3,65 ( 1f ) and 3,07 ( 1g ). The polymers 1a – 1g do not show any α- or β-transition. Increasing bulkiness of the para substituent gives rise to a decreasing dielectric constant due to an increase of the degree of syndiotacticity, as determined from ¹H and ¹³C NMR spectra.