Dermot S O'callaghan

Dr Laurent Savale
email: laurent.savale@abc.aphp.fr

Romain Magnier

Jerome Le Pavec

Philippe Herve

Xavier Jais

Andrei Seferian

Marc Humbert

Gerald Simonneau

Olivier Sitbon

Dermot O ' Callaghan

Jérôme Le Pavec

Philippe Hervé

Xavier Jaïs

Gérald Simonneau

Jérôme Le Pavec

Gérald Simonneau

Current management approaches to portopulmonary hypertension

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Chronic liver dysfunction may have devastating consequences on the pulmonary vasculature 1 . Portopulmonary hypertension (PoPH) is defined as pulmonary arterial hypertension (PAH) that develops in the context of portal hypertension irrespective of the presence or otherwise of underlying advanced hepatic disease. PoPH is incorporated in group 1 of the current pulmonary hypertension (PH) classification system as it is characterised by pathobiological mechanisms that are similar to other forms of PAH 2 . Although the disorder is most commonly observed in patients with cirrhosis, accumulated evidence indicates that is in fact the presence of portal hypertension rather that chronic liver disease per se that is the key risk factor for the development of PoPH. This review provides a summary of clinicopathological characteristics of PoPH and discusses some of the emerging therapeutic approaches.

Epidemiology and Survival

The prevalence of PoPH is estimated at 2-6% among patients with portal hypertension and is observed as a complication of about 1-2% of patients with cirrhosis [3][4][5] . However, it is likely that these estimates are conservative, as many cases remain undiagnosed 1 . In the French national PAH registry, PoPH was identified as the third most common risk factor for PAH 6 . Females appear to be at greater risk of developing the disorder compared to males, suggesting that hormonal factors may play a role in its pathogenesis 7,8 . There is no relationship between the severity of the liver disease and the risk of developing PoPH 3 .

Interestingly, patients with autoimmune liver disease appear to be at increased risk, suggesting that dysregulated immunity may be pathogenetically relevant 7,9 . Generally, the Estimates of survivals in patients with PoPH have varied widely among published studies 9 10 11 . In a small series reported by Kawut et al, the overall transplant-free 3-year survival rates for PoPH patients was 38%, worse than that observed in idiopathic PAH patients 11 . In contrast, Le Pavec et al found that one-, three-and five-year survival rates were 88%, 75% and 68%, respectively, among patients followed at the French National Referral Centre, suggesting these patients may in fact have less severe outcomes 9 . These investigators also showed that the prognosis for those with PoPH was dependent on both the severity of PAH and of the underlying liver disease, with cardiac index and Child Pugh class emerging as independent prognostic factors. In contrast, no relationship with outcome was observed for modified New York Heart Association (NYHA) functional class or exercise capacity (as quantified using the 6 min walk test distance). In this retrospective analysis, the majority of deaths were equally attributed to PAH and liver disease 9 .

Pathophysiology

Portal hypertension is both a necessary and sufficient risk factor for the development of pulmonary vascular disease. Two distinct forms of pulmonary vascular remodelling that involve the lung microvasculature are known to be associated with portal hypertension: PoPH and the hepatopulmonary syndrome (HPS). The histological characteristics observed in patients with PoPH are similar to those observed in idiopathic PAH, namely endothelial cell proliferation, smooth muscle hypertrophy and in situ thrombosis 12 . By contrast, HPS is characterised pathologically by the presence of diffuse precapillary and capillary bed dilatations that result in diffusion-perfusion abnormalities in which unsaturated venous blood passes through dilated vessels and is inadequately saturated with oxygen because of a 13 . Although PoPH and HPS show contrasting hemodynamics profiles, the co-existence of these two distinct complications in patients with portal hypertension has been reported 14 .

The pathogenic mechanisms responsible for the development of PoPH remain incompletely understood, although angiogenesis is believed to be a critically important factor in the onset and progression of both PoPH and HPS. Some investigators have proposed that angiogenic signalling may result in different effects depending on the anatomical location of its activity within the pulmonary vascular bed, with portal hypertension and/or cirrhosis probably responsible for this imbalance between pro-and antiangiogenic factors within the lung 15 . Thus, dysregulation of vascular signalling pathways may lead to pulmonary vascular dilatation, distal pulmonary vascular obstruction of more proximal muscular arteries or, rarely, both. An imbalance of vasoconstrictive and vasodilatory mediators is also likely to be aetiologically relevant, as is the case in idiopathic PAH. As distinct from other forms of PAH, however, the augmented cardiac output (CO) that is typically observed in patients with portal hypertension may itself promote pulmonary vascular remodelling.

Another hypothesis that has been proposed is that toxic products from the digestive tract that are normally cleared by hepatic metabolism bypass the liver via portosystemic shunts and directly damage the pulmonary vascular endothelium 16

Diagnosis of PoPH

A high index of clinical suspicion for PoPH in patients with cirrhosis and/or portal hypertension is required. Although dyspnoea is the most common symptom of PoPH, it is an entirely non-specific and frequently reported symptom among those with chronic liver disease that is not complicated by intrinsic pulmonary disease. In addition, a prospective study by Hadengue et al showed that 60% of patients with PoPH were asymptomatic 3 . Transthoracic Doppler echocardiography (TTE) is recommended by recent guidelines as the initial diagnostic modality where PoPH is suspected 17 . However, few data have examined the value of this tool in the screening for PAH in asymptomatic patients with portal hypertension.

Colle et al assessed the diagnostic accuracy of Doppler echocardiography for suspected pulmonary hypertension in a prospective study of orthotopic liver transplantation (OLT) candidates. Using a right ventricular systolic pressure of > 30 mmHg as a cut-off for selecting patients for confirmatory right heart catheterization, these authors found sensitivity and specificity rates of 100% and 96%, respectively, for detection of pulmonary hypertension by echocardiography 4 . However, the positive predictive value for echocardiography in this series was less than 60%, underscoring the need for diagnostic right heart catheterisation when the disorder is suspected by non-invasive assessment. In a similar study undertaken by Kim et al, TTE was found to have a sensitivity of 97% and a specificity of 77% for the diagnosis of moderate to severe PoPH in OLT candidates 18 . Because of the high risk of periand post-operative adverse outcomes, PoPH must be excluded among patients being considered for OLT. By contrast, routine screening for the disorder in other subgroups of portal hypertension patients is not currently recommended. However, further diagnostic As already highlighted, right heart catheterisation is mandatory in order to definitively establish a diagnosis of PoPH 17 . Diagnostic criteria include a mean pulmonary arterial pressure (mPAP) of ≥ 25 mmHg with a normal mean pulmonary artery occlusion pressure (i.e. < 15mmHg) and a pulmonary vascular resistance (PVR) ≥ 240 dynes.s.cm -5 , associated with evidence of portal hypertension (whether confirmed by hemodynamic confirmation or suggested by the presence of splenomegaly, thrombocytopenia, oesophageal varices, portal to systemic shunts, or portal vein abnormalities) 19 . It is important to note that, in contradistinction to other forms of PAH, the level of pulmonary vascular resistance remains integral to the diagnosis of PoPH. This is because portal hypertension is frequently associated with a hyperdynamic circulation that develops as a result of increases in cardiac output and/or blood volume. Patients that demonstrate this particular pattern of PH are distinguished in general by PVR values of < 240 dynes.s.cm -5 , reflecting a passive increase in pulmonary arterial pressures 15 . The various haemodynamic profiles that may be observed in PoPH are summarised in Table 1.

Management

Broadly speaking, the treatment strategies most commonly employed for PoPH patients are based on data from pharmacological studies and clinical experiences of populations with other forms of PAH. Indeed, there remains a paucity of data available from prospective, randomised, placebo-controlled trials to inform clinicians of the optimal therapeutic approach for PoPH as these patients have tended to be excluded from such studies. By contrast, the majority of studies specifically examining the impact of existing or been of an open-label or retrospective nature. It is also important to stress, however, that significant differences exist between PoPH and other PAH subtypes which may impact the efficacy and tolerability of PAH specific therapies. In particular, the potential for potent vasodilatator treatments to worsen portal hypertension via a direct action on the splanchnic circulation remains a significant concern.

Conventional therapy

Use of diuretics is advocated for control of symptomatic fluid overload and supplementary oxygen is routinely prescribed in order to maintain arterial oxygen saturation above 90%. However, neither of these interventions have a demonstrable effect on mortality.

In patients with cirrhosis, anticoagulants are not usually administered when there is severe hepatocellular insufficiency and/or thrombocytopenia due to hypersplenism. The use of ßadrenergic receptor blockers, which are widely employed for prophylaxis of gastrointestinal hemorrhage from oesophageal varices, may be associated with significant worsening of exercise capacity and pulmonary hemodynamics in the setting of PoPH, and are generally contraindicated 20 . Instead, ligation of oesophageal varices should be preferred in portal hypertension patients deemed to be at high risk of bleeding. There is also no role for transjugular intrahepatic portosystemic shunt (TIPS) placement in the setting of PoPH because this procedure may acutely augment cardiac preload and potentially precipitate right ventricular failure 21 . Calcium channel blockers should also be used with caution in these patients as these may promote mesenteric vasodilatation and increase the hepatic venous pressure gradient 22 . Furthermore, our group has recently showed that the frequency of

Endothelin receptor antagonists

Endothelin (ET-1) is a potent endogenous vasoconstrictor and promoter of vascular remodelling that has been implicated in the development and progression of idiopathic PAH.

There is also evidence to suggest that ET-1 not only plays an important role in the pathogenesis of PoPH but may also be aetiologically relevant in portal hypertension and hepatic fibrotic remodelling [24][25][26][27] . These observations form the basis for the hypothesis that antagonism of ET-1 may be beneficial in PoPH patients. Bosentan is an orally active ET-1 receptor antagonist that is approved for use in different forms of PAH 28 . There are now a number of reports also suggesting that bosentan is well tolerated and effective in patients with severe PoPH [29][30][31][32] . In addition, Hoeper and co-workers showed that treatment with bosentan is efficacious in patients with Child Pugh class A liver disease. 33 However, to date there have been no prospective studies of bosentan conducted in patients with advanced liver failure, mainly due to safety concerns regarding impaired drug metabolism.

Our group has recently analysed the efficacy and safety of bosentan in patients from the French national PAH referral centre with PoPH and associated with Child Pugh class A and B cirrhosis 34 . In our series, bosentan conferred significant haemodynamic improvements in patients with Child Pugh class B cirrhosis. Furthermore, the safety profile of bosentan in our study population was consistent with that from previous therapeutic studies that evaluated PAH patients without cirrhosis.

A recently published observational study has reported on the effects of ambrisentan, a selective antagonist of the ET-1 A receptor subtype, in 13 patients with moderate to severe To date, there are no data regarding plasma levels of endothelin antagonists according to the severity of cirrhosis. However, pharmacological study data indicate that mild cirrhosis does not influence bosentan metabolism 36 . Despite these encouraging findings, the risk-tobenefit ratio of endothelin receptor antagonist use in patients with liver disease must be evaluated for on a case-by-case basis. Furthermore, given the tendency for agents from this therapeutic class to cause increases in liver transaminases, clinicians must be particularly vigilant that introduction of an endothelin antagonist does not result in a worsening of liver function.

Phosphodiesterase 5 inhibitors

Nitric oxide (NO) is an endothelium-derived potent vasodilator that exerts its effects on pulmonary vascular tone through increased production of the intracellular second messenger cyclic guanosine 5′-monophospate (cGMP). The effects of cGMP are regulated by the enzyme phosphodiesterase type-5 (PDE-5). Sildenafil is a potent and selective inhibitor of PDE-5 that promotes vasodilatation and antiproliferative activity that has been granted regulatory approval in different forms of PAH 37 .

No placebo-controlled, randomised studies of PDE-5 inhibitors in PoPH have been conducted to date. However, three small retrospective studies evaluating the impact of sildenafil treatment in PoPH patients have been published [38][39][40] . Overall, treatment with this agent has been shown to favourably impact a number of relevant clinical endpoints, including 6-min walk distance, NYHA functional class and pulmonary hemodynamics, without increasing the number of significant adverse events. Of note, two of these three studies evaluated only OLT candidates, thus limiting the extrapolation of data to PoPH patients in general. Furthermore, target doses of sildenafil employed in two of the studies were higher than those recommended in published guidelines (50 mg three times daily) 38,40 while the third compared the impact of doses ranging from 60 mg to 400 mg per day 39 . This suggests that higher doses of this drug may possibly confer additional improvements in functional status and haemodynamic indices. In general, treatment was well tolerated in participants from these series, with adverse events being reported no more frequently than in other PAH populations.

However, PDE-5 inhibitors should nonetheless be employed with caution in PoPH patients, particularly as some experts have suggested this approach may increase splanchnic blood flow resulting in worsening of portal hypertension 41 .

Prostaglandin analogues

Epoprostenol is a synthetic prostacyclin analogue administered by chronic intravenous infusion that possesses potent vasodilatory, antiproliferative and anti-thrombotic activities.

Although treatment is associated with short-and long-term benefits in patients with idiopathic PAH 42,43 , no controlled clinical trials have been conducted with this agent in PoPH to date. However, numerous case series have reported positive effects on exercise capacity and pulmonary hemodynamics with epoprostenol administration in selected patients 44,45 and it is often employed as a therapeutic bridge to enable OLT to be performed. Krowka et al showed that in a cohort of moderate to severe PoPH patients, chronic epoprostenol therapy conferred significant and durable improvements in PVR, mPAP and CO 46 . However, treatment is burdensome and may be associated with severe catheter-related bloodstream infections 47 .

The use of other, more stable prostacyclin analogues has also been the focus of study in PoPH. A case of treatment successes with intravenous iloprost, which has a longer half-life than epoprostenol, used as a bridge to OLT in a patient with severe PoPH has been described 48 . Treatment with aerosolized iloprost, administered by multiple daily inhalations,

Impact of specific treatment on survival

Despite their increasingly widespread use, the impact of PAH specific therapy on survival of patients with PoPH has not been clearly established. In a retrospective analysis of 74 patients, treatment of PAH, followed or not followed by OLT, was associated with an improved outcome 52 . By contrast, others have observed no survival differences when outcomes of patients receiving long-term epoprostenol are compared to those not receiving this form of therapy 53 . Similarly, among PoPH patients followed at the French National Referral Centre, use of specific PAH treatments also failed to improve outcome overall 34 .

Interestingly, treated patients who had milder disease (defined as either those with Child-Pugh A cirrhosis or portal hypertension without cirrhosis) had a statistically significant survival advantage compared to untreated patients.

Liver transplantation

Most experts agree that liver transplantation should not be considered as a potential treatment for PoPH because of the unacceptably high associated perioperative complication rates 54 . Only rare cases of improvement of portopulmonary hypertension have been reported after OLT and there is no pathophysiological evidence to support this approach. Indeed, in patients with PoPH who do undergo OLT, it is likely that any significant reductions in mPAP that are observed postoperatively are due decreases in CO rather than a reversal of the pathologic mechanisms that drive intrinsic pulmonary vasculopathy. Moreover, residual PAH after OLT may lead to acute right failure and a dramatically increased risk of peri-and postoperative mortality. This risk appears to be directly related to the severity of pulmonary hypertension 19 . Attempts have been made to stratify risk according to pulmonary hemodynamic indices in order to identify patients in whom OLT may be considered. In their metaanalysis, Krowka and al reported a mortality rate of 100% due to PAH in patients with a preoperative mPAP > 50 mmHg and a mortality rate of 50% among those with mPAP of 35-50 mmHg and a PVR > 250 dynes.s.cm -5 55 Data from this analysis have been used to assist physicians in decision making with respect to pulmonary hemodynamics for patients with PoPH being considered for liver transplantation 19 . The risk associated with OLT is acceptable in patients with a mPAP is <35 mmHg and preserved cardiac function, in the absence of other significant comorbidities. By contrast, treatment with one of more specific PAH therapies should be considered in those with a mPAP >35 mmHg in an attempt to improve pulmonary hemodynamics and thereby allow OLT to be undertaken with acceptable risk 19 (Figure 2).

Conclusion

PoPH remains an entity that is incompletely understood, difficult to treat and often associated with a poor prognosis. The disorder should be systematically excluded in all OLT candidates.

Recent reports have shown that treatment with PAH specific agents may confer durable improvements in important clinical parameters for some patients. However, the effectiveness of these agents has yet to be rigorously evaluated in randomised clinical studies. When PoPH is identified in patients otherwise deemed good candidates for OLT, therapeutic strategies should focus on improvements in pulmonary hemodynamics in order to optimise cardiac

Relevant mechanisms in the pathogenesis of portopulmonary hypertension.

Figure 2

Proposed therapeutic algorithm for patients with portopulmonary hypertension. indicates that is in fact the presence of portal hypertension rather that chronic liver disease per se that is the key risk factor for the development of PoPH. This review provides a summary of clinicopathological characteristics of PoPH and discusses some of the emerging therapeutic approaches.

Epidemiology and Survival

The prevalence of PoPH is estimated at 2-6% among patients with portal hypertension and is observed as a complication of about 1-2% of patients with cirrhosis [3][4][5] . However, it is likely that these estimates are conservative, as many cases remain undiagnosed 1 . In the French national PAH registry, PoPH was identified as the third most common risk factor for PAH 6 . Females appear to be at greater risk of developing the disorder compared to males, suggesting that hormonal factors may play a role in its pathogenesis 7,8 . There is no relationship between the severity of the liver disease and the risk of developing PoPH 3 .

Interestingly, patients with autoimmune liver disease appear to be at increased risk, suggesting that dysregulated immunity may be pathogenetically relevant 7,9 . Generally, the Estimates of survivals in patients with PoPH have varied widely among published studies 9 10 11 . In a small series reported by Kawut et al, the overall transplant-free 3-year survival rates for PoPH patients was 38%, worse than that observed in idiopathic PAH patients 11 . The US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) database, in which data from more than 2700 patients was collected, identified PoPH as an independent predictor of increased mortality among PAH patients (hazard ratio, 3.6; 95% confidence interval, 2.4 to 5.4) 12 . In contrast, Le Pavec et al found that one-, threeand five-year survival rates were 88%, 75% and 68%, respectively, among patients followed at the French National Referral Centre, suggesting these patients may in fact have less severe outcomes 9 . These investigators also showed that the prognosis for those with PoPH was dependent on both the severity of PAH and of the underlying liver disease, with cardiac index and Child Pugh class emerging as independent prognostic factors. In contrast, no relationship with outcome was observed for modified New York Heart Association (NYHA) functional class or exercise capacity (as quantified using the 6 min walk test distance). In this retrospective analysis, the majority of deaths were equally attributed to PAH and liver disease 9 . The reasons for the conflicting results between the US and French registries are not clear.

Differences in timing of initial referral of PoPH patients for assessment and dissimilarities

with respect to the severity of liver disease at time of first assessment among the two populations may in part explain the discordance of findings from the two registries.

Pathophysiology

Portal hypertension is both a necessary and sufficient risk factor for the development of pulmonary vascular disease. Two distinct forms of pulmonary vascular remodelling that 13 . By contrast, HPS is characterised pathologically by the presence of diffuse precapillary and capillary bed dilatations that result in diffusion-perfusion abnormalities in which unsaturated venous blood passes through dilated vessels and is inadequately saturated with oxygen because of a combination of high-flow perfusion and increased depth for diffusion 14 . Although PoPH and HPS show contrasting hemodynamics profiles, the co-existence of these two distinct complications in patients with portal hypertension has been reported 15 .

The pathogenic mechanisms responsible for the development of PoPH remain incompletely understood, although angiogenesis is believed to be a critically important factor in the onset and progression of both PoPH and HPS. Some investigators have proposed that angiogenic signalling may result in different effects depending on the anatomical location of its activity within the pulmonary vascular bed, with portal hypertension and/or cirrhosis probably responsible for this imbalance between pro-and antiangiogenic factors within the lung 16 . Thus, dysregulation of vascular signalling pathways may lead to pulmonary vascular dilatation, distal pulmonary vascular obstruction of more proximal muscular arteries or, rarely, both. An imbalance of vasoconstrictive and vasodilatory mediators is also likely to be aetiologically relevant, as is the case in idiopathic PAH. As distinct from other forms of PAH, however, the augmented cardiac output (CO) that is typically observed in patients with portal hypertension may itself promote pulmonary vascular remodelling.

Another hypothesis that has been proposed is that toxic products from the digestive tract that are normally cleared by hepatic metabolism bypass the liver via portosystemic shunts and directly damage the pulmonary vascular endothelium 17 . Inflammatory stimuli that

Diagnosis of PoPH

A high index of clinical suspicion for PoPH in patients with cirrhosis and/or portal hypertension is required. Although dyspnoea is the most common symptom of PoPH, it is an entirely non-specific and frequently reported symptom among those with chronic liver disease that is not complicated by intrinsic pulmonary disease. In addition, a prospective study by Hadengue et al showed that 60% of patients with PoPH were asymptomatic 3 . Transthoracic Doppler echocardiography (TTE) is recommended by recent guidelines as the initial diagnostic modality where PoPH is suspected 18 . However, few data have examined the value of this tool in the screening for PAH in asymptomatic patients with portal hypertension.

Colle et al assessed the diagnostic accuracy of Doppler echocardiography for

suspected pulmonary hypertension in a prospective study of orthotopic liver transplantation (OLT) candidates. Using a right ventricular systolic pressure of > 30 mmHg as a cut-off for selecting patients for confirmatory right heart catheterization, these authors found sensitivity and specificity rates of 100% and 96%, respectively, for detection of pulmonary hypertension by echocardiography 4 . However, the positive predictive value for echocardiography in this series was less than 60%, underscoring the need for diagnostic right heart catheterisation when the disorder is suspected by non-invasive assessment. In a similar study undertaken by Kim et al, TTE was found to have a sensitivity of 97% and a specificity of 77% for the diagnosis of moderate to severe PoPH in OLT candidates 19 . Because of the high risk of periand post-operative adverse outcomes, screening for PoPH must be performed among patients being considered for OLT. By contrast, routine screening for the disorder in other subgroups of portal hypertension patients is not currently recommended. However, further diagnostic assessment is required for portal hypertension patients that demonstrate clinical, biological or radiological features suggestive of underlying pulmonary hypertension and/or right heart failure.

As already highlighted, right heart catheterisation is mandatory in order to definitively establish a diagnosis of PoPH 18 . Diagnostic criteria include a mean pulmonary arterial pressure (mPAP) of ≥ 25 mmHg with a normal mean pulmonary artery occlusion pressure (i.e. < 15mmHg) and a pulmonary vascular resistance (PVR) ≥ 240 dynes.s.cm -5 , associated with evidence of portal hypertension (whether confirmed by hemodynamic confirmation or suggested by the presence of splenomegaly, thrombocytopenia, oesophageal varices, portal to systemic shunts, or portal vein abnormalities) 20 . It is important to note that, in contradistinction to other forms of PAH, the level of pulmonary vascular resistance remains integral to the diagnosis of PoPH. This is because portal hypertension is frequently associated with a hyperdynamic circulation that develops as a result of increases in cardiac output and/or blood volume. Patients that demonstrate this particular pattern of PH are distinguished in general by PVR values of < 240 dynes.s.cm -5 , reflecting a passive increase in pulmonary arterial pressures 16 . The various haemodynamic profiles that may be observed in PoPH are summarised in Table 1. populations with other forms of PAH. Indeed, there remains a paucity of data available from prospective, randomised, placebo-controlled trials to inform clinicians of the optimal therapeutic approach for PoPH as these patients have tended to be excluded from such studies. By contrast, the majority of studies specifically examining the impact of existing or investigative treatments in PoPH patients have involved small numbers of patients and have been of an open-label or retrospective nature. It is important to stress that much of the current clinical practice at expert centres is based on data that would not be considered strong enough to provide the basis for recommendations for clinical guidelines. Furthermore, significant differences exist between PoPH and other PAH subtypes which may impact the efficacy and tolerability of PAH specific therapies. In particular, the potential for potent vasodilatator treatments to worsen portal hypertension via a direct action on the splanchnic circulation remains a significant concern.

Management

Conventional therapy

Use of diuretics is advocated for control of symptomatic fluid overload and supplementary oxygen is routinely prescribed in order to maintain arterial oxygen saturation above 90%. However, neither of these interventions have a demonstrable effect on mortality.

In patients with cirrhosis, anticoagulants are not usually administered when there is severe hepatocellular insufficiency and/or thrombocytopenia due to hypersplenism. In order to maintain an adequate cardiac output, many PH patients rely on a significant heart rate reserve, since stroke volume is essentially fixed. This response mechanism is particularly important in the setting of compromised left ventricular filling due to right ventricular dysfunction and dilatation. The use of ß-adrenergic receptor blockers, therefore, which are widely employed for prophylaxis of gastrointestinal hemorrhage from oesophageal varices, may be associated with significant worsening of exercise capacity and pulmonary hemodynamics in the setting of PoPH, and are generally contraindicated 21 . Instead, ligation of oesophageal varices should be preferred in portal hypertension patients deemed to be at high risk of bleeding. There is also no role for transjugular intrahepatic portosystemic shunt (TIPS) placement in the setting of PoPH because this procedure may acutely augment cardiac preload and potentially precipitate right ventricular failure 22 . Calcium channel blockers should also be used with caution in these patients as these may promote mesenteric vasodilatation and increase the hepatic venous pressure gradient 23 . Furthermore, our group has recently showed that the frequency of responses rates to acute vasodilator testing at right heart catheterisation is only 1.7% among PoPH patients 24 .

Endothelin receptor antagonists

Endothelin (ET-1) is a potent endogenous vasoconstrictor and promoter of vascular remodelling that has been implicated in the development and progression of idiopathic PAH.

There is also evidence to suggest that ET-1 not only plays an important role in the pathogenesis of PoPH but may also be aetiologically relevant in portal hypertension and hepatic fibrotic remodelling [25][26][27][28] . These observations form the basis for the hypothesis that antagonism of ET-1 may be beneficial in PoPH patients. Bosentan is an orally active ET-1 receptor antagonist that is approved for use in different forms of PAH 29 . There are now a number of reports also suggesting that bosentan is well tolerated and effective in patients with severe PoPH [30][31][32][33] . In addition, Hoeper and co-workers showed that treatment with bosentan is efficacious in patients with Child Pugh class A liver disease. 34 However, to date there have 35 . In our series, bosentan conferred significant haemodynamic improvements in patients with Child Pugh class B cirrhosis. Furthermore, the safety profile of bosentan in our study population was consistent with that from previous therapeutic studies that evaluated PAH patients without cirrhosis.

A recently published observational study has reported on the effects of ambrisentan, a selective antagonist of the ET-1 A receptor subtype, in 13 patients with moderate to severe PoPH. Treatment was associated with a significant reduction in mPAP and PVR without adverse effects on liver function tests 36 .

To date, there are no data regarding plasma levels of endothelin antagonists according to the severity of cirrhosis. However, pharmacological study data indicate that mild cirrhosis does not influence bosentan metabolism 37 . Despite these encouraging findings, the risk-tobenefit ratio of endothelin receptor antagonist use in patients with liver disease must be evaluated for on a case-by-case basis. Furthermore, given the tendency for agents from this therapeutic class to cause increases in liver transaminases, clinicians must be particularly vigilant that introduction of an endothelin antagonist does not result in a worsening of liver function.

Phosphodiesterase 5 inhibitors

Nitric oxide (NO) is an endothelium-derived potent vasodilator that exerts its effects on pulmonary vascular tone through increased production of the intracellular second messenger cyclic guanosine 5′-monophospate (cGMP). The effects of cGMP are regulated by No placebo-controlled, randomised studies of PDE-5 inhibitors in PoPH have been conducted to date. However, three small retrospective studies evaluating the impact of sildenafil treatment in PoPH patients have been published [39][40][41] . Overall, treatment with this agent has been shown to favourably impact a number of relevant clinical endpoints, including 6-min walk distance, NYHA functional class and pulmonary hemodynamics, without increasing the number of significant adverse events. Of note, two of these three studies evaluated only OLT candidates, thus limiting the extrapolation of data to PoPH patients in general. Furthermore, target doses of sildenafil employed in two of the studies were higher than those recommended in published guidelines (50 mg three times daily) 39,41 while the third compared the impact of doses ranging from 60 mg to 400 mg per day 40 . This suggests that higher doses of this drug may possibly confer additional improvements in functional status and haemodynamic indices. In general, treatment was well tolerated in participants from these series, with adverse events being reported no more frequently than in other PAH populations. However, PDE-5 inhibitors should nonetheless be employed with caution in PoPH patients, particularly as some experts have suggested that theoretically this approach may increase splanchnic blood flow resulting in worsening of portal hypertension 42 . However, there have been no studies performed to date specifically addressing the issue of whether use of PDE-5 inhibitors in PoPH may contribute to a worsening of portal hemodynamics. Further clinical investigation is warranted in this regard.

Prostaglandin analogues

Epoprostenol is a synthetic prostacyclin analogue administered by chronic intravenous Although treatment is associated with short-and long-term benefits in patients with idiopathic PAH 43,44 , no controlled clinical trials have been conducted with this agent in PoPH to date. However, numerous case series have reported positive effects on exercise capacity and pulmonary hemodynamics with epoprostenol administration in selected patients 45,46 and it is often employed as a therapeutic bridge to enable OLT to be performed. Krowka et al showed that in a cohort of moderate to severe PoPH patients, chronic epoprostenol therapy conferred significant and durable improvements in PVR, mPAP and CO 47 . However, treatment is burdensome and may be associated with severe catheter-related bloodstream infections 48 .

The use of other, more stable prostacyclin analogues has also been the focus of study in PoPH. A case of treatment successes with intravenous iloprost, which has a longer half-life than epoprostenol, used as a bridge to OLT in a patient with severe PoPH has been described 49 . Treatment with aerosolized iloprost, administered by multiple daily inhalations, has also been attempted 50,51 . Recently, Melgosa et al reported that 12 months of aerosolized iloprost treatment was associated with overall improvements in functional class and exercise capacity in a cohort of 21 patients 52 . A multicentre observational open-label study evaluating the safety and efficacy of treprostinil, a prostanoid delivered by continuous subcutaneous infusion, to facilitate liver transplantation in patients with PoPH is also underway.

Impact of specific treatment on survival

Despite their increasingly widespread use, the impact of PAH specific therapy on survival of patients with PoPH has not been clearly established. In a retrospective analysis of 74 patients, treatment of PAH, followed or not followed by OLT, was associated with an improved outcome 53 . By contrast, others have observed no survival differences when outcomes of patients receiving long-term epoprostenol are compared to those not receiving 54 . Similarly, among PoPH patients followed at the French National Referral Centre, use of specific PAH treatments also failed to improve outcome overall 35 .

Interestingly, treated patients who had milder disease (defined as either those with Child-Pugh A cirrhosis or portal hypertension without cirrhosis) had a statistically significant survival advantage compared to untreated patients.

Liver transplantation

Most experts agree that liver transplantation should not be considered as a potential treatment for PoPH because of the unacceptably high associated perioperative complication rates 55 . Only rare cases of improvement of portopulmonary hypertension have been reported after OLT and there is no pathophysiological evidence to support this approach. Indeed, in patients with PoPH who do undergo OLT, it is likely that any significant reductions in mPAP that are observed postoperatively are due decreases in CO rather than a reversal of the pathologic mechanisms that drive intrinsic pulmonary vasculopathy. Moreover, residual PAH after OLT may lead to acute right failure and a dramatically increased risk of peri-and postoperative mortality. This risk appears to be directly related to the severity of pulmonary hypertension 20 . Attempts have been made to stratify risk according to pulmonary hemodynamic indices in order to identify patients in whom OLT may be considered. In their metaanalysis, Krowka and al reported a mortality rate of 100% due to PAH in patients with a preoperative mPAP > 50 mmHg and a mortality rate of 50% among those with mPAP of 35-50 mmHg and a PVR > 250 dynes.s.cm -5 56 Data from this analysis have been used to assist physicians in decision making with respect to pulmonary hemodynamics for patients with PoPH being considered for liver transplantation 20 . The risk associated with OLT is acceptable in patients with a mPAP is <35 mmHg and preserved cardiac function, in the absence of other should be considered in those with a mPAP >35 mmHg in an attempt to improve pulmonary hemodynamics and thereby allow OLT to be undertaken with acceptable risk 20 (Figure 2).

Conclusion

PoPH remains an entity that is incompletely understood, difficult to treat and often associated with a poor prognosis. Screening for the disorder should be systematically undertaken in all OLT candidates. Recent reports have shown that treatment with PAH specific agents may confer durable improvements in important clinical parameters for some patients. However, the effectiveness of these agents has yet to be rigorously evaluated in randomised clinical studies. When PoPH is identified in patients otherwise deemed good candidates for OLT, therapeutic strategies should focus on improvements in pulmonary hemodynamics in order to optimise cardiac reserve during the peri-and postoperative periods and maximise the likelihood of a successful outcome.

Relevant mechanisms in the pathogenesis of portopulmonary hypertension.

  is established after the diagnosis of portal hypertension is made, with a mean interval between the two diagnoses of 28+/-38 months 3 .

  high-flow perfusion and increased depth for diffusion

  . Inflammatory stimuli that are activated by this mechanism are probably mechanistically important in PoPH. The development of portosystemic shunts, a decrease in liver phagocytic capacity, and increased frequency of bacterial translocation facilitate the circulation of proinflammatory cytokines, proangiogenic factors or bacterial endotoxins which probably induce pulmonary vascular endothelium dysfunction. Genetic polymorphisms in oestrogen metabolism and other signalling pathways, particularly those associated with cellular growth and apoptosis, also

  a role in the development of the disease 8 . The various factors that have been implicated in the pathogenesis of PoPH are summarised in figure 1.

  for portal hypertension patients that demonstrate clinical, biological or radiological features suggestive of underlying pulmonary hypertension and/or right heart failure.

  PoPH patients have involved small numbers of patients and have

  acute vasodilator testing at right heart catheterisation is only 1.7% among PoPH patients23 .

  was associated with a significant reduction in mPAP and PVR without adverse effects on liver function tests35 .

  attempted49,50 . Recently, Melgosa et al reported that 12 months of aerosolized iloprost treatment was associated with overall improvements in functional class and exercise capacity in a cohort of 21 patients51 . A multicentre observational open-label study evaluating the safety and efficacy of treprostinil, a prostanoid delivered by continuous subcutaneous infusion, to facilitate liver transplantation in patients with PoPH is also underway.

  peri-and postoperative periods and maximise the likelihood of a successful outcome.

Introduction

  Chronic liver dysfunction may have devastating consequences on the pulmonary vasculature1 . Portopulmonary hypertension (PoPH) is defined as pulmonary arterial hypertension (PAH) that develops in the context of portal hypertension, with or without associated advanced hepatic disease. PoPH is incorporated in Group 1 of the World Health Organization (WHO) pulmonary hypertension (PH) classification system as it is characterised by pathobiological mechanisms that are similar to other forms of PAH2 . Although the disorder is most commonly observed in patients with cirrhosis, accumulated evidence

  is established after the diagnosis of portal hypertension is made, with a mean interval between the two diagnoses of 28+/-38 months 3 .

  microvasculature are known to be associated with portal hypertension: PoPH and the hepatopulmonary syndrome (HPS). The histological characteristics observed in patients with PoPH are similar to those observed in idiopathic PAH, namely endothelial cell proliferation, smooth muscle hypertrophy and in situ thrombosis

  this mechanism are probably mechanistically important in PoPH. The development of portosystemic shunts, a decrease in liver phagocytic capacity, and increased frequency of bacterial translocation facilitate the circulation of proinflammatory cytokines, proangiogenic factors or bacterial endotoxins which probably induce pulmonary vascular endothelium dysfunction. Genetic polymorphisms in oestrogen metabolism and other signalling pathways, particularly those associated with cellular growth and apoptosis, also appear to play a role in the development of the disease 8 . The various factors that have been implicated in the pathogenesis of PoPH are summarised in figure 1.

  the treatment strategies most commonly employed for PoPH patients are based on data from pharmacological studies and clinical experiences of

  studies of bosentan conducted in patients with advanced liver failure, mainly due to safety concerns regarding impaired drug metabolism. Our group has recently analysed the efficacy and safety of bosentan in patients from the French national PAH referral centre with PoPH and associated with Child Pugh class A and B cirrhosis

  type-5 (PDE-5). Sildenafil is a potent and selective inhibitor of PDE-5 that promotes vasodilatation and antiproliferative activity which has been granted regulatory approval in different forms of PAH38 .

  potent vasodilatory, antiproliferative and anti-thrombotic activities.

  By contrast, treatment with one of more specific PAH therapies

  Plevak D, Findlay J, Rosen C, Wiesner R, Krom R. Pulmonary hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver transplantation. Liver Transpl 2000;6:443-50.

Figure 2

 2 Figure 2

Table 1 :

 1 Haemodynamic mechanisms of increased pulmonary arterial pressure in patients with portal hypertension

		PAP	CO	PVR	PCWP
	Hyperdynamic	⇑	⇑⇑	⇓	⇑⇔
	Volume overload	⇑	⇑⇔	⇓	⇑⇔
	PoPH	⇑⇑	⇑⇔⇓	⇑	⇔
	PAP: pulmonary arterial pressure; CO: cardiac output; PVR: pulmonary vascular
	resistance; PCWP: pulmonary capillary wedge pressure ; PoPH: portopulmonary
	hypertension

Table 1 :

 1 Haemodynamic mechanisms of increased pulmonary arterial pressure in patients with portal hypertension

		PAP	CO	PVR	PCWP
	Hyperdynamic	⇑	⇑⇑	⇓	⇑⇔
	Volume overload	⇑	⇑⇔	⇓	⇑⇔
	PoPH	⇑⇑	⇑⇔⇓	⇑	⇔
	PAP: pulmonary arterial pressure; CO: cardiac output; PVR: pulmonary vascular
	resistance; PCWP: pulmonary capillary wedge pressure ; PoPH: portopulmonary
	hypertension

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International Journal of Clinical Practice

International Journal of Clinical Practice


Edy Veneziano
email: edy.veneziano@parisdescartes.fr

Conversation in language development and use: An Introduction

Keywords: Children's conversations, language acquisition, pragmatic development

This editorial introduction summarizes the background to, and contents of, a Special Issue devoted to children's development of conversational skills and their relation to language acquisition and use. The centrality of conversation to language development is well recognized and the paper identifies two key approaches to research: the impact of conversational processes on language acquisition itself, and the ways in which basic language skills are put to use in conversational interactions. The papers to follow were organized according to these themes and are outlined accordingly.

First Language, 2010, 30(3-4), 241-249 2 considered from at least two main perspectives. One concerns the impact of conversational processes on children's acquisition of core language knowledge: phonological, lexical, morphological and syntactic. The other concerns the way these basic language resources are used. In development, core and pragmatic knowledge are often related to each other. Pragmatic considerations are often a component of meaning and contribute to acquire further basic language resources while the core linguistic resources at the child's disposal have a role to play in the adequate use of language.

Conversational processes and children's acquisition of core language knowledge [START_REF] Brown | The child's grammar from I to III[END_REF] noted that the transformations that utterances undergo "as they shuttle between persons in conversation" may be the "richest data available to the child" for acquiring grammar (1969: 72). They reveal the structure of grammar in the same way as transformations of matter might help children discovering invariances and the physical concept of conservation.

There are several reasons to believe that conversational functioning contributes to language acquisition. In conversation, children are active participants in communicative events, have intentions and meanings to communicate to their interlocutors, and understanding the partner is as important as making oneself understood. Thus, children are attentive to the effect that their interventions have on the partner and to the responses they obtain, including verbal ones, and children's replies reveal at the same time their understanding of them (Gallaway & Richards, 1994;Snow & Ferguson, 1977).

First Language, 2010, 30(3-4), 241-249 3 In conversations, children participate in the construction of communicatively valid behaviors and are placed upfront for observing and treating those of the more experienced partner. Adults interpret children's utterances and provide them at the same time with models of how their intentional meanings should find conventional expression. Adults use scaffolding procedures that clarify and render the children's utterances more language-like while making the meaning of their own language forms accessible to the child by basing them in shared context or linking them to previous discourse [START_REF] Howard | Conversational correlates of children's acquisition of mental verbs and a theory of mind[END_REF][START_REF] Tare | Maternal uses of non-object terms in child-directed speech: Color, number and time[END_REF][START_REF] Murase | Mother-child conversation during joint picture book reading in Japan and the USA[END_REF]Tamis-LeMonda, Baumwell, & Cristofaro, in press ;[START_REF] Tenenbaum | Gender effects on Mexican-descent parents' questions and scaffolding during toy play: A sequential analysis[END_REF][START_REF] Veneziano | Effects of conversational functioning on early language acquisition:When both caregivers and children matter[END_REF].

Recent evidence on the specific effects of conversation on children's language acquisition accentuates the importance of recurring regular frames, extended discourse, and of corrective feedback by which children can improve their production by correcting their errors (e.g., [START_REF] Chouinard | Adult reformulations of child errors as negative evidence[END_REF][START_REF] Mintz | Frequent frames as a cue for grammatical categories in child directed speech[END_REF][START_REF] Saxton | Negative evidence and negative feedback: Immediate effects on the grammaticality of child speech[END_REF][START_REF] Veneziano | Effects of conversational functioning on early language acquisition:When both caregivers and children matter[END_REF][START_REF] Weisleder | What's in the input? Frequent frames in child-directed speech offer distributional cues to grammatical categories in Spanish and English[END_REF]. Adults' correction of children's grammatical errors was once supposed to be rare. However, several studies have shown that adults provide corrective feedback in the course of conversation with their children [START_REF] Farrar | Negative evidence and grammatical morpheme acquisition[END_REF][START_REF] Chouinard | Adult reformulations of child errors as negative evidence[END_REF][START_REF] Gallaway | Negative feedback in language addressed to hearing-impaired children: A pilot study[END_REF][START_REF] Moerk | Positive evidence for negative evidence[END_REF][START_REF] Saxton | Negative evidence and negative feedback: Immediate effects on the grammaticality of child speech[END_REF][START_REF] Strapp | Mothers', fathers', and siblings' responses to children's language errors: comparing sources of negative evidence[END_REF][START_REF] Veneziano | Effects of conversational functioning on early language acquisition:When both caregivers and children matter[END_REF]. The papers that deal with partners' repairs in this special issue provide further evidence of this phenomenon (see Corrin; Laakso & Soininen; Comeau,Genesee & Mendelson, this volume). What is important in all forms of conversationally contingent responses is that the changes in form occur while the intended meanings are supposed to remain invariant. This "shuttling of utterances" [START_REF] Brown | The child's grammar from I to III[END_REF] might ultimately reveal itself one of the crucial features of conversation.

First Language, 2010, 30(3-4), 241-249 4

Conversation and language use

In conversation, children learn also how linguistic resources are used in order to function as competent speakers who address discourse and socially adequate utterances to their interlocutors, taking into account the knowledge they have of the verbal and nonverbal context, discourse characteristics and the degree of shared knowledge and "common ground" among the interlocutors (e.g. [START_REF] Marcos | Introduction: Early pragmatic development[END_REF][START_REF] Matthews | The effect of perceptual availability and prior discourse on young children's use of referring expressions[END_REF][START_REF] Gundel | Cognitive status and the form of referring expressions in discourse[END_REF]. They learn that others' requests should be answered, that demands are made on the assumption that the speaker cannot carry out the object of the demand, that refusals should be explained, that requests for clarification require that one's intentions should be better expressed, etc. (e.g., [START_REF] Clark | Pragmatics and language acquisition[END_REF][START_REF] Fagan | Toddlers' persistence when communication fails: Response motivation and goal substitution[END_REF][START_REF] Forrester | The development of other-related conversational skills: A case study of conversational repair during the early years[END_REF][START_REF] Garvey | Children's talk[END_REF][START_REF] Marcos | Addressee co-operation and request reformulation in young children[END_REF][START_REF] Ninio | Pragmatic development[END_REF][START_REF] Quay | Dinner conversations with a trilingual two-year-old: Language socialization in a multilingual context[END_REF][START_REF] Shatz | Conversational or communicative skill? A reassessment of two-years-olds' behavior in miscommunication episodes[END_REF]Veneziano, 2001a,b). Pragmatics needs to be learned in the same way as grammar and referential semantics do, pragmatics being often part of this latter knowledge (e.g., [START_REF] Ricard | Personal pronouns and perspective taking in toddlers[END_REF]Salazar Orvig et al, this volume). For example, the meaning of an indefinite article is not provided only by understanding that it does not designate any particular member of a class, but also that it refers to an entity that has already been mentioned or focused upon in previous discourse (e.g., [START_REF] Gundel | Topic, focus, and the grammar-pragmatics interface[END_REF][START_REF] Hickmann | Children's discourse: Person. space and time across languages[END_REF].

This special issue

The papers in this special issue provide an abundance of new evidence and insights in respect of the themes sketched above. They address the relation between conversation and language development and use from a variety of perspectives, exploiting a range of methodologies, and covering very early to more advanced periods of language learning.

Conversation in language acquisition

First Language, 2010, 30(3-4), 241-249 5 Clark shows that when adults introduce new words to their 2 to 5 years old children, they place these words in final position, utter them with emphatic stress, and present them in frames appropriate to the part of speech they belong.

Moreover, adults enhance opportunities to establish meaning by linking the new words not only to the reference objects or events present in the context but also to other terms in the same semantic domain. Children indeed attend to these words and are able to use them appropriately later on.

Luce and Callanan show that, at least in particular settings, parents provide their 12-, 18-, and 24-months old children with subtle cues that help them understand that names for things are in the minds of people and must be learned by listening to their talk in conversation. Parents may express uncertainty or ignorance about objects' labels, search for the right label, or qualify it with reference to internal states.

Although only a minority of the labels for unfamiliar objects are presented in this way, they may be very relevant events for children's understanding this fundamental feature of words, as it is suggested by the positive relationship between parents' use of "labels in the mind" and children's productive vocabulary.

Veneziano and Parisse examine the specific role of conversational contingencies with respect to that of child-directed speech (CDS) more in general, in the production of early verbs by two children acquiring French. They show that when the children are in the single-form verb morphology period, most of the verb types in CDS are also produced by their partners in one, or in one dominant, form only. The particular form children use for a given verb corresponds to the one adults use in CDS, for that is also reinforced in conversational contingencies. Through a method that assigns weights to the information provided by CDS and to that provided by conversation, results show that when these are not equal, conversation has a much stronger impact on children's productions than CDS.

Conversational repair sequences and the acquisition of language and discourse skills.

Corrin applies fine-grained conversational analysis to playtime conversations between child and mother in the period between 1;7 and 1;9. She argues that neutral repair initiations by the mother (e.g. hm?) are powerful conversational turns that not only call for revision of the "trouble turn", but also foster grammatical development by promoting the semantic-syntactic patterning of new constructions. Indeed, these sequences resemble another conversational phenomenon known in the literature as Successive Single Word Utterances and considered to have a very important role in the transition from single to multiword speech (e.g., [START_REF] Bloom | One word at a time[END_REF][START_REF] Greenfield | The structural and functional status of single-word utterances and their relationship to early multi-word speech[END_REF][START_REF] Herr-Israel | Successive single-word utterances and use of conversational input: a pre-syntactic route to multiword utterances[END_REF][START_REF] Scollon | A real early stage: An unzippered condensation of a dissertation on child language[END_REF][START_REF] Veneziano | Early lexical, morphological and syntactic development in French: Some complex relations[END_REF][START_REF] Veneziano | From one word to two words: Repetition patterns on the way to structured speech[END_REF]. Responses to repairs may in fact be the communicative and conversational source of certain kinds of SSWUs and the turn-by-turn in-depth conversational analysis illustrated in this paper brings us closer to understanding the motivational and communicative underpinnings of children's language learning. Laakso and Soininen distinguish different kinds of mother-initiated repairs addressed to their 3-years-old children during play interaction and, like Corrin, analyze them through fine-grained conversational analysis. Results show their positive role in sustaining on-topic conversation and in generating self-repairs by the children. Like other authors in this special issue, Laakso and Soininen emphasize the partners' mutual influence in the realization of a conversational sequence. They point out that the kind of repair mothers provide will influence the child's subsequent reply and the kind of conversational sequence structure that the dyad will realize. The comparison of bilingual and monolingual children's repairs of breakdowns in conversations reveal no differences between the two groups of children, in spite of the fact that bilinguals used the language in which they were less proficient. The authors argue that these kinds of conversational and socio-cognitive skills are not affected by the additional cognitive challenges associated with the simultaneous acquisition of two languages in the first years.

Salazar and co-authors examine the role of conversational and pragmatic factors in the production of children's third person clitic subject pronouns as they occurred in natural dialogues between 1;9 and 2;4. The pronouns' relation to the interlocutor's previous utterances and the status of its referent in shared discourse or attention state were among the variables considered. Results show that these young children use pronouns mainly to refer to entities that have been mentioned in the interlocutor's immediately preceding utterance, showing that they understand very early that the meanings and functions of morphological devices are not restricted to the realm of grammar but have inherent, pragmatic and conversational components, components that can be learned only in conversational settings. This work provides another important argument for the relevance of conversation for language acquisition and for children's early capacity to deal with mental entities (those that have already been talked about and are not there any more), with sharedness, by which the other's subjectivity becomes "common ground", and with the interlocutor's states of attention.

Children's developing knowledge about conversational rules, practices and justifications.

First Language, 2010, 30(3-4), 241-249 8 Goetz analyses spontaneous justifications occurring in the natural adult-child conversations when the children were between 2;6 and 4;11. Results show that by 3 years children provide as many justifications as their adult partners, suggesting that they have interiorized the need to provide justifications in certain circumstances.

Goetz reveals a very interesting developmental progression from an instrumental use of justifications (justifications for persuasive purposes in order to have one's intentions prevail), to an epistemic-argumentative use of justifications whose central aim is to have one's knowledge and beliefs prevail. This epistemic shift takes a step further when children start to argue in support, not of their own claims, but of those of their partners, giving rise to co-constructed justification sequences.

De Haan and Singer's analysis of peer conflicts among 2 and 3 years old children in multiethnic child-care centers in the Netherlands shows a developmental increase in children's ability to take into account both their own and their opponent's perspectives. The authors argue that this is shown by the fact that 3 years old children propose more compromises than the younger children, compromises being considered a psychologically complex strategy offering a new scenario fair to everyone.

Interestingly, the less advanced linguistic abilities in Dutch of children with mixed language background, relative to children who spoke only Dutch at home, did not prevent the mixed language background children from using psychologically advanced strategies, including compromises. The authors argue that cognitive and social developments make a greater contribution to the development of complex skills in conflict negotiation than linguistic abilities per se.

Blum Kulka, Hamo and Habib analyse 4-5 and 9-10 years old children's explanations in naturally occurring conversations among peers. They clearly situate their analysis in the interactional approach whereby explanations are a socio-First Language, 2010, 30(3-4), 241-249 communicative phenomenon whose full meaning can be captured by taking into account extended conversational sequences. They show how child-to-child talk not only manifests but also creates occasions to develop the participants' conversational competences. They suggest, in particular, that children's contributions to the conversational negotiation of conflicts help them advance from an exclusive selfcentered point of view to a consideration of the actions, needs and intentions of others.

Language knowledge, conversational skills, context and partner.

Hoff's study shows the effect of context and partner on 17 to 36 months old children. They were found to use a richer vocabulary and to provide more topiccontinuing contributions in book reading than during mealtime and toy play. In the latter setting, conversations with mothers were more conducive to the manifestation of these abilities than were conversations with siblings. The author argues that the level of language performance shown by the children depends not only on their underlying competence but also on the support provided by the setting and the conversational partner that, both, scaffold it.

Kyratzis and Deniz Tarim study the spontaneous free play conversations of middle-class preschool Turkish girls and show that these girls are able to adjust their expression of directives according to the context of use. They address their peer girls with egalitarian forms of directives but when they address boys or enact the role of the mother in pretend play, they use imperative forms, thus expressing authoritative stances. These conversational differences show that culturally-determined genderlinked social roles are practiced through directives and that conflict management in girls' peer group conversations could reflect the internalization of models offered by adult middle-class Turkish women in conversation in varied social settings.

First Language, 2010, 30(3-4), 241-249 10 Bruce, Hansson & Nettelbladt compare the conversational interactions of SLI children communicating with different kinds of partners: a typically developing agematched and a typically developing language-matched peer. This paper nicely illustrates one of the very important characteristics of conversations mentioned earlier, namely, that conversational partners mutually influence one another's functioning. Indeed, results show that SLI children present different conversational skills when interacting with the age-matched and with the language-matched peers (higher responsiveness and coherence of topic with the former than with the latter).

This study strongly suggests that low conversational skills are not an inherent and insurmountable characteristic of SLI children. Their behavior can adjust or can, at least, be shaped by the kind of conversational interaction afforded by the conversational context.

Baines and Howe show that age and task characteristics influence also four, six and nine-years-old children's conversational skills, in this case, topic management and discussion skills. In situations where goals are pursued jointly, and the interacting situation is dyadic, younger children maintain topics through collaborative discussion, something that they have difficulties in doing without the supportive structure from the setting. Older children's discussion skills are promoted by task ambiguity, while age remains a solid variable for conversational skills that require integrating the child's perspective with that of the speaking partner.

In sum, the collection of papers appearing in this special issue presents the variety of ways by which conversation can legitimately be considered a privileged eventful happening in the life of language learning children, from very young to school-age years, while bringing to light the multitude of communicatively First Language, 2010, 30(3-4), 241-249 11 meaningful processes going on in conversation, their inherent dynamical nature as well as the complexity and the relativity of the skills engaged by the participants Editing this special issue has been a challenging experience. I learned a lot from the great number of fine papers received. I also learned that editing a Journal from scratch is a daunting enterprise for a novice. I would like to thank all the authors not only for their fine contributions but also for their extraordinary patience during the long reviewing and editing process . My thanks go also to the multitude of reviewers who accepted to offer their time and intelligence to appreciate and make constructive criticisms of the papers sent to them.

First

  and Mendelson examine the conversational repair skills of 2-and 3-years old French-English bilingual children and monolingual Frenchspeaking children, as well as their responses to consecutive requests for clarification.

Acknowledgments

I wish to thank Kevin Durkin for his substantial assistance throughout the editing process.