An inferior vena cava discontinuity with an hepato-renal accessory vein development: A radio-anatomical morphometric case study.

PURPOSE: Inferior vena cava (IVC) agenesis is an uncommon congenital vascular anomaly stemming from aberrant development during embryogenesis. It results from the failure of one or more of the supracardinal veins, subcardinal veins, vitelline veins or postcardinal veins to connect. The symptomatology resulting from this vascular malformation can be either absent or extremely rich and varied. METHODS: Thoracoabdominal-pelvic CT scan projections following iodine-based contrast product injection were analyzed and a three-dimensional model of vascularization constructed. RESULTS: Herein, an asymptomatic case of IVC agenesis with absence of the suprarenal and renal segments, with azygos continuation, presenting an accessory hepatorenal vein is reported. The presence of this type of accessory vein has never been described in the literature to date. The etiology of this case of IVC agenesis is explored in depth. We also analyzed the morphometric parameters of the IVC remnant segments and the azygos vein in order to quantify the dilatation of the collateral venous pathway overdeveloped to handle blood return. CONCLUSION: Using the findings from this case and those reported in the literature, we provide general recommendations that should be taken into account before managing a patient, symptomatic or asymptomatic, admitted to the hospital with IVC agenesis.

Effects of diclofenac on sentinel species and aquatic communities in semi-natural conditions.

Due to the potential hazard of diclofenac on aquatic organisms and the lack of higher-tier ecotoxicological studies, a long-term freshwater mesocosm experiment was set up to study the effects of this substance on primary producers and consumers at environmentally realistic nominal concentrations 0.1, 1 and 10 µg/L (average effective concentrations 0.041, 0.44 and 3.82 µg/L). During the six-month exposure period, the biovolume of two macrophyte species (Nasturtium officinale and Callitriche platycarpa) significantly decreased at the highest treatment level. Subsequently, a decrease in dissolved oxygen levels was observed. High mortality rates, effects on immunity, and high genotoxicity were found for encaged zebra mussels (Dreissena polymorpha) in all treatments. In the highest treatment level, one month after the beginning of the exposure, mortality of adult fish (Gasterosteus aculeatus) caused effects on the final population structure. Total abundance of fish and the percentage of juveniles decreased whereas the percentage of adults increased. This led to an overall shift in the length frequency distribution of the F1 generation compared to the control. Consequently, indirect effects on the community structure of zooplankton and macroinvertebrates were observed in the highest treatment level. The No Observed Effect Concentration (NOEC) value at the individual level was < 0.1 µg/L and 1 µg/L at the population and community levels. Our study showed that in more natural conditions, diclofenac could cause more severe effects compared to those observed in laboratory conditions. The use of our results for regulatory matters is also discussed.

Involvement of SMAp in the intention-related long latency stretch reflex modulation: a TMS study.

When our movement is perturbed by environmental forces, the Long Latency Stretch Reflex (LLSR), generated by a transcortical loop through the primary motor cortex (M1), is the fastest reaction adapted according to our prior intent. We investigated the involvement of the caudal part of the Supplementary Motor Area (SMAp) in this intention-related LLSR modulation. Subjects were instructed either to not react (i.e. to 'let-go') or to resist a mechanical perturbation extending the wrist and Transcranial Magnetic Stimulation (TMS) was used to transiently inactivate SMAp, either at the time of the LLSR generation (TMS was applied 50 ms before the perturbation), or at the end of the preparation period (TMS was applied 150 ms before the perturbation). The effect of SMAp transient inactivation on the LLSR modulation was compared to the effect of transient inactivation of M1 or of a Control area. Compared to the Control condition, the intention-related LLSR modulation decreased when TMS was applied either over SMAp or over M1 50 ms before perturbation occurrence, suggesting that SMAp, as M1, is involved in the LLSR modulation. Moreover, the LLSR modulation also decreased when TMS was applied over SMAp 150 ms before the perturbation, indicating that anticipatory processes taking place in SMAp participate to the LLSR modulation. In addition, TMS applied over SMAp elicited Motor-Evoked Potentials (MEPs) whose latency and shape were similar to MEPs evoked by TMS over M1, suggesting that they are due to direct corticospinal projections from SMAp. Interestingly, the SMAp MEPs amplitude was modulated depending on the subject's intention to resist or to let-go. Taken together these results strongly favor the idea that, during the expectation of a perturbation, SMAp is the seat of anticipatory processes that are specific to the subject's intent and that preset M1 in order to adapt the LLSR to this intention.

In situ assessment of phytotechnologies for multicontaminated soil management.

Due to human activities, large volumes of soils are contaminated with organic pollutants such as polycyclic aromatic hydrocarbons, and very often by metallic pollutants as well. Multipolluted soils are therefore a key concern for remediation. This work presents a long-term evaluation of the fate and environmental impact of the organic and metallic contaminants of an industrially polluted soil under natural and plant-assisted conditions. A field trial was followed for four years according to six treatments in four replicates: unplanted, planted with alfalfa with or without mycorrhizal inoculation, planted with Noccaea caerulescens, naturally colonized by indigenous plants, and thermally treated soil planted with alfalfa. Leaching water volumes and composition, PAH concentrations in soil and solutions, soil fauna and microbial diversity, soil and solution toxicity using standardized bioassays, plant biomass, mycorrhizal colonization, were monitored. Results showed that plant cover alone did not affect total contaminant concentrations in soil. However, it was most efficient in improving the contamination impact on the environment and in increasing the biological diversity. Leaching water quality remained an issue because of its high toxicity shown by micro-algae testing. In this matter, prior treatment of the soil by thermal desorption proved to be the only effective treatment.

Perfluorooctanoic acid (PFOA) acts as a tumor promoter on Syrian hamster embryo (SHE) cells.

Perfluorooctane sulfonate (PFOS) (C(8)F(17)SO(3)) and perfluorooctanoic acid (PFOA) (C(8)HF(15)O(2)) are synthetic chemicals widely used in industrial applications for their hydrophobic and oleophobic properties. They are persistent, bioaccumulative, and toxic to mammalian species. Their widespread distribution on earth and contamination of human serum raised concerns about long-term side effects. They are suspected to be carcinogenic through a nongenotoxic mode of action, a mechanism supported by recent findings that PFOS induced cell transformation but no genotoxicity in Syrian hamster embryo (SHE) cells. In the present study, we evaluated carcinogenic potential of PFOA using the cell transformation assay on SHE cells. The chemical was applied alone or in combination with a nontransformant concentration of benzo[a]pyrene (BaP, 0.4 µM) in order to detect PFOA ability to act as tumor initiator or tumor promoter. The results showed that PFOA tested alone in the range 3.7 × 10(-5) to 300 µM did not induce SHE cell transformation frequency in a 7-day treatment. On the other side, the combination BaP/PFOA induced cell transformation at all PFOA concentrations tested, which revealed synergistic effects. No genotoxicity of PFOA on SHE cells was detected using the comet assay after 5 and 24 h of exposure. No significant increase in DNA breakage was found in BaP-initiated cells exposed to PFOA in a 7-day treatment. The whole results showed that PFOA acts as a tumor promoter and a nongenotoxic carcinogen. Cell transformation in initiated cells was observed at concentrations equivalent to the ones found in human serum of nonoccupationally and occupationally exposed populations. An involvement of PFOA in increased incidence of cancer recorded in occupationally exposed population cannot be ruled out.

Cortical mechanisms underlying stretch reflex adaptation to intention: a combined EEG-TMS study.

During voluntary motor acts, potential perturbations due to transient external forces are counteracted very quickly by short- and long-latency stretch reflexes (SLSR and LLSR, respectively). The LLSR, presumably linked to a transcortical loop, can be modulated by the subjects' intention. Here, we used combined TMS-EEG to study cortical mechanisms involved in this intention-related modulation both before and during the reaction to a mechanical perturbation. Subjects had to prepare for a brisk wrist extension under the instruction either to 'resist' the perturbation or to 'let-go'. Following the perturbation, the early cortical evoked activity (45-75 ms) was greater in the 'let-go' condition; moreover, its amplitude was negatively correlated with the LLSR amplitude, regardless of condition. After 100 ms the pattern reversed, the late evoked activity (presumably linked to the voluntary reaction) was greater in the 'resist' condition. The early and late evoked activities also differed in their topography. Therefore, the cortical mechanisms involved in the intention-related LLSR modulation differ from those involved in the voluntary reaction. In addition, in response to a single-pulse TMS delivered during the expectation of the mechanical perturbation, the TMS-evoked N100 amplitude decreased when subjects intended to 'let-go', suggesting anticipatory decreased activity of intracortical inhibitory sensorimotor networks. Taken together, these results support the idea that anticipatory processes preset the sensorimotor cortex so as to adapt its early reaction to the perturbation relative to the subjects' intention.

The influence of thermal desorption on genotoxicity of multipolluted soil.

A multipolluted soil sampled from a former coking plant in Lorraine (France) was evaluated for its genotoxic effects on coelomocytes of the Eisenia fetida earthworm using the comet assay. The biological efficiency of thermal desorption of the contaminated soil was also investigated. The untreated polluted soil was shown to be genotoxic to earthworms. Although thermal desorption reduced the concentration of PAHs by 94% (Sigma(16 PAHs)=1846 and 101 mg/kg before and after thermal desorption, respectively), the treatment did not eliminate the genotoxicity of soil pollutants to earthworms but increased it. The concentration of non-volatile metals did not change after thermal desorption. Among metals found in the treated soil, cadmium, chromium and nickel could explain the genotoxicity of the contaminated soil after thermal desorption. The treatment could increase the bioavailability and genotoxicity of heavy metals, through a modification of the soil's organic matter, the speciation of heavy metals and their binding to organic matter. This study underlines the importance of measuring biological effects, in order to evaluate the risk associated with formerly contaminated soils and the efficiency of remediation.

Prior intention can locally tune inhibitory processes in the primary motor cortex: direct evidence from combined TMS-EEG.

Human subjects are able to prepare cognitively to resist an involuntary movement evoked by a suprathreshold transcranial magnetic stimulation (TMS) applied over the primary motor cortex (M1) by anticipatory selective modulation of corticospinal excitability. Uncovering how the sensorimotor cortical network is involved in this process could reveal directly how a prior intention can tune the intrinsic dynamics of M1 before any peripheral intervention. Here, we used combined TMS-EEG to study the cortical integrative processes that are engaged both in the preparation to react to TMS (Resist vs. Assist) and in the subsequent response to it. During the preparatory period, the contingent negative variation (CNV) amplitude was found to be smaller over central electrodes (FC1, C1, Cz) when preparing to resist compared with preparing to assist the evoked movement whereas alpha-oscillation power was similar in the two conditions. Following TMS, the amplitude of the TMS evoked-N100 component was higher in the Resist than in the Assist condition for some central electrodes (FCz, C1, Cz, CP1, CP3). Moreover, for six out of eight subjects, a single-trial-based analysis revealed a negative correlation between CNV amplitude and N100 amplitude. In conclusion, prior intention can tune the excitability of M1. When subjects prepare to resist a TMS-evoked movement, the anticipatory processes cause a decreased cortical excitability by locally increasing the inhibitory processes.

[Acetaminophene-induced hypotension in intensive care unit: a prospective study]. / Etude prospective de l'incidence des hypotensions artérielles induites par l'injection intraveineuse de paracétamol en réanimation.

OBJECTIVES: The aim of this study was to evaluate the incidence of paracetamol-induced hypotension in intensive care unit (ICU). The secondary end-point was the description of pathophysiologic phenomenon during this hypotension and risk factors. STUDY DESIGN: An observational study in three ICU of a French teaching hospital. PATIENTS AND METHODS: All consecutives patients whom benefit from intravenous paracetamol administration were included in the study. When a 20% droop in arterial blood pressure occurred, plasma samples were obtained and tryptases were measured at 6 and 48 hours. Clinical, biological characteristics and paracetamol administration duration were prospectively monitored. RESULTS: During a 2-months period, 127 ICU patients were included in the study with 1507 paracetamol administration. Twenty droops in arterial blood pressure were recorded in ICU. The incidence rate was 1.33%. Administration duration was 32+/-9 min. No respiratory nor cutaneous manifestations occurred during hypotensions. A specific treatment was administrated in half of the patients. Hypotension incidence was higher (3.9%) in patients with brain injury. Eighty percent of patients with hypotension have a severe sepsis or a septic shock. CONCLUSION: In this cohort of ICU patients, hypotension incidence was higher than reported in drug legal mentions. Immunoallergic phenomenon was excluded. Brain injury and sepsis seems to be risk factors.

Bioavailability of chemical pollutants in contaminated soils and pitfalls of chemical analyses in hazard assessment.

Decision-making for remediation of industrial wastelands are still based on the concentrations of pollutants of concern measured in soils. In this work, two soils polluted by polycyclic aromatic hydrocarbons (PAHs) and metals were investigated for their toxicity on earthworms (Eisenia fetida), collembolae (Folsomia candida), and higher plants (Brassica chinensis, Lactucca sativa and Avena sativa) in order to study the relationships between chemical contamination and biological effects. Although the level of contamination by PAHs was elevated and commensurate in the two soils, their toxicity profile was quite different. Soil A affected survival and reproduction of invertebrates and growth of higher plants. Surprisingly, soil B, heavily contaminated by metals in addition to PAHs, was devoid of toxicity. Our results indicate that toxicity cannot simply be extrapolated from pollutant concentrations in a complex matrix in which bioavailability of pollutants may be reduced by ageing. Moreover, the use of toxicity data obtained from spiked soils characterized by readily bioavailable pollutants can also be called into question for such extrapolations. Predicting biological effects therefore requires biological tools to avoid any erroneous conclusions that can be drawn from sole extrapolation of analytical results.

Corticospinal control of the thumb-index grip depends on precision of force control: a transcranial magnetic stimulation and functional magnetic resonance imagery study in humans.

The corticospinal system (CS) is well known to be of major importance for controlling the thumb-index grip, in particular for force grading. However, for a given force level, the way in which the involvement of this system could vary with increasing demands on precise force control is not well-known. Using transcranial magnetic stimulation and functional magnetic resonance imagery, the present experiments investigated whether increasing the precision demands while keeping the averaged force level similar during an isometric dynamic low-force control task, involving the thumb-index grip, does affect the corticospinal excitability to the thumb-index muscles and the activation of the motor cortices, primary and non-primary (supplementary motor area, dorsal and ventral premotor and in the contralateral area), at the origin of the CS. With transcranial magnetic stimulation, we showed that, when precision demands increased, the CS excitability increased to either the first dorsal interosseus or the opponens pollicis, and never to both, for similar ongoing electromyographic activation patterns of these muscles. With functional magnetic resonance imagery, we demonstrated that, for the same averaged force level, the amplitude of blood oxygen level-dependent signal increased in relation to the precision demands in the hand area of the contralateral primary motor cortex in the contralateral supplementary motor area, ventral and dorsal premotor area. Together these results show that, during the course of force generation, the CS integrates online top-down information to precisely fit the motor output to the task's constraints and that its multiple cortical origins are involved in this process, with the ventral premotor area appearing to have a special role.

Stride variability in human gait: the effect of stride frequency and stride length.

This study focused on spatial and temporal variability of the stride in human gait. We determined the role of stride frequency (F) and stride length (L) on those parameters. Eight healthy subjects walked on a treadmill using 25 different FL combinations (0.95

Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappaB-dependent gene transcription.

Induction of NF-kappaB-dependent transcription requires phosphorylation and subsequent degradation of I-kappaB, an inhibitor of NF-kappaB, followed by nuclear translocation and DNA binding of NF-kappaB. Tumor necrosis factor receptor-associated factor 2 (TRAF2) plays a role in NF-kappaB activation in response to cytokines such as tumor necrosis factor alpha (TNFalpha). In this study, we purified and characterized a novel kinase (T2K, also known as TBK1 or NAK), which associates with TRAF2 and exhibits kinase activity towards I-kappaBalpha in vitro. The physiological function of T2K was investigated using T2K-deficient mice. Heterozygotes appear normal, but t2k(-/-) animals die at approximately E14.5 of massive liver degeneration and apoptosis. Never theless, hematopoietic progenitors from T2K-deficient fetal liver support normal lymphocyte development. Furthermore, t2k(-/-) embryonic fibroblasts and thymocytes do not display increased sensitivity to TNFalpha-induced apoptosis. In response to either TNFalpha or IL-1 induction, t2k(-/-) embryonic fibroblasts exhibit normal degradation of I-kappaB and kappaB-binding activity. However, NF-kappaB-directed transcription is dramatically reduced. These results demonstrate that, like I-kappaB kinase beta and the RelA subunit of NF-kappaB, T2K is critical in protecting embryonic liver from apoptosis. However, T2K has a unique role in the activation of NF-kappaB-directed transcription, apparently independent of I-kappaB degradation and NF-kappaB DNA binding.

Adaptation of neuromuscular synergies during intentional constraints of space-time relationships in human gait.

Tight frequency-to-amplitude relationships are observed in spontaneous human steady gait. They can be modified, if required; that flexibility forms a fundamental basis of the intentional adaptive capabilities of locomotion. In the present experiments, the processes underlying that flexibility were investigated at both the level of joint kinematics and the level of neuromuscular synergies. Subjects (N = 4) walked at the same speed either with a preferred or a nonpreferred frequency-to-amplitude relationship (i.e., constrained, short steps at a high frequency [COS condition] or constrained, long steps at a low frequency [COL condition]); their swing and stance phases were separately analyzed. In the COS condition, increases in EMG activity were specifically required during the swing phase. In the COL condition, several muscles required increases in EMG activity during the stance phase, but decreases of the hamstring muscles were needed during the swing phase. Whereas, in preferred walking, modification of the frequency affects the EMG patterns globally (the gain increasing with the frequency in both the stance and swing phases), the present results show that changing the frequency in a constrained manner either affects the swing phase specifically or affects both phases, but in the opposite direction. That finding indicates that a separate control is needed in both the swing and the stance phases.

Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic development.

Casper (c-FLIP) associates with FADD and caspase-8 in signaling complexes downstream of death receptors like Fas. We generated Casper-deficient mice and cells and noted a duality in the physiological functions of this molecule. casper-/- embryos do not survive past day 10.5 of embryogenesis and exhibit impaired heart development. This phenotype is reminiscent of that reported for FADD-/- and caspase-8-/- embryos. However, unlike FADD-/- and caspase-8-/- cells, casper-/- embryonic fibroblasts are highly sensitive to FasL- or TNF-induced apoptosis and show rapid induction of caspase activities. NF-kappaB and JNK/SAPK activation is intact in TNF-stimulated casper-/- cells. These results suggest that Casper has two distinct roles: to cooperate with FADD and caspase-8 during embryonic development and to mediate cytoprotection against death factor-induced apoptosis.

Protein kinase B regulates T lymphocyte survival, nuclear factor kappaB activation, and Bcl-X(L) levels in vivo.

The serine/threonine kinase protein kinase B (PKB)/Akt mediates cell survival in a variety of systems. We have generated transgenic mice expressing a constitutively active form of PKB (gag-PKB) to examine the effects of PKB activity on T lymphocyte survival. Thymocytes and mature T cells overexpressing gag-PKB displayed increased active PKB, enhanced viability in culture, and resistance to a variety of apoptotic stimuli. PKB activity prolonged the survival of CD4(+)CD8(+) double positive (DP) thymocytes in fetal thymic organ culture, but was unable to prevent antigen-induced clonal deletion of thymocytes expressing the major histocompatibility complex class I-restricted P14 T cell receptor (TCR). In mature T lymphocytes, PKB can be activated in response to TCR stimulation, and peptide-antigen-specific proliferation is enhanced in T cells expressing the gag-PKB transgene. Both thymocytes and T cells overexpressing gag-PKB displayed elevated levels of the antiapoptotic molecule Bcl-X(L). In addition, the activation of peripheral T cells led to enhanced nuclear factor (NF)-kappaB activation via accelerated degradation of the NF-kappaB inhibitory protein IkappaBalpha. Our data highlight a physiological role for PKB in promoting survival of DP thymocytes and mature T cells, and provide evidence for the direct association of three major survival molecules (PKB, Bcl-X(L), and NF-kappaB) in vivo in T lymphocytes.

Intentional on-line adaptation of stride length in human walking.

The intentional control of stride length is a fundamental basis for the adaptation of the stride to environmental constraints (obstacle avoidance, for example). Controlling the propulsive forces during the stance and/or controlling the pendular movement of the oscillating leg constitute the two potential and non-exclusive mechanisms underlying intentional stride length modulation. The present experiment was conducted in order to determine if these two mechanisms contribute to voluntary length modulation and, if so, how they cooperate according to whether the subject has to lengthen or shorten a stride and how these mechanisms are implemented at the neuromuscular level. Subjects had to produce a temporarily modulated stride of the same length, but originating from two different initial steady-states: one from shorter stride length and one from longer stride length. We found that the shortening was essentially realized by a swing-duration decrease (an increased activity in the hip extensor--biceps femoris--during the swing of the ipsilaterally shortened stride stopped the pendular leg movement earlier). The lengthening was realized by two mechanisms: (1) an increase in the propulsive forces (via an increased activity of the ankle extensor muscles--soleus--and the hip extensors--biceps femoris--from the stance of the ipsilaterally modulated stride, which was prolonged during the following stance of the contralateral leg), and (2) an increase in swing duration on the ipsilateral leg (an increased activity in hip and ankle flexors--rectus femoris and tibialis anterior--maintained the ipsilateral leg in flexion during the lengthened swing so that the foot landed later). In this experiment, the subjects were faced with a spatial constraint of the same magnitude in the direction of stride lengthening and stride shortening. However, under these conditions, subjects used a different balance between swing control (that directly modifies the foot trajectory without affecting the trajectory of the head-arm-trunk system) and/or the control of propulsive forces (that indirectly influences foot trajectory by modifying the trajectory of the head-arm-trunk system). In the first case, this concerns a voluntary control of gesture produced by the legs and usually implicated in the locomotor pointing; in the second case, this concerns a voluntary control of propulsive forces.

Contribution of proprioceptive information to preferred versus constrained space-time behavior in rhythmical movements.

Rhythmical movements are well-known to exhibit spontaneous and well-defined relationships between frequency and amplitude (preferred behavior). However, if required, these relationships can be modified (constrained behavior). This flexibility constitutes a fundamental basis for adapting motor functions to the subject's intentions in a given environment. In order to assess the role of proprioceptive information in the stabilization of preferred versus constrained rhythmical movements, we compared both cases in a deafferented patient and in a control group. Initially, the subjects were given as much time as they needed to adopt different, steady rhythmical movements in the presence of external feedback. Afterwards, the feedback was suppressed and the subjects had to maintain the same oscillating regimes for one additional minute. In the absence of feedback, the deafferented patient was able to stabilize the timing of both the preferred and the constrained movements. The spatial properties remained stationary for the preferred movements; however, large effects were observed in the constrained movements. By contrast, the control subjects were able to keep both the preferred and the constrained behaviors stationary. Our results show that, when reaching preferred regimes, the behavior remains stationary even in the absence of proprioceptive information. By contrast, proprioceptive feedbacks were shown to be necessary in order to maintain non-preferred regimes. In this case, error-correction mechanisms based on proprioceptive information allows for compensation of the natural tendency of the system to return to its preferred behavior.

Positive association of the HLA DMB1*0101-0101 genotype with rheumatoid arthritis.

OBJECTIVE: HLA DM is a non-classical major histocompatibility complex (MHC) class II molecule that has been shown to facilitate peptide loading with classical class II molecules. METHODS: In this study, we analysed the polymorphism in exon 3 of HLA DMA and DMB genes by a polymerase chain reaction-sequence-specific oligonucleotide probe method in 163 rheumatoid arthritis (RA) patients and 146 ethnically matched controls. The HLA-DRB1 genotype was also analysed by a reverse-dot blot method. RESULTS: Our results show in RA patients a significant increase in the HLA DMB*0101 allele frequency (83% vs 72.3% of the controls, P < 1.6 x 10(-3), significance at P < 0.0125) and in the HLA DMB*0101-0101 homozygote genotype frequency [70.8% vs 50% of the controls, P < 4.2 x 10(-4), significance at P < 0.00625, odds ratio (OR) = 2.4, 95% confidence interval (CI): 1.43-4]. The increase in DMB*0101 allele and homozygote genotype frequencies was independent of a linkage disequilibrium between DMB and DRB1 alleles. The analysis of non-random associations between the HLA-DM and DRB1 alleles only revealed a significant association in controls between DMB*0104 and DRB1*07 alleles (delta = 0.01, P < 7 x 10(-4), significance at P < 9.6 x 10(-4)). On the other hand, the DMB*0101-0102 genotype frequency was increased in DRB1*0401-negative RA patients as compared to controls (11% vs 2%, P < 0.011, significance at P < 0.015, OR = 6.2, 95% CI: 1.2-30). CONCLUSION: Our data suggest that HLA-DM alleles could play a role in the genetic susceptibility to RA.

CD4-mediated inhibiton of IL-2 production in activated T cells.

The role of CD4 in T cell activation has been attributed to its capacity to increase the avidity of interaction with APC and to shuttle associated Lck to the TCR/CD3 activation complex. The results presented in this study demonstrate that ligation of CD4 inhibits ongoing responses of preactivated T cells. Specifically, delayed addition of CD4-specific mAb is shown to inhibit Ag- or mAb-induced responses of both primary T cells and T cell clonal variants. The Ag responses of the latter are independent of the adhesion provided by CD4; thus the observed inhibition is not due to blocking CD4-MHC interactions. Further, analysis of the clonal variants demonstrates that CD4-associated Lck is not essential for the inhibition observed, as anti-CD4 inhibits responses of clonal variants, expressing a form of CD4 unable to associate with Lck (double cysteine-mutated CD4). The inhibition is counteracted by the addition of exogenous IL-2, demonstrating that the block is not due to a lesion in IL-2 utilization, rather its production. It is demonstrated that the delayed addition of anti-CD4 results in a rapid reduction in steady-state levels of IL-2 mRNA in both primary T cells and clonal variants.