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The mean age at which warfarin was commenced was 6.8 y (range, 0.3–14.8 y). The mean duration of treatment with warfarin was 8.2 y (range, 1.0–14.0 y).

Three hundred and twenty-one control subjects (215 males, 106 females) were recruited as described.

The anthropometric data of patients and controls are listed in Table 1 . There was no statistically significant difference in height or weight between patients and controls. The mean BMI Z-score of patients approached 0 at −0.27 (95% confidence limits, −0.81 to 0.25).

Full size table

The mean BMC, areal BMD, and BMAD are listed in Table 1 . There was a significant difference in BMAD between patients [0.10 g/cm 3 (95% confidence limits, 0.09–0.11 g/cm 3 )] and controls [0.12 g/cm 3 (95% confidence limits, 0.11–0.12 g/cm 3 )], p < 0.001. The BMAD Z-score of patients is reduced compared with controls: patients −1.96 (95% confidence limits, −2.52 to −1.40; Fig. 1 ). Multivariate analysis showed the observed difference in BMAD increased when adjustments were made for age, body weight, and height ( Table 2 ).

Areal lumbar BMD Z-score of patients on long-term warfarin.

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Children with congenital heart disease treated with long-term warfarin at the Royal Children's Hospital have significantly reduced bone density compared with controls. Although the etiology of reduced bone density in our patient group is likely to be multifactorial, the potential effect of warfarin on vitamin K–dependent proteins necessary for bone formation suggests long-term warfarin may have a impact on bone density in children. Considering the benefit of early identification of children at risk of osteoporosis, we suggest children on long-term warfarin should be considered for screening for reduced bone density. Further studies examining the direct effect of long-term warfarin on bone density of children are required.

The use of warfarin in children is rising and is directly related to the increasing incidence of thromboembolic disease in children (). Reasons for this increase include the greater use of central venous lines and the improved survival of children with congenital heart disease (). Central venous lines are used to provide essential short- and long-term venous access for a number of life-threatening conditions in children and remain the major risk factor for a child developing venous thrombosis (). Warfarin remains the mainstay of treatment of thromboembolic disease in children. This is despite a limited understanding of the significance of long-term effects of inhibition of vitamin K–dependent proteins in growing children.

A number of studies have investigated the association between warfarin and reduced bone density and osteoporosis in adult patients (,–). The results of these studies are conflicting and some of these studies are small cohort studies and had short follow-up periods. In one large study of 6314 person-years follow-up, long-term exposure to warfarin was associated with an increased rate of vertebral and rib fractures (). On the other hand, a study of 6052 adult patients followed for more than 3y, 149 of who were treated with warfarin, showed no difference in bone density or rate of fracture in the patients receiving warfarin (). A recent meta-analysis of nine cross-sectional surveys showed warfarin exposure was associated with a reduction of 0.4 SD in bone density of the radius but no significant change in bone density of the hip or spine (). This suggests that warfarin may be associated with only a modest increase in the risk of osteoporosis in adult patients.

Additional factors are likely to be important in the etiology of reduced bone density in our study population. Weight-bearing exercise is critical to ensure adequate bone mass accrual in childhood (). The exact mechanism by which weight loading increases bone mass is not known but is likely related to dynamic strains engendered in bone tissue regulating bone formation and resorption (). No attempt to assess the exercise tolerance of the children we studied was made, however, the ability of children with congenital heart disease to participate in dynamic weight bearing exercise may be limited. Dietary factors, in particular, dietary deficiency of calcium and vitamin D, may also be important in our patients. No attempt to quantify adequacy of calcium and vitamin D intake was made. The fact that the difference in bone density was independent of body size compared with controls suggests, however, that dietary factors may not be a major factor in contributing to reduced bone density in our patients.

Pubertal development has a very important influence on the development of bone density. Bone metabolism during adolescence is affected by changes in rising levels of sex hormone secretion and peak growth hormone and insulin-like growth factor-1 secretion (). It is estimated that 45% of bone mineral acquisition occurs during puberty, and pubertal delay has been associated with reduced bone density in a number of different chronic illnesses including anorexia nervosa, males with constitutional pubertal delay, and thalassemia (–). There are no studies on the incidence of pubertal delay in children with congenital heart disease, and no assessment of pubertal delay was made in the patients of our study. Because pubertal delay affects growth, we believe the persistence of a reduction in bone density between patients and controls when adjusted for parameters of growth (height, weight, and age) suggests that pubertal delay is not a major contributor to reduced bone density in our patients.

A number of therapies exist for children with reduced bone density (,). Exercise intervention trials have demonstrated a beneficial and durable effect of high-impact exercise on bone density of children (). Developing exercise programs to manage low bone density in patients with congenital heart disease may be problematic but programs incorporating jumping have been shown to improve bone mass in children and may have limited demand on the cardiovascular system (). Calcium and vitamin D supplementation can be used to increase spinal BMD (). Bisphosphonate therapy has been effective in treating children with metabolic bone disease and osteoporosis, but a number of issues, including optimal dose and duration of therapy in children, need to be resolved and studies documenting an association with a clinical outcome such as fracture would be required before bisphosphonate therapy is considered ().

A strength of this study is that we used randomly selected population based controls, which provides both a representative sample for comparison and facilitated assessment of the important question as to whether the deficit in bone mass was due to smaller body size or a reflection of true bone density. In our geographic location, there is no acceptable reference database for children and locally sourced controls were desirable. However, the controls were not from the same source population as the cases and bone density was measured using different instruments by different technicians. Although Southern Tasmania is similar in latitude to Victoria and has remarkably similar total fracture incidence rates in adults (), there is no comparative data between the two regions for bone density in children. However, recent work has found only very small differences in bone density between control populations in Hobart, Sydney, and New Zealand (M. Henry, unpublished data). Also, longitudinal coefficients of variations against a spinal dummy were consistently low for both the instruments, and, therefore, any potential differences due to location bias are very unlikely to explain the large difference we observed between cases and controls in the current study.

In conclusion, our study demonstrates significantly reduced bone density in children with congenital heart disease treated with long-term warfarin. Although there is a putative explanation for warfarin in causing reduced BMD in children, the etiology is likely to be multifactorial. Screening of children on long-term warfarin for reduced bone density is recommended and further investigation into the etiology for reduced BMD is necessary.

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Andrew M , Monagle P , Brooker L 2000 Epidemiology of venous thromboembolic events. In: Monagle P, Andrew M, Brooker L (eds) . Decker, Hamilton, ON, Canada , pp 111–146

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Rooms 12 / Architecture Alberto Laposse / Interior Design Germán Velasco / The Original Alberto Laposse

The result of a decade of careful architectural renovations, Dos Casas offers an elegant mix of cool vanguard design and warm traditionalism. Set within two adjoining 18th-century colonial houses, 12 fully outfitted guestrooms—from the chic Design Room to the three-story Townhouse with private entrance—feature midcentury modern furniture and avant-garde touches like contemporary Latin American artworks. Throughout Dos Casas’ eccentric interiors, flashes of stone, marble, wood, iron, leather, and brass evoke Mexico’s rich colonial heritage, while a third building, added in 2014, houses a phenomenal spa inspired by the healing caves of ancient Greece. Dos Casas’ on-site restaurant, Áperi, helmed by executive chef Matteo Salas, has become a local destination in its own right, winning two Travel + Leisure Gourmet Awards in 2015 with its bold use of fresh local ingredients and flavors. And a communal rooftop terrace offers guests breathtaking panoramic views of San Miguel de Allende’s UNESCO-marked 16th-century skyline.

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Áperi: contemporary Mexican cuisine, bar rooftop terrace
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The 12 spacious rooms and suites at Dos Casas all feature a king-size bed, apart from the Deluxe Room that offers either a king- or a queen-size bed. While the Deluxe Room, the Junior Suite, and the Master Suite all boast a spa bath with a rain shower and a soaking tub, the Suite plays host to a bath with a double rain shower and the Owner’s Suite either features a spa bath with a rain shower and soaking tub or a steam shower. The Junior Suite includes a sitting area and a balcony or terrace—while the Suite offers one or the other—and the Master Suite and Owner’s Suite are each home to a private terrace with a Jacuzzi and excellent views of the city. The Owner’s Suite also boasts an outdoor dining space and a living room with a dining table and a sofa, while the three-story Private Residence comprises a living room, a dining room, a small kitchen, a king-size master bedroom with a bathtub, and a rooftop terrace with a Jacuzzi.

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As elsewhere in the tropics, health risks include Gianni Bini Gemella Jeweled Suede Slide Sandals V0aKRQWswr
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Almost 5 km above sea level, Pico Bólivar is the highest mountain in Venezuela

Most Venezuelans are laid-back regarding racial issues, since white or creole persons blend naturally with natives and Afro-Venezuelans in everyday life (education, living, politics, marriage). So the word "negro" can be used regardless of who's saying it, or who is being referred to in this way. Expressions like "negrito" or "mi negro" are often used as a term of endearment. You could hear someone calling "negra" to a woman, regardless of the race of the person. And in general, Afro-Venezuelans don't find it offensive, as they are simply variations on the Spanish word for "black". Similarly, don't be offended if someone calls you "flaco" (thin) or "gordo" (fat) as these may also be used fairly indiscriminately, and often as a term of friendliness.

Differences between Brits, Americans, or Europeans are not perceived by most Venezuelans. Hence, you can expect to be called "gringo" even if you are, say, Russian. Don't let this offend you as a non Spanish-speaking visitor.

Venezuelans, like Colombians, Nicaraguans and Panamanians, have a very amusing way of pointing to objects by pouting their lips and lifting their chin, so don't assume that people are blowing kisses to you when you ask for directions.

Another important point to be kept in mind is that the Venezuelan society is severely split between "Chavistas" (those who support President Chavez) and "anti-Chavistas" (those who oppose to him), so it is strongly advisable not to talk about him and/or his politics unless you are sure on which side your Venezuelan friends are.

Venezuela has international country telephone code 58 and three-digit area codes (plus an initial '0'), and phone numbers are seven digits long.

Area codes beginning with '04' - e.g. 0412, 0414, 0416 - are mobile phones, while area codes beginning '02' - e.g. 0212 (Caracas), 0261 (Maracaibo) are land lines.

A single emergency number 171 is used in most of the country for police, ambulance and firefighters.

The international phone number format for Venezuela is +58-(area code without '0')-(phone number)


Public payphones use prepaid cards which cannot be recharged but are easily available in shopping centers, gas stations, kiosks, etc. Phone boxes are common in the cities and do not accept coins. The vast majority are operated by the former state monopoly, CANTV, although some boxes operated by Digitel or Movistar do exist, particularly in remote areas. CANTV prepaid cards can be used only in their booths.

More popular today are the ubiquitous 'communication centers' or clusters of phone booths located inside metro stations, malls, or like a normal store in the street. Most of these communication centers are operated either by CANTV or Movistar, and offer generally cheap phone calls from a normal phone in comfortable booths equipped with a seat. A log is made of all your calls and you pay when exiting the store.




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