The combination of kidney function variables with cell cycle arrest biomarkers identifies distinct subphenotypes of sepsis-associated acute kidney injury: a post-hoc analysis (the PHENAKI study).

BACKGROUND: The severity and course of sepsis-associated acute kidney injury (SA-AKI) are correlated with the mortality rate. Early detection of SA-AKI subphenotypes might facilitate the rapid provision of individualized care. PATIENTS AND METHODS: In this post-hoc analysis of a multicenter prospective study, we combined conventional kidney function variables with serial measurements of urine (tissue inhibitor of metalloproteinase-2 [TIMP-2])* (insulin-like growth factor-binding protein [IGFBP7]) at 0, 6, 12, and 24 h) and then using an unsupervised hierarchical clustering of principal components (HCPC) approach to identify different phenotypes of SA-AKI. We then compared the subphenotypes with regard to a composite outcome of in-hospital death or the initiation of renal replacement therapy (RRT). RESULTS: We included 184 patients presenting SA-AKI within 6 h of the initiation of catecholamines. Three distinct subphenotypes were identified: subphenotype A (99 patients) was characterized by a normal urine output (UO), a low SCr and a low [TIMP-2]*[IGFBP7] level; subphenotype B (74 patients) was characterized by existing chronic kidney disease (CKD), a higher SCr, a low UO, and an intermediate [TIMP-2]*[IGFBP7] level; and subphenotype C was characterized by very low UO, a very high [TIMP-2]*[IGFBP7] level, and an intermediate SCr level. With subphenotype A as the reference, the adjusted hazard ratio (aHR) [95%CI] for the composite outcome was 3.77 [1.92-7.42] (p < 0.001) for subphenotype B and 4.80 [1.67-13.82] (p = 0.004) for subphenotype C. CONCLUSIONS: Combining conventional kidney function variables with urine measurements of [TIMP-2]*[IGFBP7] might help to identify distinct SA-AKI subphenotypes with different short-term courses and survival rates.

Correction to: Urine cell cycle arrest biomarkers distinguish poorly between transient and persistent AKI in early septic shock: a prospective, multicenter study.

An amendment to this paper has been published and can be accessed via the original article.

Urine cell cycle arrest biomarkers distinguish poorly between transient and persistent AKI in early septic shock: a prospective, multicenter study.

BACKGROUND: The urine biomarkers tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) have been validated for predicting and stratifying AKI. In this study, we analyzed the utility of these biomarkers for distinguishing between transient and persistent AKI in the early phase of septic shock. METHODS: We performed a prospective, multicenter study in 11 French ICUs. Patients presenting septic shock, with the development of AKI within the first 6 h, were included. Urine [TIMP-2]*[IGFBP7] was determined at inclusion (0 h), 6 h, 12 h, and 24 h. AKI was considered transient if it resolved within 3 days. Discriminative power was evaluated by receiver operating characteristic (ROC) curve analysis. RESULTS: We included 184 patients, within a median [IQR] time of 1.0 [0.0-3.0] h after norepinephrine (NE) initiation; 100 (54%) patients presented transient and 84 (46%) presented persistent AKI. Median [IQR] baseline urine [TIMP-2]*[IGFBP7] was higher in the persistent AKI group (2.21 [0.81-4.90] (ng/ml)2/1000) than in the transient AKI group (0.75 [0.20-2.12] (ng/ml)2/1000; p < 0.001). Baseline urine [TIMP-2]*[IGFBP7] was poorly discriminant, with an AUROC [95% CI] of 0.67 [0.59-0.73]. The clinical prediction model combining baseline serum creatinine concentration, baseline urine output, baseline NE dose, and baseline extrarenal SOFA performed well for the prediction of persistent AKI, with an AUROC [95% CI] of 0.81 [0.74-0.86]. The addition of urine [TIMP-2]*[IGFBP7] to this model did not improve the predictive performance. CONCLUSIONS: Urine [TIMP-2]*[IGFBP7] measurements in the early phase of septic shock discriminate poorly between transient and persistent AKI and do not improve clinical prediction over that achieved with the usual variables. TRIAL REGISTRATION: NCT02812784.

Respiratory Variability of Pulmonary Velocity-Time Integral As a New Gauge of Fluid Responsiveness For Mechanically Ventilated Patients in the ICU.

OBJECTIVES: To evaluate reliability and feasibility of the respiratory variability of pulmonary velocity-time integral as a new dynamic marker of fluid responsiveness in mechanically ventilated patients. DESIGN: Prospective observational study. SETTING: Medical-surgical ICU of a general hospital. PATIENTS: Fifty mechanically ventilated patients with acute circulatory failure. INTERVENTIONS: Transthoracic echocardiography was performed at inclusion (transthoracic echocardiography baseline). Fluid therapy was prescribed to patients exhibiting one value greater than or equal to 13% among commonly used variables of fluid responsiveness: respiratory variability of aortic velocity-time integral, respiratory variability of inferior vena cava diameter, or pulse pressure variation. MEASUREMENTS AND MAIN RESULTS: Respiratory variability of pulmonary velocity-time integral was assessed at baseline. Respiratory variability of pulmonary velocity-time integral was significantly greater in patients who received fluid therapy (26.9 ± 12.5% vs 6.2 ± 4.3%; p < 0.0001). Respiratory variability of pulmonary velocity-time integral was correlated with respiratory variability of aortic velocity-time integral (r = 0.75; p < 0.0001), respiratory variability of inferior vena cava diameter (r = 0.42; p < 0.01), and pulse pressure variation (r = 0.87; p < 0.0001) at baseline and with the relative increase in cardiac output after fluid therapy (r = 0.44; p = 0.019). Fluid responsiveness was defined as a 10% increase in cardiac output after fluid therapy, assessed by a second transthoracic echocardiography. Respiratory variability of pulmonary velocity-time integral was associated with fluid responsiveness (adjusted odds ratio, 1.58; 95% CI, 1.08-2.32; p = 0.002). Area under the receiver operating characteristics curve was 0.972, and a value of respiratory variability of pulmonary velocity-time integral greater than or equal to 14% yielded a sensitivity of 92% and specificity of 87% to predict fluid responsiveness. Interobserver reproducibility was excellent (intraclass correlation coefficient = 0.94). CONCLUSIONS: Respiratory variability of pulmonary velocity-time integral is a simple and reliable marker of fluid responsiveness for ventilated patients in ICU.

Value and determinants of the mean systemic filling pressure in critically ill patients.

Mean systemic filling pressure (Pmsf) is a major determinant of venous return. Its value is unknown in critically ill patients (ICU). Our objectives were to report Pmsf in critically ill patients and to look for its clinical determinants, if any. We performed a prospective study in 202 patients who died in the ICU with a central venous and/or arterial catheter. One minute after the heart stopped beating, intravascular pressures were recorded in the supine position after ventilator disconnection. Parameters at admission, during the ICU stay, and at the time of death were prospectively collected. One-minute Pmsf was 12.8 ± 5.6 mmHg. It did not differ according to gender, severity score, diagnosis at admission, fluid balance, need for and duration of mechanical ventilation, or length of stay. Nor was there any difference according to suspected cause of death, classified as shock (cardiogenic, septic, and hemorrhagic) and nonshock, although a large variability of values was observed. The presence of norepinephrine at the time of death (102 patients) was associated with a higher 1-min Pmsf (14 ± 6 vs. 11.4 ± 4.5 mmHg), whereas the decision to forgo life-sustaining therapy (34 patients) was associated with a lower 1-min Pmsf (10.9 ± 3.8 vs. 13.1 ± 5.3 mmHg). In a multiple-regression analysis, norepinephrine (ß = 2.67, P = 0.0004) and age (ß = -0.061, P = 0.022) were associated with 1-min Pmsf. One-minute Pmsf appeared highly variable without any difference according to the kind of shock and fluid balance, but was higher with norepinephrine.

Therapeutic hypothermia after nonshockable cardiac arrest: the HYPERION multicenter, randomized, controlled, assessor-blinded, superiority trial.

BACKGROUND: Meta-analyses of nonrandomized studies have provided conflicting data on therapeutic hypothermia, or targeted temperature management (TTM), at 33°C in patients successfully resuscitated after nonshockable cardiac arrest. Nevertheless, the latest recommendations issued by the International Liaison Committee on Resuscitation and by the European Resuscitation Council recommend therapeutic hypothermia. New data are available on the adverse effects of therapeutic hypothermia, notably infectious complications. The risk/benefit ratio of therapeutic hypothermia after nonshockable cardiac arrest is unclear. METHODS: HYPERION is a multicenter (22 French ICUs) trial with blinded outcome assessment in which 584 patients with successfully resuscitated nonshockable cardiac arrest are allocated at random to either TTM between 32.5 and 33.5°C (therapeutic hypothermia) or TTM between 36.5 and 37.5°C (therapeutic normothermia) for 24 hours. Both groups are managed with therapeutic normothermia for the next 24 hours. TTM is achieved using locally available equipment. The primary outcome is day-90 neurological status assessed by the Cerebral Performance Categories (CPC) Scale with dichotomization of the results (1 + 2 versus 3 + 4 + 5). The primary outcome is assessed by a blinded psychologist during a semi-structured telephone interview of the patient or next of kin. Secondary outcomes are day-90 mortality, hospital mortality, severe adverse events, infections, and neurocognitive performance. The planned sample size of 584 patients will enable us to detect a 9% absolute difference in day-90 neurological status with 80% power, assuming a 14% event rate in the control group and a two-sided Type 1 error rate of 4.9%. Two interim analyses will be performed, after inclusion of 200 and 400 patients, respectively. DISCUSSION: The HYPERION trial is a multicenter, randomized, controlled, assessor-blinded, superiority trial that may provide an answer to an issue of everyday relevance, namely, whether TTM is beneficial in comatose patients resuscitated after nonshockable cardiac arrest. Furthermore, it will provide new data on the tolerance and adverse events (especially infectious complications) of TTM at 32.5-33.5°C. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01994772 .

Prospective assessment of a score for assessing basic critical-care transthoracic echocardiography skills in ventilated critically ill patients.

BACKGROUND: We studied a score for assessing basic transthoracic echocardiography (TTE) skills exhibited by residents who examined critically ill patients receiving mechanical ventilation. METHODS: We conducted a prospective study in the 16 residents who worked in our medical-surgical ICU between 1 May 2008 and 1 November 2009. The residents received theoretical teaching (two hours) then performed supervised TTEs during their six-month rotation. Their basic TTE skills in mechanically ventilated patients were evaluated after one (M1), three (M3), and six (M6) months by two experts, who used a scoring system devised for the study. After scoring, residents gave their hemodynamic diagnosis and suggested a treatment. RESULTS: The 4 residents with previous TTE skills obtained a significantly higher total score than did the 12 novices at M1 (18 (16 to 19) versus 13 (10 to 15), respectively, P = 0.03). In the novices, the total score increased significantly during training (M1, 13 (10 to 14); M3, 15 (12 to 16); and M6, 17 (15 to 18); P < 0.001) and correlated significantly with the number of supervised TTEs (r = 0.68, P < 0.0001). In the overall population, agreement with experts regarding the diagnosis and treatment was associated with a significantly higher total score (17 (16 to 18) versus 13 (12 to 16), P = 0.002). A total score ≥ 19/20 points had 100% specificity (95% confidence interval, 79 to 100%) for full agreement with the experts regarding the diagnosis and treatment. CONCLUSIONS: Our results validate the scoring system developed for our study of the assessment of basic critical-care TTE skills in residents.

Pulse pressure variations to guide fluid therapy in donors: a multicentric echocardiographic observational study.

PURPOSE: Preload responsiveness parameters could be useful in the hemodynamic management of septic shock. METHODS: A multicentric prospective echocardiographic observational study was conducted from March 2009 to August 2011. Clinically brain-dead subjects were included. Pulse pressure variations (ΔPPs) were recorded. Cardiac index, variation of the maximum flow velocity of aortic systolic blood flow, and right ventricular function parameters were evaluated via transthoracic echocardiography. Fluid responsiveness was defined by at least 15% cardiac index increase, 30 minutes after a 500-mL colloid solution infusion. The number of organs harvested was recorded. RESULTS: Twenty-five subjects were included. Pulse pressure variation could not discriminate responders (n=15) from nonresponders (n=10). The best ΔPP threshold (20%) could discriminate responders with a sensitivity of 100% and a specificity of 40%. Variation of the maximum flow velocity of aortic systolic blood flow, tricuspid annular plane systolic excursion, and right ventricle dilation could not discriminate responders from nonresponders. Eighteen subjects underwent organ harvesting. The number of organs harvested was higher in responders (3.5 [3-5]) than in nonresponders (2.5 [2-3]; P=.03). CONCLUSIONS: A ΔPP threshold of 13% is insufficient to guide volume expansion in donors. The best threshold is 20%. Fluid responsiveness monitoring could enhance organ harvesting.

Echocardiography: a help in the weaning process.

INTRODUCTION: To evaluate the ability of transthoracic echocardiography (TTE) to detect the effects of spontaneous breathing trial (SBT) on central hemodynamics and to identify indices predictive of cardiac-related weaning failure. METHODS: TTE was performed just before and at the end of a 30-min SBT in 117 patients fulfilling weaning criteria. Maximal velocities of mitral E and A waves, deceleration time of E wave (DTE), maximal velocity of E' wave (tissue Doppler at the lateral mitral annulus), and left ventricular (LV) stroke volume were measured. Values of TTE parameters were compared between baseline (pressure support ventilation) and SBT in all patients and according to LV ejection fraction (EF): >50% (n = 58), 35% to 50% (n = 30), and <35% (n = 29). Baseline TTE indices were also compared between patients who were weaned (n = 94) and those who failed (n = 23). RESULTS: Weaning failure was of cardiac origin in 20/23 patients (87%). SBT resulted in a significant increase in cardiac output and E/A, and a shortened DTE. At baseline, DTE was significantly shorter in patients with LVEF <35% when compared to other subgroups (median [25th-75th percentiles]: 119 ms [90-153]; vs. 187 ms [144-224] vs. 174 ms [152-193]; P < 0.01) and E/E' was greater (7.9 [5.4-9.1] vs. 6.0 [5.3-9.0] vs. 5.2 [4.7-6.0]; P < 0.01). When compared to patients who were successfully weaned, those patients who failed exhibited at baseline a significantly lower LVEF (36% [27-55] vs. 51% [43-55]: P = 0.04) and higher E/E' (7.0 [5.0-9.2] vs. 5.6 [5.2-6.3]: P = 0.04). CONCLUSIONS: TTE detects SBT-induced changes in central hemodynamics. When performed by an experienced operator prior to SBT, TTE helps in identifying patients at high risk of cardiac-related weaning failure when documenting a depressed LVEF, shortened DTE and increased E/E'. Further studies are needed to evaluate the impact of this screening strategy on the weaning process and patient outcome.

Acute aortic dissection detected by contrast echocardiography.

We describe the case of a man with acute aortic dissection detected by contrast transthoracic echocardiography. Conventional echocardiography was not contributory. To our knowledge, this is the first report of the usefulness of contrast echocardiography in ascending aortic dissection at bedside.

Actual incidence of global left ventricular hypokinesia in adult septic shock.

RATIONALE AND OBJECTIVE: To evaluate the actual incidence of global left ventricular hypokinesia in septic shock. METHOD: All mechanically ventilated patients treated for an episode of septic shock in our unit were studied by transesophageal echocardiography, at least once a day, during the first 3 days of hemodynamic support. In patients who recovered, echocardiography was repeated after weaning from vasoactive agents. Main measurements were obtained from the software of the apparatus. Global left ventricular hypokinesia was defined as a left ventricular ejection fraction of <45%. MEASUREMENTS AND MAIN RESULTS: During a 3-yr period (January 2004 through December 2006), 67 patients free from previous cardiac disease, and who survived for >48 hrs, were repeatedly studied. Global left ventricular hypokinesia was observed in 26 of these 67 patients at admission (primary hypokinesia) and in 14 after 24 or 48 hrs of hemodynamic support by norepinephrine (secondary hypokinesia), leading to an overall hypokinesia rate of 60%. Left ventricular hypokinesia was partially corrected by dobutamine, added to a reduced dosage of norepinephrine, or by epinephrine. This reversible acute left ventricular dysfunction was not associated with a worse prognosis. CONCLUSION: Global left ventricular hypokinesia is very frequent in adult septic shock and could be unmasked, in some patients, by norepinephrine treatment. Left ventricular hypokinesia is usually corrected by addition of an inotropic agent to the hemodynamic support.

Hemodynamic effects of passive leg raising: an echocardiographic study in patients with shock.

OBJECTIVES: To determine the effects of passive leg raising (PLR) on hemodynamics and on cardiac function according to the preload dependency defined by the superior vena cava collapsibility index (DeltaSVC). RESULTS: Forty patients with shock, sedated and mechanically ventilated, were included. Transesophageal echocardiography was performed. At baseline (T1), two groups were defined according to DeltaSVC. Eighteen patients presenting a DeltaSVC > 36%, an indicator of preload dependency, formed group 1, whereas 22 patients (group 2) exhibited a DeltaSVC < 30% (not preload-dependent). Measurements were then performed during PLR (T2), back to baseline (T3), and after volume expansion (T4) in group 1 only. At T1, DeltaSVC was significantly higher in group 1 than in group 2, 50 +/- 9% and 7 +/- 6%, respectively. In group 1, we found a decrease in DeltaSVC at T2 (24 +/- 9%) and T4 (17 +/- 7%), associated with increased systolic, diastolic and arterial pulse pressures. Cardiac index also increased, from 1.92 +/- 0.74 (T1) to 2.35 +/- 0.92 (T2) and 2.85 +/- 1.2 l/min/m(2) (T4) and left ventricular end-diastolic volume from 51 +/- 41 to 61 +/- 51 and 73 +/- 51 ml/m(2). None of these variations was found in group 2. No change in heart rate was observed. CONCLUSION: Hemodynamic changes related to PLR were only induced by increased cardiac preload.

Prone positioning unloads the right ventricle in severe ARDS.

BACKGROUND: Despite airway pressure limitation, acute cor pulmonale persists in a minority of ARDS patients. Insufficient airway pressure limitation, hypercapnia, or both may be responsible. Because prone positioning (PP) has been shown to be a safe way to reduce airway pressure and to improve alveolar ventilation, we decided to assess its effect on right ventricular (RV) pressure overload in ARDS patients. METHODS: Between January 1998 and December 2006, we studied 42 ARDS patients treated by PP to correct severe oxygenation impairment (Pao2/fraction of inspired oxygen ratio, <100 mm Hg). RV function was evaluated by bedside transesophageal echocardiography, before and after 18 h of prone-position ventilation. RV enlargement was measured by RV/left ventricular (LV) end-diastolic area ratio in the long axis. Septal dyskinesia was quantified by measuring short-axis systolic eccentricity of the LV. RESULTS: Before PP, 21 patients (50%) had acute cor pulmonale, defined by RV enlargement associated with septal dyskinesia (group 1), whereas 21 patients had a normal RV (group 2). PP was accompanied by a significant decrease in airway pressure and Paco2. In group 1, this produced a significant decrease in mean (+/-SD) RV enlargement (from 0.91+/-0.22 to 0.61+/-0.21) after 18 h of PP (p=0.000) and a significant reduction in mean septal dyskinesia (from 1.5+/-0.2 to 1.1+/-0.1) after 18 h of PP (p=0.000). CONCLUSION: In the most severe forms of ARDS, PP was an efficient means of controlling RV pressure overload.

Validation of a skills assessment scoring system for transesophageal echocardiographic monitoring of hemodynamics.

OBJECTIVE: Transesophageal echocardiography (TEE) is increasingly used in hemodynamic monitoring in the intensive care unit. This paper describes and validates a scoring system for assessing competence in TEE performed by intensivists for this indication. DESIGN: Prospective study over an 18-month period. SETTINGS: Two medical intensive care units. METHODS: The scoring system is used to assess four aspects of TEE: quality of the views (score out of 14); semiquantitative evaluation of respiratory variations in the superior vena cava, valve regurgitation, size of the right ventricle (score out of 10); accuracy of measurement of velocity-time integrals for pulmonary and aortic flow, peak velocity of the E and A waves of mitral flow, left ventricular fractional area change (score out of 8); summary and proposed treatment (score out of 8). The scoring system was validated by using it to assess intensivists after 1 month (M1), 3 months (M3) and 6 months (M6) of training. TEE was done on a mechanically ventilated, hypotensive patient and scored by comparing the intensivist's examination with that of the expert examiner. The intensivists were divided into two groups of theoretical expertise at the start of training. RESULTS: Nineteen intensivists were evaluated. The scores at M1 for level 0 (no experience in echocardiography) and level 1 (previous experience) were, respectively, 18.5 +/- 4 and 24.7 +/- 5. The scores at M1, M3, and M6 were, respectively, 20.4 +/- 5, 30.4 +/- 5 and 35.7 +/- 3. At M6, the intensivists had performed TEE 29 +/- 10 times. CONCLUSION: The scoring system was discriminatory and sensitive to change, and could be used as a tool to assess an intensivist's mastery of TEE.

Efficacy of therapeutic hypothermia after out-of-hospital cardiac arrest due to ventricular fibrillation.

AIM OF THE STUDY: We investigated implementation and efficacy of mild therapeutic hypothermia in the treatment of out-of-hospital cardiac arrest due to ventricular fibrillation. MATERIALS AND METHODS: Two periods were compared, an historical one (36 patients) between 2000 and 2002 where therapeutic hypothermia was never used, and a recent period (32 patients) between 2003 and 2005 where therapeutic hypothermia (32-34 degrees C) was implemented prospectively in our unit. Cooling was obtained by simply using wet cloths and ice packs. Survival in the two groups and factors associated with survival were analysed, together with the neurological prognosis in discharged patients. RESULTS: Survival was significantly higher in the hypothermia group (56% versus 36%), whereas no significant difference was observed in severity between the two periods. Only age, time from return to spontaneous circulation <20min, and therapeutic hypothermia were independently associated with survival. Therapeutic hypothermia was well tolerated and was associated with a significant improvement in neurological outcome. Whereas only 23% of patients actually reached the target temperature in 2003, 100% did in 2005. CONCLUSION: Therapeutic hypothermia is efficient in significantly improving survival and neurological outcome of out-of-hospital cardiac arrest with ventricular fibrillation. By using a simple method, it can be implemented easily and quickly, without side effects.

Genes required for osmoregulation and apical secretion in Caenorhabditis elegans.

Few studies have investigated whether or not there is an interdependence between osmoregulation and vesicular trafficking. We previously showed that in Caenorhabditis elegans che-14 mutations affect osmoregulation, cuticle secretion, and sensory organ development. We report the identification of seven lethal mutations displaying che-14-like phenotypes, which define four new genes, rdy-1-rdy-4 (rod-like larval lethality and dye-filling defective). rdy-1, rdy-2, and rdy-4 mutations affect excretory canal function and cuticle formation. Moreover, rdy-1 and rdy-2 mutations reduce the amount of matrix material normally secreted by sheath cells in the amphid channel. In contrast, rdy-3 mutants have short cystic excretory canals, suggesting that it acts in a different process. rdy-1 encodes the vacuolar H+-ATPase a-subunit VHA-5, whereas rdy-2 encodes a new tetraspan protein. We suggest that RDY-1/VHA-5 acts upstream of RDY-2 and CHE-14 in some tissues, since it is required for their delivery to the epidermal, but not the amphid sheath, apical plasma membrane. Hence, the RDY-1/VHA-5 trafficking function appears essential in some cells and its proton pump function essential in others. Finally, we show that RDY-1/VHA-5 distribution changes prior to molting in parallel with that of actin microfilaments and propose a model for molting whereby actin provides a spatial cue for secretion.

[Circulatory failures]. / Les défaillances circulatoires.

To treat circulatory failures and recognize their mechanisms, we need to understand circulatory physiology. What determines systemic venous return? How does the right ventricle feed the pulmonary circulation? Where is the left ventricular preload reserve located? Four types of circulatory failure are conventionally recognized: hypovolemic, obstructive, vasoplegic and cardiogenic. One or more of these mechanisms may account for circulatory failure in septic shock. Treatment of circulatory failure requires admission to a specialized unit and continuous or discontinuous hemodynamic monitoring. Prognosis is highly dependent on rapid treatment and correction of circulatory impairment.

The binding affinity of double-stranded RNA motifs to HIV-1 Tat protein affects transactivation and the neutralizing capacity of anti-Tat antibodies elicited after intranasal immunization.

In this study we examined the hypothesis that the binding affinity of two double-stranded (ds) RNA motifs to HIV-1 Tat protein might affect transactivation and the type of anti-Tat immune responses. Using surface plasmon resonance technology we demonstrated the capacity of the poly(A):poly(U) (pA:pU) motif to bind with high affinity to a totally synthetic Tat protein and to inhibit more efficiently the Tat/transactivation response element (TAR) RNA interaction as compared to the poly(I):poly(C) (pI:pC) motif. Furthermore, the pA:pU motif was tenfold more effective in inhibiting Tat-driven transactivation than the pI:pC motif. Following intranasal immunization of mice, both dsRNA motifs enhanced the antibody (serum and mucosal) and cellular responses to Tat. However, only the serum samples of mice immunized with Tat + pI:pC inhibited Tat-driven transactivation. The profile of serum antibody subclasses together with the secreted cytokines by Tat-stimulated splenocyte cultures indicated that both dsRNA motifs favored the induction of a balanced Th1 and Th2 immune response. The demonstration in this study that two dsRNA motifs had a marked effect on Tat/TAR RNA interaction and on the neutralizing capacity of anti-Tat specific antibody responses highlights their potential for biological applications and the importance of selecting the appropriate motif as an adjuvant for vaccine design.