Cédric Durand
email: cdurand@ehess.fr

Antonia López-Villavicencio
email: lopezvillavicencio@univ-paris13.fr

On the link between distribution's margins and exchange rates: the role of globalization

Keywords: JEL Classification: L16, L1, F00, C23 Distribution's margin, globalization, asymmetries, exchange rate JEL Classication: L16, L1, F00, C23 Distribution's margin, globalization, asymmetries, exchange rate

In this paper, we analyze the differences in the sensibility of the distribution and transportation margin to exchange rate variations among different sectors in several European countries between 1995 and 2007. On the one hand, we provide new evidence that the margin reacts to exchange rate movements, a fact that may help to explain the still unresolved puzzle concerning the incomplete pass-through of the exchange rate to consumer prices. On the other hand, we look for indications of the characteristics of global value chains governance through the evolution of distributional margins. In addition, in order to draw more subtle conclusions, one original feature of this work is that we empirically allow for asymmetrical reactions of distributional margins to depreciations or appreciation, an effect that was previously ignored in the literature.

Introduction

For many years, one of the major issues in international economics has been the link between exchange rates and prices. Indeed, understanding the form and the scale in which exchange rate changes are passed through to prices is an important issue for macroeconomic stability in general and for monetary policy, in particular.

Yet, despite the large body of literature and interest in the exchange rate passthrough, there are still important issues that bewilder economist and policymakers.

In particular, the persistent gap between cost shocks and consumer prices and, in a less extend, to import prices, is a well established fact and a fundamental puzzle in international economics [START_REF] Campa | Exchange Rate Pass-through into Import Prices: A Macro or Micro Phenomenon?[END_REF], [START_REF] Frankel | Slow Passthrough Around the World: A New Import for Developing Countries?[END_REF], Campa and Goldberg (2006)).

In this sense, international trade theory argues that, if all goods and services were traded at a negligible cost and if their prices reected only their production costs, then retail prices should be very responsive to exchange rate changes. In other words, under a perfect competition structure, the pass-through should be complete or almost complete. As such, the theoretical arguments to explain the important disconnection between exchange rates and nal prices are mainly explained from an imperfect competition framework. For instance, [START_REF] Engel | Expenditure Switching and Exchange-Rate Policy[END_REF] suggests three potential causes: (1) the existence of local costs (e.g., costs for non-traded services such as transportation, storage, marketing or insurance) even among goods that are typically considered to be "traded"; (2) pure nominal price rigidities (also known as "menu costs") that lead to "local-currency pricing" and (3) the adjustment of prot margins that foreign exporters and local distributors have as a result of imperfect competition [START_REF] Goldberg | A Structural Approach to Explaining Incomplete Exchange-Rate Pass-Through and Pricing-to-Market[END_REF] 1 .

Concerning the rst point, distribution costs for imported goods are shown to mitigate the overall foreign content of the consumption value of imports, and drive a wedge between border and retail prices [START_REF] Burstein | Distribution costs and real exchange rate dynamics during exchange-rate-based stabilizations[END_REF].

With respect to the second point, the literature suggests that shocks resulting from monetary non-neutrality appear to account for a great part of business uctuation [START_REF] Nakamura | Monetary Non-Neutrality in a Multisector Menu Cost Model[END_REF] and, consistently, that sticky prices represent a key determinant of exchange rate pass-through [START_REF] Devereux | Price adjustment and exchange rate pass-through[END_REF]. If prices denoted in domestic currency are sticky, as a consequence of rms facing costs of changing prices, the domestic currency (import) price will not be fully altered even if exchange rate changes aect marginal cost. This implies that import prices do not move immediately and in a one-to-one relation with the exchange rate. Nominal rigidities thus imply that exchange rate movements have a minor immediate eect on consumer price ination [START_REF] Adolfson | Export price responses to exogenous exchange rate movements[END_REF].

In the third case, the argument is that retail prices do not fully reect changes in costs mainly because exporters, producers or distributors are able to adjust their margins. Indeed, in practice, many goods and services are produced in imperfectly competitive markets. In terms of prices for these goods, rms are then able to make a prot margin over costs. If this is the case, in order to maintain stable prices or expand their market share at the retail level, the margin can be modied for exchange rate variations to be absorbed. In this sense, distributors' margins can provide partial insulation from internationally transmitted shocks because of strategic mark-up adjustments along the supply distribution chain [START_REF] Goldberg | The Sensitivity of the CPI to Exchange Rates: Distribution Margins, Imported Inputs, and Trade Exposure[END_REF].

The incomplete exchange rate pass-through to prices because of margins adjustment can be linked to issues related to the process of globalization. Indeed, the extensive literature on Global Commodity Chains (GCC from now on) insists that, because of global sourcing, fragmentation of productive processes and tougher international competition, the balance of power along GCC has signicantly evolved 2 .

For instance, [START_REF] Milberg | Shifting Sources and Uses of Prots: Sustaining US Financialization with Global Value Chains[END_REF] and [START_REF] Milberg | Shifting Sources and Uses of Prots: Sustaining US Financialization with Global Value Chains[END_REF] point out that the development of o-shoring has contributed to the improvement of US rms' mark-up thanks to reduced input prices. Gust, Leduc, and Vigfusson (2010a) and Gust, Leduc, and Vigfusson (2010b) propose that, when a rm's demand curve has a variable elasticity, a declining pass-through to import prices should be linked to trade integration because of foreign producers' mark-up adjustments along the 1 Another argument to explain the disconnection is related to the distances and costs involved in shipping goods. However, the empirical evidence suggests that geographical distance is not the main determinant for the lack of consumer price sensitivity to exchange rate movements (see, for instance, [START_REF] Engel | How Wide Is the Border?[END_REF] 2 See, in particular, Gere and Korzeniewicz (1994) and [START_REF] Bair | Frontiers of Commodity Chain Research[END_REF].

intensive margin.

From an empirical point of view, the literature that explores the role of the exchange rate in distribution margins is not especially abundant, in part because margins are not directly observable, especially not in aggregate data. A notable exception is the contribution of [START_REF] Goldberg | The Sensitivity of the CPI to Exchange Rates: Distribution Margins, Imported Inputs, and Trade Exposure[END_REF], who report that home currency depreciations are associated with statistically signicantly lower distribution margins in a single panel regression containing the United States and 9 European countries over the period 1995-2001. Unfortunately, the previous study overlooks the heterogeneity of the industrial structure 3 . On the contrary, by relying on disaggre- gated data from the Bureau of Labor Statistics' CPI and IPP databases [START_REF] Berger | Border Prices and Retail Prices, The federal Reserve Board[END_REF] nd that that distribution wedges do not vary systematically with exchange rates in the United States. Finally, [START_REF] Hellerstein | Who bears the cost of a change in the exchange rate? Pass-through accounting for the case of beer[END_REF] presents evidence that markup adjustments by manufacturers and retailers explain roughly half of the incomplete transmission in the imported beer market in the U.S.

Even less attention has been paid to the possibility of asymmetric reactions of distribution margins to exchange rate variations. Indeed, even though the theoretical literature has identied at least two possible reasons why the elasticity of prices to exchange rate changes may be asymmetric between appreciations and depreciations, not such awareness has been devoted to the possible asymmetric reactions of distribution margins. Indeed, from the exporters' point of view, if rms are attempting to increase market shares in foreign markets subject to the possibility of trade restrictions, then more pricing-to-market (PTM) may occur during appreciations of the exporters' currency. On the contrary, if rms face capacity constraints in their distribution networks, then PTM may be exaggerated during periods of depreciation of the exporters' currency [START_REF] Knetter | Is Price Adjustment Asymmetric?: Evaluating the Market Share and Marketing Bottlenecks Hypothesis[END_REF].

Following the previous claims, in this paper we argue that a similar argument can be applied to the local distributors' margins in a non competitive framework. In addition, we push the argument one step further while showing that the evolution of distribution margins and the asymmetric adjustment to exchange rate variations throughout various industries should be seen as an indicator of the evolution of the balance of power between producers and distributors.

In sum, we address the following issues: (1) Is there a positive relation between the evolution of distribution margins and globalization? (2) How much do local distribution margins respond to exchange rate uctuations? (3) Do margins respond dierently when the local currency appreciates than when it depreciates?. Addressing the aforementioned issues, the originality of our contribution will be, rst to focus on the margins-exchange rate relationship instead of the pass-through to consumer or import prices. Second, we point out the diversity of margins' levels among industries and the variety of their sensibility to exchange rate dynamics. We argue that, to some extent, this variation should be explained by the diversity of the GCC governance structure and their evolution.

This paper is organized as follows. The following section explains our conceptual framework and our research assumptions. In section 3 we explain our methodology.

3 Indeed, as noticed by [START_REF] Bottazzi | Corporate performances and market selection: some comparative evidence[END_REF], the empirical evidence reveals an impressive heterogeneity concerning, among other characteristics, protability. In addition, heterogeneity among industries and sectors is very persistent over time in the levels of whatever micro variable one looks at.

Section 4 present the data and measurement issues. The results are provided and discussed in section 5. Finally, in the conclusion we summarize our arguments, stress their originality and raise some policy issues.

Conceptual framework

In a perfect competition framework, exchange rate variations impact the general price index in the proportion of the share of imported prices in the domestic consumption.

However, even though the degree of exchange rate pass-through to import prices is an important determinant of the magnitude of the pass-through to consumer prices, incomplete pass-through also relates to market structures that deviate from perfect competition.

Indeed, the literature suggests two main phenomena that are implied in this process of mitigating the eects of exchange rate variations over consumer prices [START_REF] Burstein | Distribution costs and real exchange rate dynamics during exchange-rate-based stabilizations[END_REF]; [START_REF] Campa | Exchange Rate Pass-through into Import Prices: A Macro or Micro Phenomenon?[END_REF]; Hellerstein ( 2008)).

First, the distribution margins (i.e. transportation, storage, nance, insurance, wholesaling, and retailing activities) contribute local-value-added components to the nal consumption value of imports and reduce the weight on border prices for imports in the CPI. Second, another marginalization occurs when distributors choose to vary their margins to absorb some of the exchange rate changes in order to maintain stable prices or expand market share at the retail level [START_REF] Hellerstein | Who bears the cost of a change in the exchange rate? Pass-through accounting for the case of beer[END_REF].

Eectively, under imperfect competition, suppliers have a degree of market power, and set their price taking into account the demand of consumers. In addition, as it is the case for exporting rms in a PTM strategy, asymmetries and non-linearities can be generated at the local distribution level as well, with the pricing decision depending not only on the marginal cost but also on the structure of the market. For instance, if a distributor keeps the price of a certain product unchanged (because of the complementarity in price setting, a rm does not want its price to deviate too far from its competitors), it is optimal for producers to increase his margin in response to a dollar appreciation. An opposite situation may arise if, when faced to an exchange rate depreciation, it is not possible for the distributor to adjust the price upwards and, therefore, his margin is compressed. Accordingly, pass-through of exchange-rate changes to prices is incomplete because the distribution margin absorbs some of the variations in the exchange rate.

It is important to notice that, in the decision to adjust the price and/or the margin, the distributors' objective is to maximize his prot without losing market share. This would imply that price-setters have a bigger incentive to pass depreciations than appreciations to the nal price if their market power allows them to do so.

The previous mechanism has opposite implications on the margin level 4 . Therefore,

given that distributors have more incentives to increase their margins than to reduce them, we should expect a higher impact of the exchange rate due to appreciations than due to depreciations. In other words, the margin may react asymmetrically to movements in the exchange rate.

4 Notice that the more the distribution's margin responds to changes in the nominal exchange rate the lower the pass-through [START_REF] Berger | Border Prices and Retail Prices, The federal Reserve Board[END_REF]. Contrary, if the pass-through is complete, their margin will not respond to uctuations of the exchange rates, thus leading to a pure currency translation.

The margin's (symmetric or asymmetric) responsiveness to exchange rate movements may depend on several factors, among them the form of competition that takes place in the market for the industry and the extent of price discrimination. As such, we could expect the following heterogeneous reactions among dierent industries or sectors depending on the complexity of demand and supply channels in a non-competitive framework in each one of them:

1. A positive shock to the exchange rate of the domestic currency (i.e. a depreciation of the domestic currency) will make imports more expensive. In order not to pass completely the increase in the cost to nal prices, the local distributor reduces his margin; 2. A positive shock to the exchange rate is not passed to the margin since the local distributor decides to pass this increase in costs to the nal price. Very inelastic industries could be characterized by this eect; 3. A negative shock to the exchange rate (an appreciation of the domestic currency) will make imports less expensive. Instead of reducing the nal price of the product, the local distributor increases his margin; 4. A negative shock to the exchange rate is passed to prices (the nal price is reduced) and the margin is not aected; 5. There are no eects of exchange rate mainly because prices are internationally given, as it might be the case for the commodities.

However, it is is not satisfactory to only assess the diversity of the margin's sensibility to exchange rate variations in a static framework. In eect, globalization, has fueled a dramatic change in industrial organization and competition regimes that should be present when looking at the evolution of distribution margins. Indeed, the margins' adjustment to exchange rate variations participate in the process of vertical competition along commodity chains.

In this sense, several contributions account for less stickiness of exchange rate pass-through to prices in case of intra-rm trade in comparison to arms length (i.e. market relations between dierent entities) 5 . The existing literature shows that intra- rm prices are chosen to maximize the sum of the manufacturer's and distributor's prots [START_REF] Neiman | Stickiness, synchronization, and pass-through in intra-rm trade prices[END_REF]. Contrastingly, arm's length prices are xed according to the balance of power between the conicting objectives of prot maximization of the manufacturer and the distributor. Looking at the relationship between exchange rate and margins and the asymmetries previously mentioned is thus relevant to analyze how globalization has impacted the balance of power between retailers and producers among industries.

In the early nineties, Gere and Korzeniewicz (1994), the initiators of the socalled Global Commodity Chains framework, proposed conceptual tools in order to analyze globalization as a phenomena characterized by a pattern of geographical dispersion of functionally integrated economic activities [START_REF] Dicken | Global Shift: The internationalisation of economic activity[END_REF]; Feenstra (1998)). The distinction they make between Buyer-Driven Commodity Chains and 5 See, for instance, [START_REF] Neiman | Stickiness, synchronization, and pass-through in intra-rm trade prices[END_REF].

Producer-Driven Commodity Chains is very useful for our discussion on the exchange rate and the distribution margin.

More in detail, buyer driven commodity chains concerns the whole set of activities which contribute to the elaboration of light and labor intensive consumption goods, such as textile, apparel or agro-food. For the distribution of such products, a few number of leading retailers have a very favourable market power position because of, rst, their control over access to a very high number of nal consumers and, second, their global sourcing capacities, which increase competitive pressure in upstream segments 6 . This phenomenon has accelerated during the past two decades with, on the one hand, the segmentation of productive processes [START_REF] Feenstra | integration of trade and disintegration of production in the global economy[END_REF] and, on the other hand, the internationalization of leading retailers [START_REF] Durand | Institutional and Economic Determinants of Transnational Retailer Expansion and Performance: A Comparative Analysis of Wal-Mart and Carrefour[END_REF]; [START_REF] Coe | The Internationalization of retailing: implications for supply networks restructuring in East Asia and Eastern Europe[END_REF]; Coe and Wrigley ( 2007)). It is thus expected that the share of imported goods for this kind of products has increased and that the market power of retailers has improved. As a result, we could expect that retailers are able to pass through to consumers -or to prevent their suppliers to pass through -the cost of the rise of prices resulting from currency depreciation. On the contrary, they can improve their margins in case of a negative shock to the exchange rate by keeping their prices unchanged. Overtime, this asymmetrical reaction to exchange rate shock is supposed to lead to an increase in the distribution margins for this kind of goods.

Such a result should be consistent with previous research showing a link between o shoring and protability [START_REF] Milberg | Shifting Sources and Uses of Prots: Sustaining US Financialization with Global Value Chains[END_REF] and [START_REF] Milberg | Shifting Sources and Uses of Prots: Sustaining US Financialization with Global Value Chains[END_REF]) as far as it concerns retailing (Baud and Durand, forthcoming).

In the case of producer-driven chains, which concern particularly capital intensive industries such as the automotive and machine building industries, the dynamics is supposed to be dierent. On the one hand, the nal use of the goods is less dispersed, as it occurs with a smaller recurrence and, to a greater extent, within rms and administration. As a result, distribution costs are less important and the position between the nal consumer and the nal seller is less asymmetrical. Moreover, as producers occupy a leading position in the chain and organize supply and distribution networks, they are supposed to be able to pass to others the cost of adjustment to exchange rate. Thus, the asymmetric adjustment to exchange rate is supposed to be made at the expense of the distribution margin. The trend should then be a stabilization or a a reduction of distribution margins overtime which could reect the reduction of logistic costs during the past decades.

The issue of the dynamics of margins concerning commodities and, more generally, resource-based industries, should be considered as very distinctive from the previous cases. Indeed, whereas wholesale and retail components dominate distribution costs for most of the industries, this is not the case for mining and resource intensive industries where transportation, storage, nance and insurance cost dominate the distribution margins [START_REF] Goldberg | The Sensitivity of the CPI to Exchange Rates: Distribution Margins, Imported Inputs, and Trade Exposure[END_REF]. Moreover, the high volatility of international prices of these products deprives margins analysis to most of its meaning. Indeed, the evolution of the margin should not provide information to account for the evolution of the balance of power within the industry. Consequently, looking at market power and chain governance issues through the evolution 6 For instance, since the 1960s, rich markets from developed countries have been linked to low cost manufacturers from South-East Asia because of the rise of global buyers (Hamilton and Gere (2009)).

As previously mentioned, exchange rate movements can have a direct eect in the distribution margins. Therefore, changes in the margin of a given industry/sector are assumed to consist of two components specic to the type of good and to the time period, independent of the exchange rate, and a reaction to exchange rate movements. On a panel data model, this can be expressed in the following way:

∆dm it = µ it + τ t + β∆s it + γ∆y it + ε it (1)
where dm it is the distribution margin of a certain sector in country i at time t, dened as the log dierence of the margin over price, s is the real eective exchange rate dened such that an increase represents a depreciation, ∆ is the rst dierence operator, such that the equation links the rate of growth of the margin to the rate of depreciation (appreciation) and ε it is a vector of error terms, which are assumed to be white noise. We should expect β 1 to be positive: that is, an appreciation (depreciation) which reduces (increases) the prices of imported goods, should allow increases (decreases) in the distribution margin. Following [START_REF] Goldberg | The Sensitivity of the CPI to Exchange Rates: Distribution Margins, Imported Inputs, and Trade Exposure[END_REF], Equation (1) also controls for the country's business cycle conditions by including the GDP growth (∆y it ). In addition, µ it and τ t denote country and year specic eects, respectively.

The previous equation assumes that both depreciations and appreciations are passed to the margin in the same magnitude (but with dierent sign). However, as it was previously suggested, a priori, there is no reason to believe that the margin reacts in such a simplistic way. The reason is simple: the nal distributor has more incentive to increase the margin than to reduce. If this is the case, Equation (1) is very restrictive to capture such an asymmetric behavior.

In order to account for the possibility of asymmetric reactions of the margin, we dene two dummy variables, D 1 and D 2 , that take the value of 1 when the RER depreciates or appreciates, respectively, and 0 otherwise. Then, we dene our variables of depreciation and appreciation of the exchange rate as:

s + it = ∆s it × D 1 s - it = ∆s it × D 2
Such that s + t captures real depreciation and s - t real appreciation. Replacing ∆s it in Equation (1) by its decomposition into positive and negative variations, we modied our baseline equation as follows:

∆dm it = µ it + τ t + β 1 s + it + β 2 s + it + γ∆y it + δr it + ε it (2)
where all the variables were previously dened. Note that s + it (s it ) takes positive (negative) values when the RER depreciates (appreciates), and 0 otherwise. Hence, the coecient β 1 in Equation (2) will be negative and signicant if we expect the margin to be hindered by RER depreciations. Equally, the coecient β 2 will be also negative if RER appreciations (i.e. a decrease in the exchange rate) increase the margin.

Data description and measurement issues

The key variable of our analysis, the distribution margin, is not directly observable, especially not in aggregate data. Following [START_REF] Goldberg | The Sensitivity of the CPI to Exchange Rates: Distribution Margins, Imported Inputs, and Trade Exposure[END_REF], we derive annual distributions margins from the supply and use tables of input-output tables for the following countries: Austria, Belgium, Germany, Finland, France, Denmark, Netherlands, Ireland, Italy, Luxembourg, Spain, Sweden, Portugal and the United Kingdom, for the 1995-2007 period.

In the supply table, ows of goods and services are valued at basic prices. In the use table, the ows are valued at purchasers' prices. In order to attain identities between supply and use, trade and transport margins and taxes less subsidies on products have to be added to the supply table. The total of trade margins by product is equal to the total of trade margins by the trade industries, plus the secondary trade margins by other industries. An analogous equation holds for the transport margins.

The transport margins include transportation costs paid separately by the purchaser and included in the use of products at purchasers' prices but not in the basic prices of a manufacturers' output or in the trade margins of wholesale or retail traders.

From this information, we derive our dependent variable, which is the rst difference of the distribution margin, dened as: dm = trade and transport margin total supply at purchaser's price-taxes less subsidies

(3)

All the data comes from the Input-Output tables provided by Eurostat. We considered the following 25 sectors for which data is available for our period of time: Agriculture, forestry, shing, coal and lignite, metal ores, food and beverages, tobacco products, textiles, wearing apparel and furs, leather products, products of wood, paper products, coke, chemical products, rubber and plastic, basic metals, metal products, fabricated machinery, computers, electrical machinery, radio and television, medical instruments, vehicles, other transport equipment and furniture.

Regarding the exchange rate, we use real eective exchanges extracted from the Bank of International Settlements (BIS) database. Finally, the control variables, the rate of growth of the GDP and the real interest rate were collected from the OECD's main economic statistics.

Results

In this Section, we provide our main results. In a rst moment, we present stylized facts and preliminary descriptive results to build intuition for the results from the econometric model. We then present our main econometric results.

5.1 Margins, imports and nal uses: Main features of cross industry evolution patterns (1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007) Table 1 summarize some stylized facts concerning the level of margins and imports both as a proportion of the total price in 2007, as well as their respective evolution between 1995 and 2007. Note that the data do not account for the distinction between transportation, wholesale and retail sale, as the wholesale and retail components dominate distribution costs in almost all industries reporting data, accounting for about 90% of the total distribution costs added to the basic prices of goods [START_REF] Goldberg | The Sensitivity of the CPI to Exchange Rates: Distribution Margins, Imported Inputs, and Trade Exposure[END_REF]. Indeed, the transport margins are typically less than 5% of the basic prices, with the exception of some of the mining and extractive resource industries. It is usually only in the mining and resource intensive industries that we observe transportation margins dominating the distribution costs. Moreover, we observe that for all the products, particularly in sectors such as tobacco, wearing apparel or leather products, the share of imports in the total net purchaser price increased during the period, probably due to the rising regional and global economic integration. However, we categorized three main groups of goods in order to point out more heterogeneous trends on the basis of the characteristics of the products and the dominant form of their use in the economy 7 .

First, we named "Light consumption goods" those goods for which the nal use by households is the most important kind of use. For all these labour intensive manufacturing and agro-food products the nal use by households represent more than 50% of total use, except in the case of textile (37%). Moreover, among these goods, the proportion of the margin in the nal price are very important (above 25%) except for wearing, apparel and furs and leather products, which are typically more expensive items. The most striking gure is that not only margins in all these industries represent an important share of the price, but they also increased during the period, most of them at an annual rate of more that 1%, particularly in the case of textiles. The other important feature is that the share of imports, while not being particularly high, increased considerably, at about 3% each year for all industries.

The second category, "Manufacturing Goods", regroups mainly mechanic, electric and electronic industries, which are more capital intensive industries than the light consumption goods. Their uses are variously distributed between nal use by households, input of industries, and gross capital formation. Typically, the margins in this group are between 10 and 12%, with the exception of other transport equipment, which include items such as railway equipment, ships aircraft and spacecraft.

Contrary to the rst category, margins are a less signicant part of the price and we observe in all the cases, with the exception of machinery a reduction over the period.

However, there is no clear trend as far as the evolution of imports is concerned: imports represent a very important share, but their evolution was rather limited in most of the cases.

Finally, the products of the third groups are at more than 50% used as "Input for Industries" except chemicals (40.6%) and coke and rened petroleum (48.5%).

The proportion of the margins in the total price is relatively low. Most of them, with the exception of metal products and chemicals, are commodities or resourcebased manufacturing products. In this category there is no trend concerning the evolution of margins, which represent about 10% of the price. Similarly, there is no homogeneity regarding the share of imports and their evolution: while imports represent more than 80% of the price for metal ores and coal, they are not particularly important in metal products.

Econometric Results

Table 2 below reports the results from the panel estimation of Equations ( 1) and

(2), for each of the sectors considered. Columns 2 and 3 report results from the symmetric specications while columns 4 through 7 show the relevant estimated parameters of the equation that allows for asymmetric responses due to real exchange rate depreciations (s + it ) and appreciations (s

- it ).
Before turning to the results of the asymmetric equation (i.e. when the real exchange rate variation is decomposed into its positive and negative components), let us rst notice that the elasticity of the margin to the exchange rate is negative and signicant in most cases. Indeed, as expected, when the real exchange rate depreciates, the margin decreases in almost all the sectors. The elasticity is substantially higher in oce machinery and computers, radio and television and agriculture. On information on the form of use of the products. the contrary, the estimates of the elasticity is not signicant for most of the resource based products such as metal ores, coal and lignite, metal products, basic metals and rubber and plastic and some other sectors such as tobacco. In the rest of the cases, the elasticity is signicant and around 40-50%.

Regarding the asymmetric equations, we can distinguish, broadly speaking, three main situations regarding the elasticity of the distribution margin due to positive and negative variations of the exchange rate. Indeed, rst, even when allowing for asymmetric eects of the exchange rate, the margin in many resource based products is rather insensible to movements in the exchange rate, even when asymmetries are allowed for in the specication.

Second, several sectors, basically light consumption goods such as food and beverage, textiles, wearing apparel and leather products, are characterized by signicant eects of exchange rate appreciations. On the contrary, the low signicance of the 6 Conclusions

In this paper, we provide new empirical evidence that exchange rate devaluations and appreciations impact asymmetrically distribution margins. This phenomenon, previously ignored in the literature, signals eects of globalization on the industrial structure of European economies.

Pointing out an imperfect competition structure within Global Commodity Chains, we set out to build a framework that can be used to explain and identify the dierent responses of the distribution margin towards exchange rate variation. In particular, we developed a simple empirical model that introduces the possibility of asymmetric responses of the distributions margin to depreciations and appreciation at the industry level for several European countries between 1995 and 2007. By doing so, our analysis yields several interesting ndings.

First, at the descriptive level, we document an important and increasing margin for light consumption goods, such as wearing apparel, textiles and food products which are mainly used by households. Typically this evolution occurs in a context of rapid growing of the share of imports. Contrary, margins for goods that are more capital intensive industries and which use is more equally distributed between households, inputs for industries and investment, have typically smaller and decreasing distribution margins. For these mechanic and electronic products, the increase of the share of imports is important but it increased at a smaller rate. We suggest that the two distinctive dynamics are linked to distinctive commodity chains organizational forms: a) the light consumption goods, being mainly buyer driven chains dominated by retailers and b) manufacturing goods, being mostly elaborated within producer driven chains.

Second, we are able to distinguish three opposite reactions of the margin towards exchange rate variations. First, for buyer driven chains (i.e. light consumption goods), distributors can use their favourable market power position to increase their margin in case of exchange rate appreciation, whereas depreciations do not reduce margins in the same magnitude. For this type of goods, producers and consumers may also share the costs of depreciations. Second, asymmetries in producer driven goods are less evident, since producers occupy a leading position in the chain and are organizing supply and distribution networks, being able then to pass to distributors some of the cost of exchange rate variations. Under this scenario, the distributor's margin may also be reduced in case of depreciation. Finally, given that transportation, storage, nance and insurance cost dominate the distribution margins, we provide evidence that exchange rate variations do not aect the margin for most of the resource based products.

We can draw from these empirical results some important conclusions. On the policy side, our results suggest that nal prices will not react one-for-one after an exchange rate movement, but that margin compression will aect market structures.

Second, globalization has aected variously rms depending on their position within the commodity chains and the products elaborated along them. It appears thus relevant to incorporate the insights of the global commodity chain literature when examining the issue of exchange rate pass-through to price.

Third, the rise of distribution margins for light consumption goods shows the growing economic power of retailers, which provide outlets for overcrowded industries in a context of more tense international competition. It suggests that a sectoral shift for the industries concerned is occurring towards the downstream segments of the chains. This evolution is consistent with the literature analyzing oshoring and its consequences on labor in rich countries (mainly a weakening of the position of blue collar workers and the tertiaziation of employment, [START_REF] Glyn | Capitalism Unleashed[END_REF]). In all, a variation in the exchange rates can have redistributive eects across sectors and rms.

Finally, it should be interesting to analyse the relationships between the evolution of prices and the evolution of margins. Indeed, an increase in the distribution margins in a context of stable or diminishing prices may suggest a kind of Baumol [START_REF] Baumol | Performing Arts: The Economic Dilemma[END_REF]) at the industry level, with a growing weight of distribution services because of their weaker productivity dynamism than manufacturing activities. Such a mechanism being conrmed, it would imply that the prospects for further contribution to economic growth of the chains concerned are limited.

Table 1 :

 1 Distribution margins, imports (as a proportion of the price and annual average growth rate) and uses (as a proportion of total use).1995- 2007

			Margins		Imports		Uses, 2007
	Products	% of	Growth	% of	Growth	Households	Inputs	Investment
		net price 1995-2007 net price 1995-2007	% of	% of	% of
		2007		2007		total use	total use	total use
	Light consumption
	Tobacco products	40.6	1.5	43.3	6.7	91.8	0.8	2.2
	Wearing apparel	40.1	1.0	64.4	3.3	74.5	9.6	2.1
	Fishing	30.8	0.5	50.1	3.3	57.6	30.2	0.9
	Leather products	35.9	1.2	64.9	3.0	55.0	21.3	1.8
	Furniture	29.9	0.4	42.5	2.9	54.1	16.7	12.8
	Food and beverages	24.7	1.1	22.9	3.0	54.0	31.4	1.2
	Textiles	24.9	2.0	42.5	1.9	37.6	36.8	1.8
	Manufacturing
	Computers	23.4	-0.9	79.4	1.3	9.1	24.6	24.1
	Machinery	12.9	0.2	39.2	0.9	7.8	29.1	23.5
	Medical instruments	17.5	-0.7	45.7	0.4	12.7	28.4	16.6
	Other transport eq.	5.3	-9.3	41.8	1.9	9.4	30.6	16.3
	Vehicles	13.2	-1.3	49.4	1.0	26.1	25.1	13.8
	Radio, television	15.6	-0.4	58.7	2.4	16.6	32.7	11.8
	Electrical machinery	11.7	-0.6	42.2	1.1	4.9	51.3	10.9
	Resource based
	Metal ores	13.5	1.2	80.0	-0.1	0.0	90.9	0.0
	Coal and lignite	8.7	-4.6	82.4	3.5	6.4	85.3	0.5
	Products of wood	14.4	0.6	25.8	1.2	7.5	72.7	4.1
	Metal products	10.5	0.2	20.4	1.2	5.2	67.1	10.3
	Forestry	14.1	-0.4	29.5	1.7	13.0	66.9	4.4
	Basic metals	7.4	-2.7	45.9	1.6	0.1	65.2	0.2
	Paper products	14.1	0.9	30.1	1.2	12.5	61.5	0.2
	Rubber and plastic	13.1	0.4	34.9	1.6	11.1	61.0	1.0
	Agriculture	19.3	1.8	26.7	2.1	31.2	54.3	2.4
	Coke and fef. pet.	13.7	-4.1	37.8	2.3	35.4	48.5	1.1
	Chemical products	17.7	0.5	46.3	1.1	14.3	40.7	0.3
	Source: author's own calculation based on Eurostat input-output information.

Table 2 :

 2 Margin's adjustments to real eective exchange rate variations

	Symmetric		Asymmetric
	∆s	t-stat	s + it	t-stat	s -it	t-stat

it correspond to real exchange rate variations, depreciation and appreciation, respectively.

Note that we do not consider exports or government consumption, as they do not provide

positive component of the exchange rate implies that the margin is not aected by exchange rate depreciations. That is, in this group, with the exception of furniture, the margin increases due to appreciations but does not decrease due to depreciations.

While not being classied as "light consumption goods", other sectors, such as wood and paper products and agriculture also present this characteristic 8 .

The third important situation arises when both appreciations and depreciations have signicant eects, although not of the same magnitude. This is the case in many manufacturing goods such as computers, machinery, radio and television, other vehicles and some other sectors not classied as pure manufacturing goods, like chemical products. Note that, in all these cases, the eects of depreciations (i.e. reductions in the margin) are relatively higher. The non signicance of the asymmetric coecients in the case of vehicles may imply that the symmetric specication is more appropriate, with both appreciations and depreciations aecting the margin more or less in the same magnitude. Among the manufacturing goods, only electrical machinery reacts as a buyer driven good, with increases in the margins due to exchange rate appreciations.

More specically, our results allow us to distinguish three regime of margins variation and of margins relations with the exchange rate among industries. In particular, two of them reect dynamics which can be interpreted within the Global Commodity Chains perspective (light consumption goods and manufacturing goods), which is not the case for the third one (resource-based products).

Indeed, in general terms, the evolution of the margin for light consumption goods and manufacturing goods is consistent with our hypothesis. First, we observed a signicant increase in the margin for light consumption brought to nal users through buyer-driven chains where, at the same time, the share of imported goods became more important. This evolution proceeds from asymmetrical reactions to exchange rate variations which favours preservation or increase of distribution margins. It conrms the hypothesis that, for this kind of goods, globalization has beneted rms which control access to market at the expense of producers.

We observe the opposite trend in several manufactured goods elaborated in producer-driven chains. As in the case of the previous group, there has been an increase in the share of imported goods. However, the trend is generally less clear, with the exception of computers and, to a lesser extent, machinery and vehicles.

The most striking fact is that distribution margins have evolved negatively for all the products considered, except in the case of machinery. This can be explained by the fact that, while both appreciations and depreciations impact the margin, the magnitude of such eect is relatively higher in the second case (such is the case in computers, machinery, other transport equipment and radio and television). In other words, the relative weight trade margin has been eroded because of unfavorable adjustment to exchange rate movements.

Finally, as far as resource based products are concerned, the results suggest that margins are not relevant for such products since they represent a relatively small proportion of the price.

8 Even though it is not the objective of this paper, we could expect that the distributor passes the depreciation, but not the appreciation, to the nal price. In other words, the price would increase in case of depreciation of the local currency, but it would hardly decrease. In case of appreciation, is the distributor the one who "prots" by increasing his margin.


Nicolas Leboulanger
email: nicolas.leboulanger@trs.aphp.fr

Bruno Louis
email: bruno.louis@inserm.fr

Raphael Vialle
email: raphael.vialle@trs.aphp.fr

Benedicte Heron
email: benedicte.heron@trs.aphp.fr

Brigitte Fauroux
email: brigitte.fauroux@trs.aphp.fr

Raphaël Vialle

Bénédicte Heron

Pr Brigitte Fauroux

Analysis of the upper airway by the acoustic reflection method in children with mucopolysaccharidosis

Keywords: mucopolysaccharidosis, acoustic reflection method, upper airways, child, airway resistance, acoustic pharyngometry mucopolysaccharidosis, acoustic reflection method, acoustic pharyngometry, children, upper airways mucopolysaccharidosis, acoustic reflection method, acoustic pharyngometry, children, upper airways

Introduction

Mucopolysaccharidoses (MPS), OMIM 252700, are a group of rare metabolic inherited disorders caused by the lack or deficiency of specific lysosomal enzymes involved in the degradation of mucopolysaccharids (glycosaminoglycans). 1 The accumulation of partially degraded molecules interferes with cell, tissue, and organ function. Depending on the MPS subtype, the disease may display various degrees of severity. Mental retardation is common and often severe but may be absent in some MPS (MPS VI).

Upper airway obstruction and its management is a challenging concern in children and adults with MPS. Due to tissue infiltration, airway obstruction may affect the different levels of the respiratory tract. Patients may present narrowed nasal airways, adenotonsillar hypertrophy, macroglossy, thickened tongue, a short and infiltrated neck, and a narrowed pharynx and larynx with a thickened epiglottis. This airway obstruction is associated with an increase in morbidity even in early childhood. 2 . Indeed, severe obstructive sleep apnoea syndrome has been reported in children with MPS. [3][4][5][6][7] This upper airway obstruction may also complicate the perioperative anaesthetic management, for endotracheal intubation is known to be especially difficult in MPS patients because of soft tissues infiltration and frequent cervical spine malformations. Intubation may require an endoscopic procedure [8][9][10] and is not always able to prevent a fatal outcome even for routine procedures. 11 The acoustic reflection method (ARM) is an interesting noninvasive technique based on the analysis of the reflection of a single transient planar wave, allowing the calculation of the longitudinal cross-sectional area profile of the examined cavity. An analysis of the mechanical properties of the airways by the forced-oscillations method is also possible by this technique. 12 . The ARM has been first reported in humans in 13 Since then, ARM has been used to explore the pharyngeal cavity in snoring patients (acoustic pharyngometry) 14,15 , the nasal compliance (acoustic rhinometry) 16 , the obstruction of endotracheal tubes by mucus plugging 17 , the misplacement of endotracheal tubes 18 , the vocal tract dimensions in adolescents 19 and in children with Down syndrome. 20 The ARM has also been used to measure tracheal size and distensibility in healthy adults and patients with cystic fibrosis or achondroplasia. 21,22 We have recently evaluated the feasibility and established normal values of the upper airways by the ARM in a large group of healthy children. Accurate measurements could be obtained in all the children older than 2 years of age. 23 Normal values of the minimal cross sectional area (MCAv), which corresponds to the narrowest part of the upper airways (i.e the subglottic region), were established and correlated mainly with height, and to a lesser extend with age and weight. As children with MPS may present upper airway obstruction, we hypothesised that the ARM may be particularly adapted to this population because this technique is noninvasive, simple, and rapid, with a procedure taking less than one minute.

The aim of the present study was to evaluate by the feasibility of the ARM in children with MPS, and to compare the characteristics of the upper airways evaluated by the ARM in patients with MPS to a matched group of healthy children.

Material and methods

Patients

The study was proposed to the parents of 10 patients with MPS, followed in our institution and expected to be able to perform the ARM manoeuvre. To be included, the patient had to be free of any acute upper or lower airway disease since at least one month. The ARM measurements were realised during a scheduled hospital visit or hospitalisation.

The following information was assessed from the patient's chart: history of endotracheal intubation and/or any respiratory or upper airway disease, and sleep studies when available.

Control group

A control group was recruited among siblings of the patients and a large group (n>60) of outpatients from the otolaryngology department (mostly for middle ear surgery). All controls were free of any upper or lower airway disease or symptom since at least 3 months. The control group was secondarily established in order to match with the MPS patients' height, weight, and body mass index (BMI).

The study was approved by our institutional board and written consent was obtained from all the patients and the controls when possible, and all the parents.

The acoustic reflection measurement

The device used in this study, as well as its calibration method, has been previously described. 12,24 Briefly, the acoustic reflection device consists in a Plexiglas tube of 22 cm in length and 16 mm in diameter. Two microphones (piezoresistive pressure transducers, 8510-B; Endevco France, Le Pré Saint-Gervais, France) are For a reliable ARM measurement, the subject has to breathe by mouth during ≈ 4 s. As such, only the airways beyond the mouth were analyzed. During these 4 seconds, the ARM device generates 10 consecutive acoustic waves at a frequency of 2.5 Hz and the corresponding areas distance curves are inferred. As previously shown, ARM measurements are influenced by the position of the head and the connecting equipment. [25][26][27][28] For the recording, the subjects were thus asked to have their head in a neutral position and to breathe through an elastomer mouthpiece (Air Safety Ltd, ref A539, Morecambe, United Kingdom) and a single use filter (Intersurgical Clear-Guard™, ref 1664, Wokingham, United Kingdom).

Data are given on a 2 dimensional graph with the distance from the end of the wave tube on the x-axis and the cross-sectional area on the y-axis (Figure 1). A program calculates the cross-sectional area of the airway as a function of the distance along the longitudinal axis with a spatial step increment ∆L ≅ 0.4 cm. For every point on the x-axis value, i.e. distance on the airway, the mean value of the 10 curves is calculated but if the coefficient of variation of the 10 curves area exceeds 10% the test is discarded and a new test is performed. A visual control by the operator of the 10 curves (allowing to hand-mark the appropriate areas), as well as the checking of an eventual rejection of a measurement, are systematically associated to this computer analysis. The analysis software also gives the results of each measurement in a numerical format, allowing an accurate estimation of 19,20 , our procedure implies a subjective part in the determination of landmarks. This choice was dictated by the expected lack of cooperation of children with mental retardation. In order to deemphasise the effect of any error on the landmarks definition, we only focussed on parameters that are not, or very partially, affected by the landmarks choice. We used thus the MCAv and mean area over a region of interest and we disregarded the cavity length and the cavity volume.

The software allows also the calculation of the mechanical properties of the respiratory system by the forced oscillations technique, as previously demonstrated. 12 The system's impedance, defined as the ration between pressure and flow at the mouth, appears as a function of the frequency. Here, the patient's airways' total resistance (R) was defined as the average of the real part of the impedance between 15 and 45 Hz.

Statistical analysis

Data were expressed as mean ± standard deviation. Comparison between the patients and the controls was performed using Student's T Test. A p value less than 0.05 was considered statistically significant.

Results

Patients and feasibility

Thirty-eight children with a MPS are followed in our institution: MPS III, n=22 (58%), mean age 11.8 ± 2.3 year-old; MPS II, n=9 (24%), mean age 10.3 ±1.1 yearold; MPS IV and VI, n=3 each (8%), mean age 8.5 ± 1.7 and 21 year-old respectively; and 1 (2%) other MPS type, aged 10.5 years. Patients "non suitable for ARM" were pre-selected by our paediatrician neurologist (BH), as they were expected to be unable to perform the ARM manoeuvres because of severe mental retardation and/or major behaviour problems. Ten patients were selected and participated to the study (Figure 2).

Accurate ARM measurements could only be obtained in 7 patients. Indeed, despite pre-selection, 3 patients were unable to breathe normally by mouth for 3 to 4 seconds despite the pre-selection on their capacity, patience, adequate explanations, and parental reassurance (Table 1). No patient with a MPS III could be included because of severe mental retardation and behavioural disorders. One patient had a fucosidosis, considered as a Hurler-like syndrome. 29 Among the 7 patients, 4 patients had no respiratory symptoms, 3 patients complained of dyspnea at exertion (n=3) and 2 (#6 and #7) had documented nocturnal alveolar hypoventilation and were treated by long-term noninvasive positive pressure ventilation (NPPV). The sleep studies of these 2 patients during spontaneous breathing and before initiation of NPPV showed a desaturation index of 34 and 36 per hour, hypoxemia (minimum pulse oximetry (SpO 2 ) 66 ± 5.6%) and hypercapnia (maximum transcutaneous carbon dioxide (PtcCO 2 ) 49 ± 5.6 mmHg) (Table 2). One of these two patients previously underwent an endoscopic examination showing an infiltration of the posterior pharyngeal wall, the base of the All patients had previously undergone an endotracheal intubation for a surgical procedure (adenoidectomy, dental care, spine surgery). Four patients (#1, #5, #6 and #7) had a history of difficult intubation, which required the use of a fiberoptic bronchoscope for 2 of them (#5 and #6). None had a history of tracheotomy.

The characteristics of the patients are given in Tables 2 and3.

Control group

The control group consisted of 14 healthy children (mean age 7.3 ± 2 years) who were matched to the patients with regard to height and weight (Table 3). The ARM recording was successful in all the subjects. Due to the impaired growth and development of MPS patients, the healthy subjects matched for height and weight were significantly younger than the patients (p=0.04).

Cross-sectional area values

The MPS patients had a significantly lower mean MCAv than their healthy counterparts (1.6 ± 0.3 cm² and 1.8 ± 0.3 cm² for MPS patients and controls, respectively; p=0.03) (Figure 3 and4 and Table 3). The mean pharyngeal and tracheal area values were also lower in the MPS group than in the controls, but this difference was not statistically significant. Concerning the individual data, MCAv results were clearly different from the controls for 4 MPS patients (patients #3, #5, #6, and #7). Of note, 2 of these patients (patients #6 and #7) were those with severe upper airway obstruction treated with NPPV. Because of the abnormal MCAv results in the two other patients (patients #3 and #5), sleep studies were performed. Although the results were within the normal range, the apnoea index was 1 and the hypopnoea index was 2 in patient #3, and the patient #5 had a hypopnoea index of 5 and spent 12% of sleep time with a low SpO 2 between 90 and 95%.

Upper airways resistance

The mean resistance (R) of the upper airways was higher in the MPS group (7.9 ± 1.8 cmH 2 O.l -1 .s) than in the control group (5.5 ± 1.2 cmH 2 O.l -1 .s) (p=0.0064) (Figure 4 and Table 3).

Again, when looking at the individual data, the R results were clearly different from the controls for 4 MPS patients (patients #3, #4, #6, and #7). These 4 patients comprised 3 of the previous patients (patients #3, #6, and #7). The last patient (#4) is scheduled for a sleep study in the coming weeks.

These complementary data are given in table 2.

Discussion

This study shows that the ARM is able to identify a significant reduction of the upper airway calibre in children with MPS. Indeed, the mean MCAv was significantly lower and the mean airway resistance was significantly higher in 7 patients with MPS as compared to a matched control group. However, individual results were without the normal range in 5 of the 7 patients, of whom 2 were treated with NPPV for severe upper airway obstruction.

Technical issues

We chose the ARM as a tool to study the upper airways in patients with MPS, in whom cooperation may be difficult, because this technique is simple, noninvasive and takes only several seconds. We have recently reported the excellent feasibility of this technique which can be realized in healthy children after the age of 2 years.

However, because of a lack of cooperation, mental retardation, and behavioural problems, reliable, accurate ARM measurements could only be obtained in 7 out of 10 selected patients. The experience of our team in performing ARM recordings in children was undoubtedly helpful but was not sufficient. Moreover, if the pre-selection of our patients allowed us to achieve enough successful recordings to obtain workable data, the extension of our results to all the paediatric MPS population must be made with caution. We could only perform ARM measurement in 7/38 (18%) of all our MPS patients and even if this percentage may be improved (inclusion of adults, multiple examinations in an optimal environment), examination of the total population seems unrealizable. Of note, no patient with a MPS III could be studied. Exploring the airways of MPS patients is challenging. Evaluations have been done with CT-scanning but in addition to the irradiation it delivers, this imaging technique also requires cooperation and hold breathing for a few seconds to give reliable data. This seems difficult to achieve in MPS patients, especially in the stressogenic supine position in the scanner machine. 30 Fiberoptic examination gives accurate morphological data but may also be difficult to perform in children with behavioural problems, and does not provide reliable airway measurements because of the distortion of the images in the optic fibre and the bias of images' interpretation by one practitioner only. However, at least one fiberoptic examination seems recommendable prior to a general anaesthesia in MPS patients. 31

Clinical relevance of the results

The MCAv is the most important parameter for the evaluation of the upper airway because the minimal airway diameter influences both the clinical presentation and the therapeutic management. 32 In healthy subjects, the MCAv corresponds to the subglottic area, which is physiologically the narrowest region of the upper airways. As none of our patients had a history of airway surgery of prolonged intubation, it is likely that their MCAv also corresponds to the subglottic area. The mean MCAv value was significantly reduced in the group of patients with MPS compared to the control group. This can be explained by the infiltration of the airways' wall by the partially degraded molecules inherent to MPS. The mean values of the pharynx and the trachea cross-sectional areas also showed a trend to be reduced compared to healthy children, but this did not reach statistic significance. A significant threshold might have been reached with the inclusion a larger group of patients. Even if the The overall resistance of the airways was significantly higher in the MPS group as compared to the control group. This can be explained by the modification of the wall compliance, and the reduction of the cross-sectional area of the pharynx, larynx, and trachea, and the lower airways.

Interestingly, the patients with obstructive sleep apnoea and a need for a nocturnal NPPV (#6 and #7) had clearly MCAv and airway resistance values outside the normal range. This led us to screen the 3 patients having also abnormal values for upper airway obstruction by a sleep study. The sleep results of these clinically asymptomatic patients were not totally normal (Table 2), underlining the potential value of the ARM as a screening tool for the detection of mild and/or subclinical OSAS in patients with MPS.

Interestingly, MPS patients with abnormal MCAv and airway resistance seemed to be older than those with normal values (12.6 vs. 7.9 years of age). This may be explained by the progressive infiltration of the airways' wall with time. Further studies are warranted to evaluate the usefulness of systematic sleep studies in older patients with MPS in order to detect clinically asymptomatic upper airway obstruction. Selection of subjects eligible for the acoustic reflection measurement among the patients with a mucopolysaccharidosis followed in our institution Nicolas LEBOULANGER 1,2,3,4,5,8 nicolas.leboulanger@trs.aphp.fr Bruno LOUIS 3,4 bruno.louis@inserm.fr

Raphaël VIALLE 1,6,9 raphael.vialle@trs.aphp.fr

Bénédicte HERON 1,7,9 benedicte.heron@trs.aphp.fr

Brigitte FAUROUX 1,4,8,9 brigitte.fauroux@trs.aphp.fr The acoustic reflection method is a noninvasive technique that can analyse the calibre of the upper airways. The aim of the study was to evaluate the feasibility of the acoustic reflection method in children with mucopolysaccharidosis, and to compare the characteristics of the upper airways evaluated by the acoustic reflection method in patients with mucopolysaccharidosis to matched healthy counterparts.

Methods

Open, single centre, prospective, study

Results

Accurate acoustic reflection measurements could be obtained in 7 of 10 patients (mean age: 10.4 ± 3.9 years; mucopolysaccharidosis type II (n=3); type IV (n=2), type VI (n=1), and fucosidosis (n=1)). The mean minimum cross-sectional area was lower in mucopolysaccharidosis patients (1.6 ± 0.3 cm²) as compared to 14 healthy counterparts (1.8 ± 0.3 cm²; p=0.03). The mean resistance of the airways was significantly higher in the MPS group (7.9 ± 1.8 cmH 2 O.l -1 .s) as compared to the controls (5.5 ± 1.2 cmH 2 O.l -1 .s; p=0.006).

Conclusion

This study is the first to analyze the upper airways by the noninvasive acoustic reflection method in children with mucopolysaccharidosis. Due to a lack of cooperation, reliable measurements could only be obtained in 70% of a selected group of patients. Children with mucopolysaccharidosis have significant upper airway obstruction as assessed by the reduction of the minimal cross-sectional area of the upper airways and the increase in airway resistance.

Introduction

Mucopolysaccharidoses (MPS), OMIM 252700, are a group of rare metabolic inherited disorders caused by the lack or deficiency of specific lysosomal enzymes involved in the degradation of mucopolysaccharids (glycosaminoglycans). 1 The accumulation of partially degraded molecules interferes with cell, tissue, and organ function. Depending on the MPS subtype, the disease may display various degrees of severity. Mental retardation is common and often severe but may be absent in some MPS (MPS VI).

Upper airway obstruction and its management is a challenging concern in children and adults with MPS. Due to tissue infiltration, airway obstruction may affect the different levels of the respiratory tract. Patients may present narrowed nasal airways, adenotonsillar hypertrophy, macroglossy, thickened tongue, a short and infiltrated neck, and a narrowed pharynx and larynx with a thickened epiglottis. This airway obstruction is associated with an increase in morbidity even in early childhood. 2 . Indeed, severe obstructive sleep apnoea syndrome has been reported in children with MPS. [3][4][5][6][7] This upper airway obstruction may also complicate the perioperative anaesthetic management, for endotracheal intubation is known to be especially difficult in MPS patients because of soft tissues infiltration and frequent cervical spine malformations. Intubation may require an endoscopic procedure [8][9][10] and is not always able to prevent a fatal outcome even for routine procedures. 11 The acoustic reflection method (ARM) is an interesting noninvasive technique based on the analysis of the reflection of a single transient planar wave, allowing the calculation of the longitudinal cross-sectional area profile of the examined cavity. An analysis of the mechanical properties of the airways by the forced-oscillations method is also possible by this technique. 12 . The ARM has been first reported in humans in 13 Since then, ARM has been used to explore the pharyngeal cavity in snoring patients (acoustic pharyngometry) 14,15 , the nasal compliance (acoustic rhinometry) 16 , the obstruction of endotracheal tubes by mucus plugging 17 , the misplacement of endotracheal tubes 18 , the vocal tract dimensions in adolescents 19 and in children with Down syndrome. 20 The ARM has also been used to measure tracheal size and distensibility in healthy adults and patients with cystic fibrosis or achondroplasia. 21,22 We

Material and methods

Patients

The study was proposed to the parents of 10 patients with MPS, followed in our institution and expected to be able to perform the ARM manoeuvre. To be included, the patient had to be free of any acute upper or lower airway disease since at least one month. The ARM measurements were realised during a scheduled hospital visit or hospitalisation.

The following information was assessed from the patient's chart: history of endotracheal intubation and/or any respiratory or upper airway disease, and sleep studies when available.

Control group

A control group was recruited among siblings of the patients and a large group (n>60) of outpatients from the otolaryngology department (mostly for middle ear surgery). All controls were free of any upper or lower airway disease or symptom since at least 3 months. The control group was secondarily established in order to match with the MPS patients' height, weight, and body mass index (BMI).

The study was approved by our institutional board and written consent was obtained from all the patients and the controls when possible, and all the parents.

The acoustic reflection measurement

The device used in this study, as well as its calibration method, has been previously described. 12,24 Briefly, the acoustic reflection device consists in a Plexiglas tube of 22 cm in length and 16 mm in diameter. Two microphones (piezoresistive pressure transducers, 8510-B; Endevco France, Le Pré Saint-Gervais, France) are Data are given on a 2 dimensional graph with the distance from the end of the wave tube on the x-axis and the cross-sectional area on the y-axis (Figure 1). A program calculates the cross-sectional area of the airway as a function of the distance along the longitudinal axis with a spatial step increment ∆L ≅ 0.4 cm. For every point on the x-axis value, i.e. distance on the airway, the mean value of the 10 curves is calculated but if the coefficient of variation of the 10 curves area exceeds 10% the test is discarded and a new test is performed. A visual control by the operator of the 10 curves (allowing to hand-mark the appropriate areas), as well as the checking of an eventual rejection of a measurement, are systematically associated to this computer analysis. The analysis software also gives the results of each measurement in a numerical format, allowing an accurate estimation of 19,20 , our procedure implies a subjective part in the determination of landmarks. This choice was dictated by the expected lack of cooperation of children with mental retardation. In order to deemphasise the effect of any error on the landmarks definition, we only focussed on parameters that are not, or very partially, affected by the landmarks choice. We used thus the MCAv and mean area over a region of interest and we disregarded the cavity length and the cavity volume.

The software allows also the calculation of the mechanical properties of the respiratory system by the forced oscillations technique, as previously demonstrated. 12 The system's impedance, defined as the ration between pressure and flow at the mouth, appears as a function of the frequency. Here, the patient's airways' total resistance (R) was defined as the average of the real part of the impedance between 15 and 45 Hz.

Statistical analysis

Data were expressed as mean ± standard deviation. Comparison between the patients and the controls was performed using Student's T Test. A p value less than 0.05 was considered statistically significant.

Results

Patients and feasibility

Thirty-eight children with a MPS are followed in our institution: MPS III, n=22 (58%), mean age 11.8 ± 2.3 year-old; MPS II, n=9 (24%), mean age 10.3 ±1.1 yearold; MPS IV and VI, n=3 each (8%), mean age 8.5 ± 1.7 and 21 year-old respectively;

and 1 (2%) other MPS type, aged 10.5 years. Patients "non suitable for ARM" were pre-selected by our paediatrician neurologist (BH), as they were expected to be unable to perform the ARM manoeuvres because of severe mental retardation and/or major behaviour problems. Ten patients were selected and participated to the study (Figure 2).

Accurate ARM measurements could only be obtained in 7 patients. Indeed, despite pre-selection, 3 patients were unable to breathe normally by mouth for 3 to 4 seconds despite the pre-selection on their capacity, patience, adequate explanations, and parental reassurance (Table 1). No patient with a MPS III could be included because of severe mental retardation and behavioural disorders. One patient had a fucosidosis, considered as a Hurler-like syndrome. 29 Among the 7 patients, 4 patients had no respiratory symptoms, 3 patients complained of dyspnea at exertion (n=3) and 2 (#6 and #7) had documented nocturnal alveolar hypoventilation and were treated by long-term noninvasive positive pressure ventilation (NPPV). The sleep studies of these 2 patients during spontaneous breathing and before initiation of NPPV showed a desaturation index of 34 and 36 per hour, hypoxemia (minimum pulse oximetry (SpO 2 ) 66 ± 5.6%) and hypercapnia (maximum transcutaneous carbon dioxide (PtcCO 2 ) 49 ± 5.6 mmHg) (Table 2). One of these two patients previously underwent an endoscopic examination showing an infiltration of the posterior pharyngeal wall, the base of the All patients had previously undergone an endotracheal intubation for a surgical procedure (adenoidectomy, dental care, spine surgery). Four patients (#1, #5, #6 and #7) had a history of difficult intubation, which required the use of a fiberoptic bronchoscope for 2 of them (#5 and #6). None had a history of tracheotomy.

The characteristics of the patients are given in Tables 2 and3.

Control group

The control group consisted of 14 healthy children (mean age 7.3 ± 2 years) who were matched to the patients with regard to height and weight (Table 3). The ARM recording was successful in all the subjects. Due to the impaired growth and development of MPS patients, the healthy subjects matched for height and weight were significantly younger than the patients (p=0.04).

Cross-sectional area values

The MPS patients had a significantly lower mean MCAv than their healthy counterparts (1.6 ± 0.3 cm² and 1.8 ± 0.3 cm² for MPS patients and controls, respectively; p=0.03) (Figure 3 and 4 and Table 3). The mean pharyngeal and tracheal area values were also lower in the MPS group than in the controls, but this difference was not statistically significant. Although the results were within the normal range, the apnoea index was 1 and the hypopnoea index was 2 in patient #3, and the patient #5 had a hypopnoea index of 5 and spent 12% of sleep time with a low SpO 2 between 90 and 95%.

Upper airways resistance

The mean resistance (R) of the upper airways was higher in the MPS group (7.9 ± 1.8 cmH 2 O.l -1 .s) than in the control group (5.5 ± 1.2 cmH 2 O.l -1 .s) (p=0.0064)

(Figure 4 and Table 3).

Again, when looking at the individual data, the R results were clearly different from the controls for 4 MPS patients (patients #3, #4, #6, and #7). These 4 patients comprised 3 of the previous patients (patients #3, #6, and #7). The last patient (#4) is scheduled for a sleep study in the coming weeks.

These complementary data are given in table 2.

Discussion

This study shows that the ARM is able to identify a significant reduction of the upper airway calibre in children with MPS. Indeed, the mean MCAv was significantly lower and the mean airway resistance was significantly higher in 7 patients with MPS as compared to a matched control group. However, individual results were without the normal range in 5 of the 7 patients, of whom 2 were treated with NPPV for severe upper airway obstruction.

Technical issues

We chose the ARM as a tool to study the upper airways in patients with MPS, in whom cooperation may be difficult, because this technique is simple, noninvasive and takes only several seconds. We have recently reported the excellent feasibility of this technique which can be realized in healthy children after the age of 2 years.

However, because of a lack of cooperation, mental retardation, and behavioural problems, reliable, accurate ARM measurements could only be obtained in 7 out of 10 selected patients. The experience of our team in performing ARM recordings in children was undoubtedly helpful but was not sufficient. Moreover, if the pre-selection of our patients allowed us to achieve enough successful recordings to obtain workable data, the extension of our results to all the paediatric MPS population must be made with caution. We could only perform ARM measurement in 7/38 (18%) of all our MPS patients and even if this percentage may be improved (inclusion of adults, multiple examinations in an optimal environment), examination of the total population seems unrealizable. Of note, no patient with a MPS III could be studied. Exploring the airways of MPS patients is challenging. Evaluations have been done with CT-scanning but in addition to the irradiation it delivers, this imaging technique also requires cooperation and hold breathing for a few seconds to give reliable data. This seems difficult to achieve in MPS patients, especially in the stressogenic supine position in the scanner machine. 30 Fiberoptic examination gives accurate morphological data but may also be difficult to perform in children with behavioural problems, and does not provide reliable airway measurements because of the distortion of the images in the optic fibre and the bias of images' interpretation by one practitioner only. However, at least one fiberoptic examination seems recommendable prior to a general anaesthesia in MPS patients. 31

Clinical relevance of the results

The MCAv is the most important parameter for the evaluation of the upper airway because the minimal airway diameter influences both the clinical presentation and the therapeutic management. 32 In healthy subjects, the MCAv corresponds to the subglottic area, which is physiologically the narrowest region of the upper airways. As none of our patients had a history of airway surgery of prolonged intubation, it is likely that their MCAv also corresponds to the subglottic area.

Selection of subjects eligible for the acoustic reflection measurement among the patients with a mucopolysaccharidosis followed in our institution

Figure 3

An acoustic reflection tracings in a patient with mucopolysaccharidosis (patient ).

Note the reduced value of the mean cross sectional area and of the cross-sectional area all along the airway (arrows)

  et al.

  tube which is connected to a horn driver. The 'microphone' side of the tube is oriented toward the patient, and the other one toward open air. An acoustic wave (0.2 -6 kHz) is generated by the horn driver, which is driven by a personal computer via a digital-to-analog converter; microphone outputs are fed into an analog-to-digital converter (14 bits, 24-µs sampling period).

  resistances, as well as the analysis of defined portions of the studied airways chosen by the clinician. For the purpose of the present study, the mean pharyngeal and tracheal cross-sectional airway surface, as well as the minimal airway area value, (MCAv) were calculated. The choice of the landmarks is made according to the curve's profile and the knowledge of the anatomy of the upper airways. Clearly, and by comparison to the classic procedure as recently described by Xue et al.

  the epiglottis, with a tongue base obstruction and a granular aspect of the mucosa.

  successfully used in several studies to assess nasal cavities, we intentionally chose not to perform such measurements in our patients because of the difficulty of achieving an accurate nasal recording in patients with behavioural problems.

15 Conclusions

 15 This study is the first that analyses the upper airways (nose excluded) by the ARM in children with a MPS. Patients with MPS have a significant reduction of the minimal cross-sectional area of the upper airways and an increase of the airways' resistance, as compared to a matched control group.

1

 1 Figure 1

Figure 3 Figure 4 22 Table 1 :

 34221 Figure 3

1 : 2 : 3 : 4 : 5 : 9 :

 123459 UPMC University Paris 06, France Pediatric Otolaryngology-Head and Neck Surgery Department, INSERM, Unité U955, Créteil, F-94010, France ; Université Paris-Est, Faculté de Médecine, U955, Créteil, F-94010, France ; AP-HP, Armand-Trousseau Children's Hospital, 26 Avenue du Dr Arnold Netter -is common in children with mucopolysaccharidosis.

  et al.

  tube which is connected to a horn driver. The 'microphone' side of the tube is oriented toward the patient, and the other one toward open air. An acoustic wave (0.2 -6 kHz) is generated by the horn driver, which is driven by a personal computer via a digital-to-analog converter; microphone outputs are fed into an analog-to-digital converter (14 bits, 24-µs sampling period).For a reliable ARM measurement, the subject has to breathe by mouth during ≈ 4 s. As such, only the airways beyond the mouth were analyzed. During these 4 seconds, the ARM device generates 10 consecutive acoustic waves at a frequency of 2.5 Hz and the corresponding areas distance curves are inferred. As previously shown, ARM measurements are influenced by the position of the head and the connecting equipment.[25][26][27][28] For the recording, the subjects were thus asked to have their head in a neutral position and to breathe through an elastomer mouthpiece (Air Safety Ltd, ref A539, Morecambe, United Kingdom) and a single use filter (Intersurgical Clear-Guard™, ref 1664, Wokingham, United Kingdom).

  , as well as the analysis of defined portions of the studied airways chosen by the clinician. For the purpose of the present study, the mean pharyngeal and tracheal cross-sectional airway surface, as well as the minimal airway area value, (MCAv) were calculated. The choice of the landmarks is made according to the curve's profile and the knowledge of the anatomy of the upper airways. Clearly, and by comparison to the classic procedure as recently described by Xue et al.

  the epiglottis, with a tongue base obstruction and a granular aspect of the mucosa.

  Concerning the individual data, MCAv results were clearly different from the controls for 4 MPS patients (patients #3, #5, #6, and #7). Of note, 2 of these patients (patients #6 and #7) were those with severe upper airway obstruction treated with NPPV. Because of the abnormal MCAv results in the two other patients (patients #3 and #5), sleep studies were performed.

15 Conclusions 1

 151 Figure 1

Figure 4 22 Table 1 :

 4221 Figure 4

  Figure 1 254x190mm (96 x 96 DPI)

Table 2 :

 2 characteristics of the patients

									Sleep					Maximal
								History of	study					sleep
	Patient Gender	Condition	Age	Height	Weight	Mental	difficult	< 6	Minimal		DI	Snoring	CO2
				(y)	(cm)	(kg)	retardation	intubation	months	sleep SpO2 RDI	(/h)	index	(mmHg)	NPPV
	#1	M	MPS II: Hunter syndrome	5.8	120	30	Severe	Yes	No						No
	#2	M	MPS IV-A: Morquio syndrome	7	110	19	None	No	No						No
	#3	M	MPS IV-A: Morquio syndrome 7.5	95	17	None	No	Yes	93%	6	0	61		No
	#4	F	Fucosidosis	10.5	125	25	Severe	No	No						No
	#5	M	MPS II: Hunter syndrome	11.5	135	36	Severe	Yes	Yes	91%	5	0	55	45	No
	#6	M	MPS II: Hunter syndrome	15	134	32	Severe	Yes	n/a	65%	7	34	8	64	Yes
			MPS VI: Maroteaux-Lamy
	#7	M	syndrome	15.6	131	35	Mild	Yes	n/a	70%	17	36	82	53	Yes

M: male; F: female; MPS: mucopolysaccharidosis; y: years; SpO 2 : pulse oximetry; RDI: respiratory disturbance index; DI: desaturation index; /h: by hour; CO 2 : carbon dioxide; NPPV: noninvasive positive pressure ventilation; n/a: non applicable.

Table 3 :

 3 acoustic measurements in MPS patients and healthy subjects

	MPS patients

MPS: mucopolysaccharidosis; SD: standard deviation; BMI: body mass index; R: airway resistance; MCAv: minimal cross-sectional area value Page 24 of 52 John Wiley & Sons, Inc.

Analysis of the upper airway by the acoustic reflection method in children with mucopolysaccharidosis Running head

: Acoustic reflection in mucopolysaccharidosis

  have recently evaluated the feasibility and established normal values of the upper airways by the ARM in a large group of healthy children. Accurate measurements could be obtained in all the children older than 2 years of age.

	F o r
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	e
	e r
	R
	e
	v i e
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	6

23

Normal values of the minimal cross sectional area (MCAv), which corresponds to the narrowest part of the upper airways (i.e the subglottic region), were established and correlated mainly with height, and to a lesser extend with age and weight. As children with MPS may present upper airway obstruction, we hypothesised that the ARM may be particularly adapted to this population because this technique is noninvasive, simple, and rapid, with a procedure taking less than one minute.

The aim of the present study was to evaluate by the feasibility of the ARM in children with MPS, and to compare the characteristics of the upper airways evaluated by the ARM in patients with MPS to a matched group of healthy children.

  The mean MCAv value was significantly reduced in the group of patients with MPS compared to the control group. This can be explained by the infiltration of the airways' wall by the partially degraded molecules inherent to MPS. The mean values of the pharynx and the trachea cross-sectional areas also showed a trend to be reduced compared to healthy children, but this did not reach statistic significance. A significant threshold might have been reached with the inclusion a larger group of patients. Even if the The overall resistance of the airways was significantly higher in the MPS group as compared to the control group. This can be explained by the modification of the wall compliance, and the reduction of the cross-sectional area of the pharynx, larynx, and trachea, and the lower airways.Interestingly, the patients with obstructive sleep apnoea and a need for a nocturnal NPPV (#6 and #7) had clearly MCAv and airway resistance values outside the normal range. This led us to screen the 3 patients having also abnormal values for upper airway obstruction by a sleep study. The sleep results of these clinically asymptomatic patients were not totally normal (Table2), underlining the potential value of the ARM as a screening tool for the detection of mild and/or subclinical OSAS in patients with MPS.Interestingly, MPS patients with abnormal MCAv and airway resistance seemed to be older than those with normal values (12.6 vs. 7.9 years of age). This may be explained by the progressive infiltration of the airways' wall with time. Further studies are warranted to evaluate the usefulness of systematic sleep studies in older patients with MPS in order to detect clinically asymptomatic upper airway obstruction.

	ARM has been successfully used in several studies to assess nasal cavities, we
	intentionally chose not to perform such measurements in our patients because of the
	difficulty of achieving an accurate nasal recording in patients with behavioural
	problems.
	F o r
	P
	e
	e r
	R
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	w
	14

Table 3 :

 3 acoustic measurements in MPS patients and healthy subjects

	MPS patients

MPS: mucopolysaccharidosis; SD: standard deviation; BMI: body mass index; R: airway resistance; MCAv: minimal cross-sectional area value Page 48 of 52 John Wiley & Sons, Inc.

John Wiley & Sons, Inc.Pediatric Pulmonology

John Wiley & Sons, Inc.

List of abbreviations

MPS: mucopolysaccharidosis ARM: acoustic reflection method

MCAv: minimum cross-sectional area value BMI: body mass index NRS: noninvasive respiratory support OSAS: obstructive sleep apnea syndrome

Competing interests

The authors declare that they have no competing interests.

Authors' contribution

The study was designed by NL, RV, and BF. Patients' selection was made by BH. Measurements and data management were made by NL. Technical supervision was made by BL. The manuscript was written and approved by all the co-authors.

Authors' information

Nicolas

Competing interests

The authors declare that they have no competing interests.

Authors' contribution

The study was designed by NL, RV, and BF. Patients' selection was made by BH. Measurements and data management were made by NL. Technical supervision was made by BL. The manuscript was written and approved by all the co-authors.

Authors' information

Nicolas


MD Gianantonio Saviola

Lul Abdi-Ali

Maurizio Paola Baiardi

) Lul

MD Abdi Ali

MD Maurizio Benucci

CAN CLODRONATE BE EFFECTIVE IN THE TREATMENT OF DISABLING HYDROXYAPATITE CRYSTAL DEPOSITION DISEASE ? -A REPORT OF TWO CASES

published or not. The documents may come

Can clodronate be effective in the treatment of disabling hydroxyapatite crystal-deposition disease? A report of two cases

(3) New Hospital San Giovanni di Dio, Azienda Sanitaria Fiorentina, Rheumatology Unit, Florence, Italy.

Corresponding author: Dr Gianantonio Saviola, Salvatore Maugeri Foundation IRCCS, Rheumatology and Rehabilitation Unit, 46042, Castel Goffredo, Mantua, Italy; phone 0376 77471, fax 0376 779886 e-mail adress: gianantonio.saviola@fsm.it SUMMARY : Hydroxyapatite crystals are often deposited in the vicinity of joints, where they can cause a clinical periarthritis. Clodronate is a first generation bisphosphonate which has the ability to reduce ectopic calcifications. Two women were affected by disabling calcific periarthritis of the shoulders lasting for years and resistant to any traditional drug (including glucocorticoids), infiltration and surgical treatment. We treated both patients with low-dose methylprednisolone added to intramuscular clodronate at the daily dose of 100 mg administered for 20 days every 3 months for 5 cycles (18 months). In both cases the results were clinically evident within 1 month, showing a significant reduction of pain and disability. After 18 months the result was furthermore radiologically evident in both cases with a great reduction in the size of calcifications. These improvements were still present at follow-up after 7 and 5 years respectively with complete functional recovery. A woman, began suffering from bilateral shoulder calcific periarthritis at the age of 35, treated with several anti-inflammatory drugs, including high-dose GC per os and intra-articular GC. Nevertheless she developed a right "frozen shoulder" and underwent surgical treatment of irrigation in arthroscopy with no results. At the age of 44 the plane X-ray of the shoulders showed bilateral coarse calcifications which reached 3 cm in diameter on the right hand side.

We diagnosed an Hydroxyhapatite crystal-deposition disease (HADD). We treated her with low-dose GC (MP [4 mg) added to a cycle of intramuscular clodronate (Clasteon ®, Abiogen Pharma, Pisa, Italy) 100 mg daily for 20 days. Within 30 days the pain and disability disappeared and the patient's health greatly improved. The treatment continued with complete success for 18 months with MP 2 mg daily added to CLO 100 mg im for 20 days every 3 months. At the end of this period a new plane x-ray of the right shoulder showed a great reduction in the size of the calcification from 3 to 1 cm in diameter (Fig. 1).

The treatment with low-dose MP (2 mg daily) was then continued. In the next 7 years of follow-up the patient had no relapse, could work and do sports without any problem. A further plane x-ray demonstrated that calcification at the right shoulder still maintains the small size (1 cm).

CASE REPORT N° 2

A woman began suffering from bilateral calcific shoulder periarthritis at the age of 30. She was treated with antinflammatory drugs and intra-articular glucocorticoids obtaining only partial and temporary amelioration. At the age of 54 the left shoulder was affected by a disabling pain resistant to any traditional therapy .

A plane-x-ray of the left shoulder showed a calcification with a diameter of 12 mm. We diagnosed an HADD and we treated her with low-dose GC (MP 2 mg) added to im clodronate (Clasteon ®, Abiogen Pharma, Pisa, Italy) 100 mg daily for 20 days. Within 30 days the pain and disability disappeared and the patient's health improved greatly. The treatment continued with complete success for 18 months with MP 2 mg daily added to CLO 100 mg im for 20 days every 3 months. At the end of this period a new plane x-ray of the left shoulder showed a great reduction in the size of the calcification (from 12 to 5 mm in diameter) (fig. 2).

The treatment with low-dose MP (2 mg daily) was then continued. In the next 5 years of follow-up the patient had no relapse and could work without any problem. A further plane x-ray demonstrated that calcification at the left shoulder still maintains the small size (5 mm). DISCUSSION : The main characteristics and outcomes of the patients are shown in table 1.

HADD was identified as a new arthropathy in 1976 by Dieppe who recognized it as a third type of crystaldeposition disease [START_REF] Dieppe | Apatite deposition disease. A new arthropathy[END_REF]. HA crystals are a very common cause of periarticular disease giving rise to acute inflammation of tendons, intervertebral discs, joint capsules, synovium and cartilage [START_REF] Bonavita | Hydroxyapatite deposition disease[END_REF][START_REF] Mccarty | Crystal related arthropathies[END_REF].

The shoulder is the most common joint involved in HADD. Clinical symptoms are often represented by chronic pain and restricted joint motion [START_REF] Garcia | Hydroxyapatite crystal deposition disease[END_REF].

Calcifying periarthritis is found in about 3% of adult patients and in up to 17% of painful shoulder syndromes. Rupture of the crystal deposit into the next subacromial bursa is usually followed by an acute disabling pain attack with important reduction of the range of motion. Sometimes crystal deposits may persist for years leading to a chronic shoulder pain probably due to an impingement mechanism. Surgical treatments include the break of the calcifications or the percutaneous needle aspiration followed by a lavage [START_REF] Pfister | Chronic calcifying tendinitis of the shoulder-therapy by percutaneous needle aspiration and lavage: a prospective open study of 62 sholuders[END_REF].

BPs were used primarily as inhibitors of calcifications and resorption. They are able to bind to HA crystals thus inhibiting crystal growth [START_REF] Fleisch | Bisphosphonates: mechanism of action[END_REF]. CLO is a first generation non-nitrogen-containing BP also available in ampoules for im and iv injections. CLO is currently registered for the treatment of postmenopausal osteoporosis, multiple myeloma, primary hyperparathyroidism and cancer osteolysis. Each BP in vitro has a different kinetic binding affinity for HA, attributed to differences in the R2 side chain. These characteristics can explain some of BPs clinical activities [START_REF] Nancollas | Novel insight into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite[END_REF].

CLO has a low antiresorptive potency but can be able to inhibit nonskeletal and soft tissues calcifications in both experimental models and in humans [START_REF] Bevilacqua | Bisphosphonates and atherosclerosis: why?[END_REF]. Moreover BPs, and particularly CLO have been successfully studied to prevent the development of experimental atherosclerosis, because of the ability of CLO to remove calcium from atheromatous lesions [START_REF] Bevilacqua | Bisphosphonates and atherosclerosis: why?[END_REF]9]. This property is probably linked to CLO's low affinity for *Disease duration is measured from the beginning of the disease to the start of the treatment with clodronate.

  ABBREVIATIONS: HA Hydroxyapatite CLO Clodronate BP Bisphosphonate HADD Hydroxyapatite crystal deposition disease GC Glucocorticoids MP 6-methylprednisolone im intramuscular iv intravenous CASE REPORT N°1

1 :

 1 bone and HA. In fact, risedronate, which has the same low affinity for bone and HA crystals, can prevent ectopic calcifications in rheumatic patients affected by CREST syndrome [10]. IN CONCLUSION: CLO could be an effective drug in the treatment of HADD reducing the size of calcifications with significant clinical improvement: the association with other drugs, as low-dose GC, could help maintaining results even in unresponsive cases. The Authors declare no conflict of interest. 9) Ylitalo R, Syvala H, Touhimaa P, Ylitalo P. Suppression of immunoreactive macrophages in atheromatous lesions of rabbits by clodronate. Pharmacology & Toxicology, 2002; 90:139-143. 10) Fujii N, Hamano T, Isaka Y, Ito T, Imai E. Risedronate : a possible treatment for extraosseous calcification. Clin Calcium, 2005;15 S1:75-8. Baseline characteristics and outcomes of the two reported patients.

Fig. 1 :

 1 Fig. 1: case n°1. Plane x-ray of the right shoulder at the baseline (on the left side) compared with the same shoulder

Fig. 2 :

 2 Fig. 2: case n°2. Plane x-ray of the left shoulder at the baseline (on the left side) compared with the same shoulder after