The correction of BMD measurements for bone strontium content.

Strontium ranelate (SR) is a new oral treatment for osteoporosis associated with large increases in bone mineral density (BMD) compared with alternative therapies such as bisphosphonates. Much of the BMD increase during SR treatment is a physical effect caused by the increased attenuation of X-rays due to the accumulation of strontium in bone tissue. The aim of this study was to assess the contribution made by bone strontium content (BSC) to the overall BMD increase by evaluating the percentage F of the BMD change explained by the physical presence of strontium in bone. A value of F less than 100% would provide evidence of the anabolic effect of SR as an additional factor contributing to the overall BMD increase. Studies of mixtures of strontium hydroxyapatite (SrHA) and calcium hydroxyapatite (CaHA) scanned on a variety of dual-energy X-ray absorptiometry (DXA) systems show that a 1% molar ratio of SrHA/(CaHA+SrHA) causes a 10% overestimation of BMD. The correction of spine BMD measurements for the physical effects of strontium depends on knowledge of 2 further factors: (1) bone biopsy measurements of iliac crest BSC and (2) the ratio R of BSC at the DXA site to BSC at the iliac crest measured in animal studies. We used clinical trial data and values of R(spine) measured in studies of monkeys and beagle dogs to determine values of F(spine) for 1, 2, and 3 yr treatment with SR. Based on the average value of R(spine) approximately 0.7 for male and female monkeys, we found values for F(spine) approximately 75-80% for 1, 2, and 3 yr of treatment. Using the value of R(spine) approximately 1.0 from the beagle study gave values of F(spine) approximately 100%. Although values of F(spine) as low as 40% are possible, we conclude that the most likely figure is 75% or greater. However, it is apparent that there are large uncertainties in the correction of BMD results for the effect of bone strontium and that the most important of these is the inference of BSC values at DXA scan sites from measurements of iliac crest bone biopsy specimens.     

Cough and paradoxical vocal fold motion

OBJECTIVES: The differential diagnosis and treatment of patients with chronic cough, paradoxical vocal fold motion, and disordered breathing can be a challenge to most practicing otolaryngologists. Tracheobronchial (ie, asthma, bronchitis, and tracheal stenosis), laryngeal (ie, vocal fold paralysis and neoplasms), and rhinologic (ie, allergies and rhinosinusitis) etiologies are commonly diagnosed and treated effectively. However, occasionally one is faced with patients who are refractory to medical treatment and have no obvious rhinologic, laryngeal or pulmonary cause. STUDY DESIGN AND SETTING: We conducted a review of the literature. METHODS: We present a thorough review of the current medical literature exploring the complex neurologic mechanisms involved in the production of cough and the relationship between gastroesophageal reflux disease, vagal neurapathy, and paradoxical vocal fold motion. RESULTS: The diagnosis and successful treatment of chronic cough can be complex. It requires a thorough understanding of the neurologic mechanisms behind cough excitation and suppression. Successful treatment strategies include aggressive management of the patient's reactive airway disease, gastroesophageal reflux disease, and, in select cases, paradoxical vocal fold motion. This may involve a well-coordinated effort among pulmonologists, otolaryngologists, gastroenterologists, and speech pathologists. CONCLUSION: Gastroesophageal reflux disease, vagal neuropathy, and paradoxical vocal fold motion are additional causes of chronic cough and disordered breathing that need to be considered, in the absence of obvious laryngotracheal and/or rhinologic pathology. A high index of suspicion is essential in making the diagnosis and formulating an effective multidisciplinary treatment plan for these patients.     

The effect of implant constraint on results of conversion of unicompartmental knee arthroplasty to total knee arthroplasty

A series of unicompartmental knee arthroplasty (UKA) revision to total knee arthroplasty (TKA) was compared to a group of primary TKAs performed at the same institution. The UKA revision group had a higher incidence of local wound complications and inferior clinical results as measured by Knee Society scores. When the revisions were stratified by the degree of interface constraint, knees revised with posterior cruciate ligament (PCL) substituting designs had superior knee scores that were comparable to the primary group. The use of a PCL-substituting knee design is recommended when converting a UKA to TKA.     

Evaluation of ABM/P-15 versus autogenous bone in an ovine lumbar interbody fusion model

A prospective, randomized study was performed in an ovine model to compare the efficacy of an anorganic bovine-derived hydroxyapatite matrix combined with a synthetic 15 amino acid residue (ABM/P-15) in facilitating lumbar interbody fusion when compared with autogenous bone harvested from the iliac crest. P-15 is a biomimetic to the cell-binding site of Type-I collagen for bone-forming cells. When combined with ABM, it creates the necessary scaffold to initiate cell invasion, binding, and subsequent osteogenesis. In this study, six adult ewes underwent anterior-lateral interbody fusion at L3/L4 and L4/L5 using PEEK interbody rings filled with autogenous bone at one level and ABM/P-15 at the other level and no additional instrumentation. Clinical CT scans were obtained at 3 and 6 months; micro-CT scans and histomorphometry analyses were performed after euthanization at 6 months. Clinical CT scan analysis showed that all autograft and ABM/P-15 treated levels had radiographically fused outside of the rings at the 3-month study time point. Although the clinical CT scans of the autograft treatment group showed significantly better fusion within the PEEK rings than ABM/P-15 at 3 months, micro-CT scans, clinical CT scans, and histomorphometric analyses showed there were no statistical differences between the two treatment groups at 6 months. Thus, ABM/P-15 was as successful as autogenous bone graft in producing lumbar spinal fusion in an ovine model, and it should be further evaluated in clinical studies.     

The effect of bone strontium on BMD is different for different manufacturers' DXA Systems

Osteoporotic patients treated with strontium ranelate show relatively large increases in bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) due to the replacement of some of the calcium atoms in bone by strontium. A study published by Pors Nielsen and colleagues reported that replacement of 1% of calcium atoms by strontium causes a 10% increase in BMD. We refer to the ratio of the percentage increase in BMD to the molar percentage of strontium in bone as the strontium ratio. Theoretically it is expected that the strontium ratio should vary between different manufacturers' DXA equipment depending on the effective photon energy of the device, an effect that arises because of the proximity of the X-ray energies produced by lower energy devices to the strontium K-edge at 16 keV. In this study we report theoretical estimates of the strontium ratio for two axial DXA systems and two peripheral DXA devices based on their broad spectrum X-ray emission. The theoretical figures were verified in an experimental study in which the strontium ratio for each device was measured using phantoms containing mixtures of hydroxyapatite and strontium hydrogen-phosphate. The theoretical values of the strontium ratio were 11.0 for the Hologic Discovery, 9.9 for the GE-Lunar Prodigy, 9.1 for the Demetech Calscan, and 8.5 for the Osteometer Dexacare G4. Experimental results were 11.2 for the Discovery, 9.9 for the Prodigy, 8.6 for the Calscan and 6.3 for the Dexacare G4. The results confirm both theoretically and experimentally that the effect of bone strontium on BMD measurements is different for different DXA systems. In the future it might be possible to exploit this effect to make a non-invasive estimate of average bone strontium content in groups of patients receiving strontium medication for osteoporosis.     

Comparative efficacy and safety of remifentanil and fentanyl in 'fast track' coronary artery bypass graft surgery: a randomized, double-blind study

This multi-centre, parallel group, randomized, double-blindstudy compared the efficacy and safety of high-dose remifentaniladministered by continuous infusion with an intermittent bolusfentanyl regimen, when given in combination with propofol forgeneral anaesthesia in 321 patients undergoing elective coronaryartery bypass graft surgery. A significantly lower proportionof the patients who received remifentanil had responses to maximalsternal spread (the primary efficacy endpoint) compared withthose who received fentanyl (11% vs 52%; P<0.001). More patientswho received remifentanil responded to tracheal intubation comparedwith those who received fentanyl (24% vs 9%; P<0.001). However,fewer patients who received remifentanil responded to sternalskin incision (11% vs 36%; P<0.001) and sternotomy (14% vs60%; P <0.001). Median time to extubation was longer in thesubjects who received remifentanil than for those who receivedfentanyl (5.1 vs 4.2 h; P=0.006). There were no statisticallysignificant differences between the two groups in the timesfor transfer from intensive care unit or hospital dischargebut time to extubation was significantly longer in the remifentanilgroup. Overall, the incidence of adverse events was similarbut greater in the remifentanil group with respect to shivering(P<0.049) and hypertension (P<0.001). Significantly moredrug-related adverse events were reported in the remifentanilgroup (P=0.016) There were no drug-related adverse cardiac outcomesand no deaths from cardiac causes before hospital dischargein either treatment group. Br J Anaesth 2001; 87: 718–26     

Fluid trapping of erythrocytes under hypoosmolar conditions

Summary ¹²⁵I albumin was used to assess the amount of trapped fluid after microhematocrit centrifugation of erythrocytes suspended in buffers of different osmolality. Surprisingly the total amount of trapped fluid per volume unit of packed erythrocytes decreased with decreasing osmolality of the suspending buffer despite erythrocyte swelling. However, if the contribution of the individual erythrocyte to the trapped fluid was calculated, the trapped fluid per erythrocyte did not change between 311 mosm/kg and 256 mosm/kg. For osmolalities below 256 mosm/kg a significant increase of trapped fluid was obtained. It is concluded that the packing ability of erythrocytes is not impaired in suspending fluid of moderate to severe infraphysiological tonicity. The daily clinical experience that considerable degrees of plasma hypoosmolality are tolerated in vivo without hemolysis or impairment of oxygen transport by erythrocytes may be explained by the excellent ability of shape adaptation of erythrocytes to each other and to other surfaces such as vascular endothelia. The method of trapped fluid determination might be of potential value as a complementary method in the evaluation of erythrocyte rheology if the amount of trapped fluid is related to the individual erythrocyte.     

Thalidomide teratogenesis: evidence for a toxic arene oxide metabolite.

It was postulated that thalidomide causes birth defects by being metabolized to a toxic electrophilic intermediate. This hypothesis was tested by using an in vitro assay in which drug toxicity to human lymphocytes was assessed in the presence of a hepatic microsomal drug metabolizing system. Maternal hepatic microsomes from pregnant rabbits mediated the production of a metabolite that was toxic to lymphocytes. Toxicity was enhanced by inhibitors of epoxide hydrolase (EC 3.3.2.3) and abolished by adding the purified enzyme to the incubation medium. The metabolite thus appears to be in arene oxide, consistent with the previously reported isolation of phenolic metabolites of thalidomide from the urine of treated animals. Two teratogenic analogs of thalidomide (phthalimidophthalimide and phthalimidinoglutarimide) were also toxic in the system; two nonteratogenic analogs (phthalimide and hexahydrothalidomide) were not toxic, even in the presence of epoxide hydrolase inhibitors. The toxic metabolite of thalidomide was not produced by rat liver microsomes (the rat is not sensitive to thalidomide teratogenesis) but was produced by hepatic preparations from maternal rabbits, and rabbit, monkey, and human (all sensitive species) fetuses. A toxic arene oxide therefore may be involved in the teratogenicity of thalidomide.