Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton.

Angiotensin receptor blockers (ARBs) are a group of anti-hypertensive drugs that are widely used to treat pediatric hypertension. Recent application of ARBs to treat diseases such as Marfan syndrome or Alport syndrome has shown positive outcomes in animal and human studies, suggesting a broader therapeutic potential for this class of drugs. Multiple studies have reported a benefit of ARBs on adult bone homeostasis; however, its effect on the growing skeleton in children is unknown. We investigated the effect of Losartan, an ARB, in regulating bone mass and cartilage during development in mice. Wild type mice were treated with Losartan from birth until 6 weeks of age, after which bones were collected for microCT and histomorphometric analyses. Losartan increased trabecular bone volume vs. tissue volume (a 98% increase) and cortical thickness (a 9% increase) in 6-weeks old wild type mice. The bone changes were attributed to decreased osteoclastogenesis as demonstrated by reduced osteoclast number per bone surface in vivo and suppressed osteoclast differentiation in vitro. At the molecular level, Angiotensin II-induced ERK1/2 phosphorylation in RAW cells was attenuated by Losartan. Similarly, RANKL-induced ERK1/2 phosphorylation was suppressed by Losartan, suggesting a convergence of RANKL and angiotensin signaling at the level of ERK1/2 regulation. To assess the effect of Losartan on cartilage development, we examined the cartilage phenotype of wild type mice treated with Losartan in utero from conception to 1 day of age. Growth plates of these mice showed an elongated hypertrophic chondrocyte zone and increased Col10a1 expression level, with minimal changes in chondrocyte proliferation. Altogether, inhibition of the angiotensin pathway by Losartan increases bone mass and accelerates chondrocyte hypertrophy in growth plate during skeletal development.

Treatment of the stress positive ligamentous SE4 ankle fracture: incidence of syndesmotic injury and clinical decision making.

OBJECTIVES: The objective of the study was to review our experience with the treatment of stress positive (+) supination and external pattern injuries using shared decision making with the patients. DESIGN: Retrospective case review. SETTING: Level 1 trauma center. PATIENTS: Over a 9-year period, we treated 114 patients (aged 19-76 years, average 43 years) with stress (+) supination and external rotation type fibula fractures, who were included in the present study. INTERVENTION: X-rays were reviewed, and the medial clear space (MCS) measured on the presentation, stress, and final united radiographs. The decision for surgical or nonsurgical management was made by the patient and surgeon after a discussion of risks/benefits of both. Syndesmotic instability for the operative cases was diagnosed by medial widening and talar subluxation on abduction/external rotation stress after fibular fixation. MAIN OUTCOME MEASURE: MCS measurement at union. RESULTS: Of the 114 cases, 54 were definitively treated in a cast, and 60 were treated operatively. Twenty-seven (45%) of the operative cases demonstrated syndesmotic instability on radiographic examination. The MCS on stress examination was statistically different, with greater widening seen for operatively treated patients (4.8 ± 0.5 vs. 6.9 ± 0.86) (P < 0.001). No patient healed with any subluxation on weight bearing x-rays. CONCLUSIONS: Stress (+) SE pattern fibular fractures with minimal MCS widening on stress examination may be treated in a cast to union with predictable healing. In those patients treated operatively, the treating surgeon should be aware of the high rate of syndesmotic injury. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

The darker side of randomized trials: recruitment challenges.

Randomized trials are thought to provide optimal evidence if carried out correctly. Their application to important questions is the best guide to clinical decision-making. However, these trials are expensive to complete and have a variety of challenges in design and application. This article will review some of the factors that affect our ability to recruit patients into randomized controlled trials for conditions that may be treated surgically by different methods or for conditions for which both nonsurgical and surgical treatments exist.

Combined intravitreal bevacizumab with phacoemulsification in visually significant cataract and visually significant exudative maculopathy.

PURPOSE: We investigated the visual outcome of combined phacoemulsification with intravitreal bevacizumab, in eyes with dense cataract and visually significant exudative maculopathy. MATERIALS AND METHODS: Prospective longitudinal pilot study of consecutive patients treated by two surgeons in 2006, using intravitreal bevacizumab at the end of phacoemulsification. The historical control group consisted of consecutive subjects with exudative maculopathy and dense cataract treated by the same surgeons with the help of phacoemulsification without intravitreal bevacizumab prior to 2006. RESULTS: Thirty-one treated patients had the mean (SD) logMar best corrected visual acuity improving from - 1.48 (0.50) preoperatively to - 0.67 (0.38) in the first postoperative week (P < 0.001), to - 0.64 (0.40) in the first postoperative month (P < 0.001), and to - 0.62 (0.42) (P < 0.001) on the last follow-up (mean 4.2 months, range 1 - 9 months). Fourteen control patients had the mean (SD) logMar best corrected visual acuity improving from - 1.78 (0.79) preoperatively, to - 0.91 (0.53) in the first postoperative week (P < 0.001), to - 0.86 (0.45) in the first postoperative month (P < 0.001), and to - 0.90 (0.47) (P < 0.001) on the last follow- up (mean 19.6 months, range 1 - 49 months). Initial visual acuities, final visual acuities, and percentage of visual improvement at one month were all not significantly better in the intervention compared to the control group at one month. In the study group, the fovea was flattened at the one-month follow-up, by 90-diopter slit lamp examination and / or Optical coherence tomography. CONCLUSION: The combination of intravitreal bevacizumab and phacoemulsification is beneficial for maximal visual rehabilitation in the first postoperative month.

Anabolic agents and bone quality.

BACKGROUND: The definition of bone quality is evolving particularly from the perspective of anabolic agents that can enhance not only bone mineral density but also bone microarchitecture, composition, morphology, amount of microdamage, and remodeling dynamics. QUESTIONS/PURPOSES: This review summarizes the molecular pathways and physiologic effects of current and potential anabolic drugs. METHODS: From a MEDLINE search (1996-2010), articles were identified by the search terms "bone quality" (1851 articles), "anabolic agent" (5044 articles), "PTH or parathyroid hormone" (32,229 articles), "strontium" or "strontium ranelate" (283 articles), "prostaglandin" (77,539 articles), and "statin" or "statins" (14,233 articles). The search strategy included combining each with the phrase "bone quality." Another more limited search aimed at finding more novel potential agents. RESULTS: Parathyroid hormone is the only US Food and Drug Administration-approved bone anabolic agent in the United States and has been the most extensively studied in in vitro animal and human trials. Strontium ranelate is approved in Europe but has not undergone Food and Drug Administration trials in the United States. All the studies on prostaglandin agonists have used in vivo animal models and there are no human trials examining prostaglandin agonist effects. The advantages of statins include the long-established advantages and safety profile, but they are limited by their bioavailability in bone. Other potential pathways include proline-rich tyrosine kinase 2 (PYK2) and sclerostin (SOST) inhibition, among others. CONCLUSIONS: The ongoing research to enhance the anabolic potential of current agents, identify new agents, and develop better delivery systems will greatly enhance the management of bone quality-related injuries and diseases in the future.

Seasonal variation of retinal detachment in Lebanon.

BACKGROUND: The literature remains controversial regarding seasonal variation of rhegmatogenous retinal detachment (RRD). METHODS: In this retrospective chart review, seasonal variation of RRD was examined based on the records of 211 consecutive patients operated for idiopathic RRD in one referral medical center over a 13-year period. RESULTS: The number of eyes with RRD recorded per season was 46 in autumn, 46 in winter, 62 in spring and 57 in summer. There was a significant seasonal variation (p < 0.05) with an increase in RRD in the warm seasons (spring and summer) compared to the cold seasons (winter and autumn; 56 vs. 44%). Right eyes were more likely to be affected than left eyes (54 vs. 46%), and cases presented with a significantly younger age at onset in the warm than in the cold seasons (47 vs. 54 years, p = 0.007). A literature review of 8,533 cases including the present case series established further the seasonal variation of RRD (p < 0.001). CONCLUSION: There is convincing evidence for a seasonal variation of RRD in Lebanon and in the literature. This is likely to be related to sun exposure and outdoor activities in the warm seasons.

Infectious Collet-Sicard syndrome in the differential diagnosis of cerebrovascular accident: a case of head-to-neck dissociation with skull-based osteomyelitis.

BACKGROUND CONTEXT: Collet-Sicard syndrome (CSS) is a rare condition that includes palsies of cranial nerves IX, X, XI, and XII. There are multiple reported causes in the literature, although infection is particularly unusual. PURPOSE: To report an unusual case of CSS as a result of infection causing head-to-neck dissociation with involvement of the upper cervical spine. STUDY DESIGN: Case report. METHODS: A 56-year-old male with medical comorbidities developed a cranial-based infection secondary to initial incomplete treatment of otitis media. The mass effect of the infection resulted in multiple cranial nerve palsies and extremity symptoms initially confused with a cerebrovascular accident. Clinical course of the patient and a review of CSS are presented. RESULTS: With progression of the disease, further evaluation revealed a disseminated upper cervical and skull-based infection causing destructive head-to-neck infectious instability. This was treated with posterior occipitocervical debridement, fixation, and fusion and appropriate long-term antibiotics. Over the course of several months, the infection resolved and there was a significant improvement in his dysphagia, dysarthria, and hearing. CONCLUSIONS: Delay in diagnosis of CSS is common, and this syndrome should be considered in patients who present with a constellation of lower cranial nerve palsies. Early recognition and treatment should result in successful recovery, but even in cases of delayed detection, suitable intervention can result in substantial clinical improvement.

Comparison of domestic and war ocular injuries during the Lebanese Civil War.

OBJECTIVE: To examine the differences between war and domestic ocular injuries during the Lebanese Civil War in terms of baseline characteristics, treatment provided and prognosis. METHODS: We retrospectively reviewed the charts of subjects with traumatic ocular injuries referred to a major medical center from 1980 to 1996. The variables were tabulated according to the international classification of ocular trauma. RESULTS: Compared to domestic ocular injuries, war injuries were significantly more likely to include males (84.7 vs. 75.1%) and adults (72.7 vs. 39.1%), concomitant systemic injury (43.7 vs. 10.1%), and bilateral ocular affection (19.3 vs. 4.4%). Also, patients with war injuries had significantly worse initial and final visual acuities, less visual improvement (28.6 vs. 44.8%), and more intraocular foreign bodies (42.9 vs. 11%), the majority being metallic removed via an electric magnet. Moreover, war injuries had significantly more posterior scleral involvement 5 mm behind the limbus (25.2 vs. 11.6%) with more secondary retinal detachment (10.3 vs. 4.8%) and vitreous hemorrhage (36.6 vs. 17.1%). Primary evisceration was performed significantly more frequently in war injuries (24.0%) than in domestic injuries (7.7%). CONCLUSIONS: During the Lebanese Civil War, war injuries compared to domestic ones were severer resulting in more enucleation/evisceration and more retinal detachment, tended to be bilateral, and were accompanied by concurrent systemic injuries and less visual recovery. Wearing special glasses and imposing an international arms embargo are recommended to decrease ocular injuries and blinding consequences in potential future wars.

Violent behavior among adolescents in post-war Lebanon: the role of personal factors and correlation with other problem behaviors.

BACKGROUND: Adolescent violence is a significant public health problem. The primary objective of this study is to assess the prevalence and correlates of violent behavior among adolescent students in Lebanon. METHODS: A cross-sectional study was conducted among a representative sample of 827 secondary students enrolled in public and private schools in Beirut. Using a series of multiple logistic regression techniques, socio-demographic variables which significantly associated with violent behavior were included as potential confounders in building the models for risk behavior. RESULTS: Nearly 42 and 17% of adolescents reported being involved in physical fights and weapon carrying, respectively. Boys were significantly more likely to use violence than girls. Whereas associations with physical fights were stronger for socio-economic variables and perceived rank in class, weapon carrying was significantly associated with problem behaviors, such as unintentional injury, substance abuse and sexual activity, with effect measures being stronger than those estimated for physical fighting. CONCLUSION: Compared with other countries, the rates of violent behavior in Lebanon are relatively high. The results from this study are discussed in light of the political ecology of Lebanon which may contribute to a culture that perpetrates violent behavior and may have influenced the clustering pattern of risk behaviors.

Internal decapitation: survival after head to neck dissociation injuries.

STUDY DESIGN: Case series. OBJECTIVE: To describe survival and outcomes after occipitocervical dissociation injuries. SUMMARY OF BACKGROUND DATA: Historically, occipitocervical dissociation injuries have a high rate of associated neurologic deficit with a relatively high incidence of mortality. METHODS: Six patients with occipitocervical dissociation injuries are reported and their management and imaging findings reviewed. Possible contributory factors for survival are discussed. RESULTS: All patients had upper neck and head dissociation injuries. The pattern of injury in all of these cases included a distraction type mechanism. All cases demonstrated soft tissue disruption in the zone of injury, which was consistent and apparent on all imaging studies. In these patients, the extent and severity of injury was more apparent on magnetic resonance imaging (MRI) than on radiograph or computed tomography scan. Management of these injuries included immobilization followed by surgery with particular care taken to avoid application of distraction forces to the neck. CONCLUSION: Patients with occipitocervical dissociation injuries may survive their injury and even retain neurologic integrity. Initial in-line head stabilization is emphasized to prevent catastrophic neurologic injury. The resting osseous relationships and vertebral alignment at the time of imaging evaluation may be deceivingly normal, and the damage often primarily or exclusively involves disruption of the perivertebral soft tissue structures. Prevertebral soft tissue swelling was apparent in all cases. For these injuries that involve primarily damage to the ligamentous structures, MRI seems to be the optimal test for revealing the magnitude of the injury.

De novo three-way chromosome translocation 46,XY,t(4;6;21)(p16;p21.1;q21) in a male with cleidocranial dysplasia.

Cleidocranial dysplasia (CCD) is an autosomal dominant skeletal dysplasia associated with cranial, clavicular, and dental anomalies. It is caused by mutations in the RUNX2 gene, which encodes an osteoblast-specific transcription factor and maps to chromosome 6p21. We report clinical and molecular cytogenetic studies in a patient with clinical features of CCD including wormian bones, delayed fontanel closure, hypoplastic clavicles and pubic rami, and supernumerary dentition. Additional abnormalities of bone growth and connective tissue, including easy bruisability, scarring, bleeding, joint hypermobility, and developmental delay were also observed. Molecular cytogenetic studies identified a de novo apparently balanced three-way translocation 46,XY,t(4;6;21)(p16;p21.1;q21). Further mapping revealed the breakpoint on 6p21 to be approximately 50 kb upstream of exon 1 of the RUNX2 gene, with RUNX2 being intact on the derivative chromosome 6. We hypothesize that the proband's CCD has arisen from disruption of the developmentally regulated gene RUNX2 at the 6p21 breakpoint, due to a position effect mutation which may have altered the expression of the gene. Further studies might unravel a new regulatory element for RUNX2.

A positive or a negative confounding variable? A simple teaching aid for clinicians and students.

Anticipating the direction of a confounding variable can be problematic especially to introductory students. Using elementary rules of mathematics, we describe below a simple instructional tool for deriving the direction of confounding bias. The tool is illustrated with examples and a heuristic mathematical justification is also described.

Prevalence of coronary artery calcium among asymptomatic men and women in a developing country: comparison with the USA data.

BACKGROUND: Coronary artery calcium score (CACS) correlates with atherosclerotic burden and predicts cardiac events. Most of the published data have been derived from the USA population. OBJECTIVE: To study the prevalence of coronary calcium in an asymptomatic population from the eastern Mediterranean region and compare it to data obtained from a large population study in the USA. RESULTS: A total of 1154 asymptomatic men and women from Lebanon underwent EBCT screening because of the presence of one or more CAD risk factors. Mean CACS as well as the percentile cut-points increased consistently with increasing age and, except for those above 74 years of age, were higher in men than women in each age stratum. Age, hypercholesterolemia, diabetes and smoking showed significant associations with CACS in men, while only age and hypercholesterolemia were significantly associated with CACS in women. Among men, the 75th and 90th percentile distributions were comparable to what is observed in developed countries such as the USA. CONCLUSION: Findings, from this first study in the region, suggest that despite a higher rate of diabetes and smokers in our study population, the CACS distribution in Lebanon is similar to that observed in the USA.

Ethnic differences in weight loss behavior among secondary school students in Beirut: the role of weight perception.

OBJECTIVES: Assessing the prevalence of weight loss attempts in Beirut, Lebanon, a country characterized by a diversity of ethnic and religious groups and examining the interplay between ethnicity, body mass index (BMI) and weight perception and their relationship to weight loss behavior. METHODS: A school-based survey of risk behaviors conducted among secondary students (grade 10-12) in 1997. Subjects consisted of 827 boys and girls, aged 15 to 23 years, the majority of whom were Moslems (65.4%). Multiple logistic regression was used to estimate the association between ethnicity and weight perception with the likelihood of trying to lose weight controlling for BMI and a number of potential covariates. RESULTS: The prevalence of weight loss attempts was 19.1% and 42.6% in boys and girls respectively. Christians were more likely to perceive themselves as overweight and to attempt weight loss than Moslems across all BMI levels, however this trend was significant in the underweight category. While controlling for BMI did not change appreciably the results observed, after controlling for weight perception, ethnic differences in weight-loss behavior disappeared. CONCLUSION: Findings of the study suggest that whereas actual weight may constitute only partially the driving force for differentials by ethnicity, the perception of body weight acts as a mediating factor in the relationship between ethnicity and weight loss behavior. Understanding the disparities in weight management behavior across various adolescent groups is key to develop culturally appropriate educational and intervention programs for the youths.