Azacitidine-venetoclax versus azacitidine salvage treatment for primary induction failure or first relapsed acute myeloid leukaemia patients.

OBJECTIVES: To compare the efficacy of venetoclax-azacitidine (VEN-AZA) with AZA in the real-life for patients with first relapsed or refractory acute myeloid leukaemia (R/R AML). METHODS: We retrospectively analysed R/R AML patients treated with VEN-AZA at the Institut Paoli Calmettes between September 2020 and February 2022. We compared them to a historical cohort of patients treated with AZA between 2010 and 2021. RESULTS: Thirty-five patients treated with VEN-AZA were compared with 140 patients treated with AZA. There were more favourable cytogenetics (25.7% vs. 8.6%; p = 0.01) and less FLT3-ITD mutated AML (8.8% vs. 25.5%; p = .049) in the VEN-AZA group. The overall 30-day mortality rate was 7.4% and the overall 90-day mortality was 20%, with no difference between the groups. The complete remission rate was 48.6% in the VEN-AZA group versus 15% (p < .0001). The composite complete response rate was 65.7% in the VEN-AZA group versus 23.6% (p < .0001). OS was 12.8 months in the VEN-AZA group versus 7.3 months (p = 0.059). Patients with primary refractory AML, poor-risk cytogenetics, prior hematopoietic stem-cell transplantation (HSCT) and FLT3-ITD mutated AML had lower response and survival rates. CONCLUSION: VEN-AZA was associated with a better response rate and a longer survival than AZA monotherapy in AML patients who relapsed after or were refractory to intensive chemotherapy.

Quantum limits of position-sensitive photodiodes.

The split photodiode and the lateral effect photodiode are two popular detectors for measuring beam displacement. For small displacements of a Gaussian beam, which is the case of interest here, they are often seen as equivalent and used interchangeably, giving a signal proportional to the displacement. We show theoretically and experimentally that in the limit of low technical noise, where the signal to noise ratio is dominated by the shot noise of the light, the lateral effect photodiode produces a better signal to noise ratio than the split photodiode, owing to its optimum spatial detector response. This quantum advantage can be practically exploited in spite of the intrinsic thermal noise of the lateral effect photodiode.

Graduate Student Literature Review: The effect of chain length and stall width on common outcome measures of dairy cow welfare in stall-based housing systems.

Given increased societal concern for the welfare of dairy cattle and the heightened concern of consumers about the ability of cows to fulfill their needs for rest and for movement, an understanding of the effect of stall-based housing systems on such needs becomes of prime scientific importance. In tie-stall systems, the ability of the cow to express her need for movement is largely affected by tethering; increasing chain length increased the cow's ease of movement in the space allowed to her. Regarding the ability of the cow to rest, the size of the stall bed (including its width) has been linked with measures of lying time. For the most part, current industry recommendations are not being followed on commercial farms, although improvements in terms of compliance seem to have been made in the last decade. Following the recommendations for chain length appears to aid in reducing the prevalence of injuries and may even aid in maintaining the cleanliness of the cows, although the few studies available are inconsistent. Wider stalls were associated with increased lying time and reduced prevalence of injuries, although in the latter case, data from different studies show inconsistent results. The link between stall width and common welfare outcome measures appears more clearly in tiestall systems, although improving the lateral space allowance for cows reduces collisions with equipment in freestall systems as well. Overall, the width of the stall and the length of the chain play roles in modulating the cows' ability to rest and to move comfortably in the confines of the stall, and should be carefully considered when designing stall-based housing systems that enhance the welfare of dairy cows.

Making tiestalls more comfortable: II. Increasing chain length to improve the ease of movement of dairy cows.

Although most farms in Canada still use tiestall housing for dairy cows, little information is available pertaining to cow comfort and behavior in such systems. Tiestalls are often criticized as they offer a reduced dynamic space to cows, thereby restricting their ability to move. The object of this study was to see if increasing the length of the tie chain provides cows with improved movement opportunities and to measure its effect on cows' rising and lying movements and behaviors. Two treatments were tested: the current recommendation of 1.00 m (recommended) and a longer chain of 1.40 m (long). Twenty-four cows (12/treatment) were blocked by parity number and lactation stage, then randomly allocated to a treatment and a stall within one of 2 rows in the research barn for 10 wk. Leg-mounted accelerometers were used to record lying behaviors and moments of transition between lying and standing positions for all cows. Cows were video-recorded for 24 h/wk using cameras positioned above the stall. The videos were used to evaluate the cows' rising and lying-down movements on wk 1, 2, 3, 6, 8, and 10. Six rising and 6 lying-down motions per cow per week were assessed by a trained observer to detect the presence of abnormal behaviors. Differences between and within treatments over time were analyzed in SAS (SAS Institute Inc., Cary, NC) using a mixed model with treatment, week, and block as fixed effects and with row and cow as random effects. Data from wk 1-3 were grouped together as the short-term effects, and those from wk 8-10 as the long-term effects. Week 6 was used as the mid-term assessment for analysis. Multiple comparisons between terms were accounted for using a Scheffé adjustment. Results indicate that duration of intention movements (exploratory head movements made by cows before lying down) is shorter in cows with longer chains (13.6 ± 1.03 s vs. 16.8 ± 1.01 s). It was also significantly shorter in the long term compared with the short term for both treatments (13.3 ± 0.92 s vs. 16.9 ± 0.81 s). These results suggest that increasing the chain length improves the cows' ease of movement and transitions, although all cows became more at ease in their surroundings with time. It may provide evidence of a potential way to improve the dynamic space provided to cows in tiestall systems, using a simple, affordable modification.

Making tiestalls more comfortable: III. Providing additional lateral space to improve the resting capacity and comfort of dairy cows.

Dairy cows housed in tiestalls are restricted to one space; therefore, this space should be designed to accommodate all the activities cows need to perform. Lying is a very important behavior for dairy cows as well as a critical measure in the assessment of stall designs, to ensure that the cows' needs for resting space are met. The objective of this study was to determine if increasing tiestall width alters the lying behavior of lactating dairy cows. Two treatments were compared: the current recommendation (139 cm) and a double stall (284 cm). Sixteen cows were blocked by parity and lactation stage, then randomly allocated to a treatment and a stall within 1 of 2 rows in the research barn, for 6 wk. The average stall length was 188 cm. Leg-mounted accelerometers were used to record lying behaviors. Cows were video-recorded 24 h/wk using surveillance cameras positioned above the stalls. Video data from wk 1, 3, and 6 were extracted at a rate of 1 image/min and analyzed by a trained observer to assess the position and the location of the cow's body, head, and limbs during the lying hours. Lying behaviors and frequency of each position and location were analyzed in SAS (SAS Institute Inc., Cary, NC) using a mixed model in which treatment, block, and week were included as fixed factors, and cow and row as random factors. Multiple comparisons were adjusted using the Scheffé method. Results indicate that cows in double stalls fully extended their hindlimbs more often than single stall cows (21.7 vs. 7.6% of lying time). Cows in double stalls also intruded in the neighboring stalls with their hindlimbs less often (1.3 vs. 14.7% of lying time), instead positioning them inside their own stall more often (92.7 vs. 84.6% of lying time). Use of the second stall in the double stall group totaled 11.6, 5.1, 33.8, and 18.0% of lying time, respectively, for the head, front legs, hind legs, and body. Total lying time was not statistically different between double (716 min/d) and single stall (671 min/d) groups. Contacts with stall hardware during lying-down movements were also less frequent in double stalls (43.1 vs. 77.1% of lying events) compared with single stalls. These results suggest that dairy cows housed in double stalls modified their resting habits and used the extra space made available to them. Increasing stall width beyond the current recommendation is likely to benefit the cows by improving their ability to rest.

Post-remission therapy of adults aged 60 and older with acute myeloid leukemia in first complete remission: role of treatment intensity on the outcome.

Although complete remission (CR) is achieved in 50 to 70% of older fit patients with acute myeloid leukemia (AML), consolidation therapy in this age group remains challenging. In this retrospective study, we aimed to compare outcome in elderly patients treated with different post-remission modalities, including allogenic and autologous hematopoietic stem cell transplantation (HSCT), intensive chemotherapy, and standard-dose chemotherapy (repeated 1 + 5 regimen). We collected data of 441 patients ≥ 60 years in first CR from a single institution. Median age was 67 years. Sixty-one (14%) patients received allo-HSCT, 51 (12%) auto-HSCT, 70 (16%) intensive chemotherapy with intermediate- or high-dose cytarabine (I/HDAC), and 190 (43%) 1 + 5 regimen. Median follow-up was 6.5 years. In multivariate analysis, allo-HSCT, cytogenetics, and PS had a significant impact on OS and LFS. In spite of a more favorable-risk profile, the patients who received I/HDAC had no significantly better LFS as compared with patients treated with 1 + 5 (median LFS 8.8 months vs 10.6 months, p = 0.96). In transplanted patients, median LFS was 13.3 months for auto-HSCT and 25.8 months for allo-HSCT. Pre-transplant chemotherapy with I/HDAC had no effect on the outcome. Toxicity was significantly increased for both transplanted and non-transplanted patients treated with I/HDAC, with more units of blood and platelet transfusion and more time spent in hospitalization, but no higher non-relapse mortality. This study shows that post-remission chemotherapy intensification is not associated with significantly better outcome as compared with standard-dose chemotherapy in elderly patients for whom, overall results remain disappointing.

Heterogeneity of virological suppression in the national antiretroviral programme of Cameroon (ANRS 12288 EVOLCAM).

OBJECTIVES: In terms of HIV infection, western and central Africa is the second most affected region world-wide, and the gap between the regional figures for the testing and treatment cascade and the Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 targets is particularly worrying. We assessed the prevalence of virological suppression in patients routinely treated in 19 hospitals in Cameroon. METHODS: A cross-sectional survey was performed in adult patients receiving antiretroviral therapy (ART) in the Centre and Littoral regions. The prevalences of virological suppression (<1000 HIV-1 RNA copies/mL) were compared among all 19 hospitals using the χ2 test. Potential individual and health care-related determinants of virological suppression were assessed using multivariate logistic regression models. RESULTS: A total of 1700 patients (74% women; median age 41 years; median time on ART 3.7 years) were included in the study. The prevalence of virological suppression was 82.4% overall (95% confidence interval 80.5-84.2%). It ranged from 57.1 to 97.4% according to the individual hospital (P < 0.001). After adjustment, virological suppression was associated with age, CD4 cell count at ART initiation, disclosure of HIV status to family members, interruption of ART for more than two consecutive days, and location of patient's residence and hospital (rural/urban). These factors did not explain the heterogeneity of virological suppression between the study hospitals (P < 0.001). CONCLUSIONS: The overall prevalence of virological suppression was reassuring. Nevertheless, the heterogeneity of virological suppression among hospitals highlights that, in addition to programme-level data, health facility-level data are crucial in order to tailor the national AIDS programme's interventions with a view to achieving the third UNAIDS 90 target.

Heterosexual practices of women and men living with HIV attending hospital outpatient services (ANRS-VESPA2 survey): a French comparative study with the general population (CSF survey).

HAART has improved the well-being of many people living with HIV (PLWH). This study aimed at (i) comparing heterosexual practices between PLWH and the general population by gender, and (ii) identifying factors associated with sexual practices and at-risk behaviors in the two populations. Self-reported data were collected among PLWH attending hospitals (VESPA2 survey; n = 3022) and the general population (CSF survey; n = 10,280). Significant differences between the two samples were corrected for by implementing propensity score matching on both socio-demographic characteristics and sexual behavior in terms of number of partners. Men not reporting heterosexual intercourse were excluded. After matching, 61% of women (out of 707) and 68% of men (out of 709) were sexually active in both populations. PLWH practiced oral sex less than the general population and used condoms more consistently over the previous 12-month period, irrespective of having multiple sexual partners or not. For women living with HIV: those with several sexual partners and those consuming drugs over the previous 12 months were more likely to practice oral sex; those living in a couple for at least 6 years and migrants were less likely to practice anal intercourse. For men living with HIV: those reporting bisexual relationships and those with multiple sexual partners over the previous 12 months were more likely to practice anal heterosexual intercourse; migrants reported less oral sex, irrespective of HIV status. Error term correlations showed that anal intercourse was not linked to condom use for women or men from either population. Our results show that PLWH had a lower rate of heterosexual practices compared with the general population, and used condoms more often, irrespective of the number of sexual partners and strong cultural background (e.g., for Sub-Saharan African women). Further preventive information needs to be disseminated on the risk of infection transmission through heterosexual anal intercourse.

Tunable delay of Einstein-Podolsky-Rosen entanglement.

Entangled systems display correlations that are stronger than can be obtained classically. This makes entanglement an essential resource for a number of applications, such as quantum information processing, quantum computing and quantum communications. The ability to control the transfer of entanglement between different locations will play a key role in these quantum protocols and enable quantum networks. Such a transfer requires a system that can delay quantum correlations without significant degradation, effectively acting as a short-term quantum memory. An important benchmark for such systems is the ability to delay Einstein-Podolsky-Rosen (EPR) levels of entanglement and to be able to tune the delay. EPR entanglement is the basis for a number of quantum protocols, allowing the remote inference of the properties of one system (to better than its standard quantum limit) through measurements on the other correlated system. Here we show that a four-wave mixing process based on a double-lambda scheme in hot (85)Rb vapour allows us to obtain an optically tunable delay for EPR entangled beams of light. A significant maximum delay, of the order of the width of the cross-correlation function, is achieved. The four-wave mixing also preserves the quantum spatial correlations of the entangled beams. We take advantage of this property to delay entangled images, making this the first step towards a quantum memory for images.

Complement mediates human immunodeficiency virus type 1 infection of a human T cell line in a CD4- and antibody-independent fashion.

Incubation of the human T cell lymphotropic virus (HTLV)-IIIB and HTLV-RF strains of human immunodeficiency virus type 1 (HIV-1) with normal seronegative human serum under conditions that allow complement activation resulted in enhancement of infection of the MT2 human T cell line cultured in the presence of low amounts of virus. Infection of MT2 cells was assessed by measuring reverse transcriptase activity in supernatants at day 9 of culture. Complement activation by viral suspensions occurred through the alternative pathway. Opsonization of HTLV-RF viral particles with complement was sufficient to allow a productive infection to occur in cells exposed to suboptimal amounts of virus. Infection of MT2 cells with suboptimal amounts of serum-opsonized HIV-1 was suppressed by blocking the C3dg receptor (CR2, CD21) on MT2 cells with monoclonal anti-CR2 antibody and rabbit F(ab')2 anti-mouse immunoglobulin antibodies. Blocking of the gp120-binding site on CD4 under similar experimental conditions had no inhibitory effect on infection of MT2 cells with opsonized virus. Opsonization of HIV-1 with seronegative serum also resulted in a CR2-mediated enhancement of the infection of normal peripheral blood mononuclear cells and T lymphocytes. These results indicate that complement in the absence of antibody may enhance infection of C3 receptor-bearing T cells with HIV-1, and that the interaction of opsonized virus with the CR2 receptor may result by itself in the infection of target T cells in a CD4- and antibody-independent fashion.

Quantum correlated light beams from non-degenerate four-wave mixing in an atomic vapor: the D1 and D2 lines of 85Rb and 87Rb.

We present experimental results showing that quantum correlated light can be produced using non-degenerate, off-resonant, four-wave mixing (4WM) on both the D1 (795 nm) and D2 (780 nm) lines of (85)Rb and (87)Rb, extending earlier work on the D1 line of (85)Rb. Using this 4WM process in a hot vapor cell to produce bright twin beams, we characterize the degree of intensity-difference noise reduction below the standard quantum limit for each of the four systems. Although each system approximates a double-lambda configuration, differences in details of the actual level structure lead to varying degrees of noise reduction. The observation of quantum correlations on light produced using all four of these systems, regardless of their substructure, suggests that it should be possible to use other systems with similar level structures in order to produce narrow frequency, non-classical beams at a particular wavelength.

Impact of a multifaceted prevention program on ventilator-associated pneumonia including selective oropharyngeal decontamination.

PURPOSE: We describe the impact of a multifaceted program for decreasing ventilator-associated pneumonia (VAP) after implementing nine preventive measures, including selective oropharyngeal decontamination (SOD). METHODS: We compared VAP rates during an 8-month pre-intervention period, a 12-month intervention period, and an 11-month post-intervention period in a cohort of patients who received mechanical ventilation (MV) for > 48 h. The primary objective was to assess the effect on first VAP occurrence, using a Cox cause-specific proportional hazards model. Secondary objectives included the impact on emergence of antimicrobial resistance, antibiotic consumption, duration of MV, and ICU mortality. RESULTS: Pre-intervention, intervention and post-intervention VAP rates were 24.0, 11.0 and 3.9 VAP episodes per 1000 ventilation-days, respectively. VAP rates decreased by 56% [hazard ratio (HR) 0.44, 95% CI 0.29-0.65; P < 0.001] in the intervention and by 85% (HR 0.15, 95% CI 0.08-0.27; P < 0.001) in the post-intervention periods. During the intervention period, VAP rates decreased by 42% (HR 0.58, 95% CI 0.38-0.87; P < 0.001) after implementation of eight preventive measures without SOD, and by 70% after adding SOD (HR 0.30, 95% CI 0.13-0.72; P < 0.001) compared to the pre-intervention period. The incidence density of intrinsically resistant bacteria (to colistin or tobramycin) did not increase. We documented a significant reduction of days of therapy per 1000 patient-days of broad-spectrum antibiotic used to treat lower respiratory tract infection (P < 0.028), median duration of MV (from 7.1 to 6.4 days; P < 0.003) and ICU mortality (from 16.2 to 13.5%; P < 0.049) for patients ventilated > 48 h between the pre- and post-intervention periods. CONCLUSIONS: Our preventive program produced a sustained decrease in VAP incidence. SOD provides an additive value.

[Recent advances in the treatment of myelodysplastic syndromes]. / Avancées dans la prise en charge des syndromes myélodysplasiques.

OBJECTIVES: Myelodysplastic syndromes (MDS) are a group of clonal hematologic disorder, which combine ineffective hematopoiesis and evolution to acute myeloid leukemia. Significant progress has been made in the understanding of the disease pathogenesis, diagnostics and classification. Promising new agents and innovative therapeutic strategies are currently used. In this article we will review these achievements and their impact on the treatment of MDS. CURRENT KNOWLEDGE AND KEY POINTS: The pathogenesis of MDS involves abnormalities of the MDS clone itself such as abnormal apoptosis, signalling or epigenetic regulation and abnormalities of the microenvironment such as immune deregulation or increased angiogenesis, which represent potential therapeutic targets. There is currently no standard treatment for MDS and allogeneic stem cell transplantation remains the only curative strategy. However, besides conventional chemotherapy and growth factors, new agents including hypomethylating agents, antiangiogenic drugs, immune modulatory agents have proved effective. FUTURE PROSPECTS AND PROJECTS: The interesting results achieved with these new agents show that it is necessary to continue investigation in order to improve therapeutic strategies in MDS.

Oxidative DNA damage photo-induced by 3-carbethoxypsoralen and other furocoumarins. Mechanisms of photo-oxidation and recognition by repair enzymes.

DNA photosensitization by several furocoumarins (including 3-carbethoxypsoralen (3-CPs), 8-methoxypsoralen (8-MOP), 5-methoxypsoralen (5-MOP) and angelicin was investigated by using DNA sequencing methodology. 3-CPs induces photo-oxidation of guanine residues leading to alkali-labile sites in DNA (revealed by hot piperidine), whereas 8-MOP, 5-MOP and angelicin do not. There is a preferential photo-oxidation of G when located on the 5' side of GG doublets, likely to reflect a better accessibility of the G moiety in such a context. Mechanisms operating via both radicals (type I) and singlet oxygen (type II) are involved in the photo-oxidation of G residues by 3-CPs. Photo-oxidized G residues are produced independently of the formation of photoadducts, and scavengers of singlet oxygen or radicals do not inhibit photobinding of 3-CPs to DNA. This leads us to propose that covalent photoadducts arise from the intercalated excited sensitizer molecules, whereas G photo-oxidations are produced either by electron transfer reactions involving bound 3-CPs or by energy transfer to molecular oxygen, thereby producing singlet oxygen that subsequently reacts with guanine bases. Quantification of both types of DNA lesions indicated that in vitro photo-oxidized G residues are produced in DNA by 3-CPs plus ultraviolet light at least to the same extent as photoadducts, under our conditions. A calf thymus redoxyendonuclease, equivalent to the endonuclease III of Escherichia coli, specific for oxidative DNA damages, recognizes and cleaves DNA at sites of photo-oxidized G residues. The extent of the cleavage by this enzyme was close to that observed by hot piperidine and followed the amount of photo-oxidized G residues produced when the lifetime of excited oxygen species is modified. The redoxyendonuclease did not incise DNA treated with 8-MOP, 5-MOP or angelicin plus ultraviolet light. The exonuclease III and endonuclease IV of E. coli also involved in the repair of oxidative DNA damage, convert the replicative form I of 3-CPs-treated DNA to replicative form II. This suggests that the lesions recognized by these enzymes are apurinic-like lesions. In view of the low toxicity and mutagenicity of 3-CPs, DNA photo-oxidation products induced by the photodynamic effect of 3-CPs are likely to be efficiently taken care of by the DNA repair system(s). It is clear that 3-CPs photo-induces several classes of DNA damage, including oxidative damage.(ABSTRACT TRUNCATED AT 400 WORDS)

Viscosupplementation: techniques, indications, results.

Viscosupplementation by hyaluronic acid (HA) injections is frequently used for local treatment of osteoarthritis (OA), due to ease of use and good tolerance. A profusion of linear or reticulated HA derivates are marketed, with varied characters and levels of evidence. Viscosupplementation has demonstrated moderate but significant efficacy (20%) versus placebo in terms of pain and function, with a high rate of responders (60-70%) in knee osteoarthritis. It allows reduced administration of opioid analgesics and NSAIDs, with improved risk/benefit ratio, and may delay joint replacement. Cartilage protection remains to be proven. Clinical efficacy shows 1-4 weeks' later onset than corticosteroids, but is maintained for 6 or even 12 months. Systematic association of corticosteroid and HA injection is not justified, and an interval has to be left before undertaking arthroplasty. Intra-articular injection of HA requires a skilled specialist, and may be difficult in a non-swollen joint; some tips and tricks may be helpful. In other joints than the knee, radiologic or ultrasound guidance is recommended. The efficacy of viscosupplementation is a matter of ongoing debate, after discordant findings in some meta-analyses. Some poor results may be due to inappropriate use of HA injections, poorly adapted to the patient's OA phenotype. Viscosupplementation is a treatment for chronic moderate symptomatic OA, and not for flares with joint swelling. Application in sport-related chondropathy has yet to be properly assessed. The optimal response profile remains to be determined. The ideal indication in the knee seems to be moderate femorotibial OA without swelling. Results have been generally disappointing in hip osteoarthritis but promising in OA of the ankle and shoulder (with and without rotator cuff tear). Further studies are needed to determine response profile and optimal treatment schedule, according to the joint.

A 2-year follow-up of an anti-HIV immune reaction in HIV-1 gp160-immunized healthy seronegative humans: evidence for persistent cell-mediated immunity.

The first trial of an anti-HIV immunization, using a recombinant vaccinia virus expressing gp160 (rV) for priming and paraformaldehyde-fixed rV-infected PBLs and soluble gp 160 for boosting, clearly showed an in vitro HIV-protective immune reaction. This result led us to carry out an additional 2 year Phase I clinical trial in 25 HIV-seronegative volunteers, using HIV gp 160 antigens for immunization in four different protocols. The 2 year trial showed (a) the safety of the preparations, (b) a transient humoral immunity following each boost, and (c) a long-lasting memory T-cell response. Memory cytotoxic T-lymphocytes (CTLs) induced by gp 160 antigen with or without vaccinia vector lysed HLA class I restricted target cells expressing HIV-1 env antigens. These results are consistent with CTLs being an effective component of an AIDS vaccine to control cell-to-cell viral replication, dissemination in the organism, and subsequent evolution toward AIDS.

Ready protease-catalyzed synthesis of carbohydrate-amino acid conjugates.

The protease-catalyzed synthesis of amino acid est-carbohydrate conjugates as glycopeptide analogues has been achieved in a highly regioselective and carbohydrate-specific manner using amino acid vinyl ester acyl donors and minimally or completely unprotected carbohydrate acyl acceptors, which together probed active sites of proteases to reveal yield efficiencies that are modulated by the carbohydrate C-2 substitutent, and that may be exploited to allow selective one-pot syntheses.

Aerosolized tachykinin antagonists inhibit pentamidine-induce bronchoconstriction in guinea pigs.

To investigate the role of tachykinins in pentamidine-induced bronchoconstriction and airway microvascular leakage in the guinea pig, we examined the effects on bronchoconstriction and microvascular leakage of the nonpeptide antagonists of NK1 and NK2 tachykinin-receptors, respectively, CP-96,345 and SR 48968. Respiratory system resistance was measured by the occlusion method in anaesthetized, tracheotomized and mechanically ventilated guinea pigs. Airway microvascular permeability was evaluated by measuring the quantity of Evans blue dye in the trachea and main bronchi. Aerosolized CP-96,345 or SR 48968 partially abolished pentamidine-induced bronchoconstriction (at 5 to 30 mg/mL pentamidine; 60 breaths) whereas the combination of the two prevented it. In contrast, CP-96,345 and SR 48968 did not prevent the increase in airway microvascular permeability induced by pentamidine (50 mg/mL; 90 breaths) whether they were administered separately or together, by aerosol or intravenously. These results demonstrate that in the guinea pig, pentamidine-induced bronchoconstriction is mediated through both NK1 and NK2 tachykinin-receptor activation and that when directly administered into the airways, tachykinin antagonists effectively prevent pentamidine-induced bronchoconstriction.

Maternal humoral factors associated with perinatal human immunodeficiency virus type-1 transmission in a cohort from Kigali, Rwanda, 1988-1994.

OBJECTIVES: to study different parameters of humoral immunity responses in the serum of 39 human immunodeficiency virus type-1 infected pregnant women from Kigali, (Rwanda) in correlation with perinatal transmission. METHODS: this study was done between 1988 and 1994. Thirty nine HIV-1 infected women, 18 transmitting (T) and 21 non-transmitting (NT) mothers, have been chosen based on the quantity of sera available for analysis. Maternal data were collected at the time of delivery or during the preceding month. Quantification of viral load was performed by the signal amplification bDNA assay. Specific reactivity of antibody was tested against recombinant p24 protein and five different synthetic peptides from gp120 and gp41 based on HIV LAI-strain sequences. Neutralization assays were performed against laboratory (RII strain of the HIV-1 C subtype) and primary strains (two NSI and one SI of the HIV-1 A subtype). Antibody Dependent Cellular Cytotoxicity assay was performed with CEM.NK(R) cells against a laboratory HIV-1 strain. RESULTS: absence of correlation regarding maternal viral load, or viral subtype and vertical transmission was observed. By contrast, the CD4/CD8 ratio was significantly higher in non-transmitting mothers compared to transmitting mothers. Moreover, high anti-p24 antibody avidity was correlated with a lower risk of perinatal transmission. Furthermore, transmission risk appeared significantly higher with reactivity of serum samples to linear epitopes of gp41 (amino acids 566-582, 578-594), whereas risk appeared lower with reactivity to the immunodominant domain of gp41 (amino acids 597-609). No significant difference was observed in titres of antibody neutralizing primary isolates (two NSI (non syncitium inducer) and one SI (syncitium inducer) of the HIV-1 A subtype) and laboratory strain (RII strain, of the HIV-1 C subtype) between transmitting and non-transmitting mother's sera. In addition, titres of Antibody Dependent Cellular Cytotoxicity were similar in transmitting versus non-transmitting mothers. However, high Antibody Dependent Cellular Cytotoxicity titres were correlated with a good clinical status of children. CONCLUSIONS: three parameters such as high CD4/CD8 ratio, high anti-p24 antibody avidity and high reactivity against the immunodominant epitope of gp41 have been shown to be correlated with no perinatal transmission. High Antibody Dependent Cellular Cytotoxicity titres appeared to be linked to a good clinical status of children after birth. One parameter, reactivity against two linear epitopes of gp41, appeared to be correlated with vertical transmission.

[HIV and pregnancy: 2013 guidelines from the French expert working group]. / Infection par le VIH et grossesse: nouvelles recommandations 2013 du groupe d'experts français.

With effective antiretroviral therapy, the risk of mother to child transmission (MTCT) is now under 1%. The 2013 French guidelines emphasize early antiretroviral lifelong antiretroviral therapy. Thus, the current trend for women living with HIV is to take antiretroviral therapy before, during and after their pregnancies. A major issue today is the choice of antiretroviral drugs, to maximize the benefits and minimize the risks of fetal exposure. This requires interdisciplinary care. The use of effective therapies permits gradual but profound changes in obstetric practice. When maternal plasma viral load is controlled (<50 copies/ml), obstetrical care can be more similar to standards in HIV-negative women. Prophylactic cesarean section is recommended when the viral load in late pregnancy is above 400 copies/mL. Intravenous zidovudine during labor is recommended only if the last maternal viral load is>400 copies/mL or in case of complications such as preterm delivery, bleeding or chorio-amnionitis during labor. In case of premature rupture of membranes before 34 weeks, a multidisciplinary decision should be made, based on gestational age and control of maternal viral load; if the woman is under antiretroviral therapy and especially if her viral load is undetectable, steroids and antibiotics should be offered and pregnancy can be continued except in case of signs or symptoms of chorio-amnionitis. Breastfeeding is not recommended in women living with HIV in France, as in industrialized countries. Prophylaxis in the newborn is usually zidovudine for 1 month. In case of significant exposure to HIV perinatally, in particular when, maternal viral load is>1000 copies/mL, prophylactic combination therapy is recommended. Monitoring of the child is necessary to determine whether or not it is free of HIV infection and to monitor possible adverse effects of perinatal exposure to antiretroviral drugs.