Structural Strength Development at the Proximal Femur in 4‐ to 10‐Year‐Old Precompetitive Gymnasts: A 4‐Year Longitudinal Hip Structural Analysis Study

Gymnastics, a high‐impact weight‐bearing physical activity, has been shown to be highly osteogenic. Previously in this cohort, bone mass development (bone mineral content accrual [BMC]) was shown to be positively associated with low‐level (recreational) gymnastics exposure (1 to 2 hours per week); however, BMC is only one single component of bone strength. Bone strength is influenced not only by bone mineralization but also bone geometry, bone architecture, and the imposing loads on the bone. The aim of this study was to investigate whether low‐level gymnastics training influenced the estimated structural geometry development at the proximal femur. A total of 165 children (92 gymnasts and 73 non‐gymnasts) between the ages of 4 and 6 years were recruited into this study and assessed annually for 4 years. During the 4 years, 64 gymnasts withdrew from the sport and were reclassified as ex‐gymnasts. A dual‐energy X‐ray absorptiometry (DXA) image of each child's hip was obtained. Values of cross‐sectional area (CSA), section modulus (Z), and cortical thickness (CT) at the narrow neck (NN), intertrochanter (IT), and shaft (S) were estimated using the hip structural analysis (HSA) program. Multilevel random‐effects models were constructed and used to develop bone structural strength development trajectories (estimate ± SEE). Once the confounders of body size and lifestyle were controlled, it was found that gymnasts had 6% greater NN CSA than non‐gymnasts controls (0.09 ± 0.03 cm², p < 0.05), 7% greater NN Z (0.04 ± 0.01 cm³, p < 0.05), 5% greater IT CSA (0.11 ± 0.04 cm³, p < 0.05), 6% greater IT Z (0.07 ± 0.03 cm³, p < 0.05), and 3% greater S CSA (0.06 ± 0.03 cm³, p < 0.05). These results suggest that early exposure to low‐level gymnastics participation confers benefits related to geometric and bone architecture properties during childhood and, if maintained, may improve bone health in adolescence and adulthood. © 2013 American Society for Bone and Mineral Research.     

Platelet Na+,K+-ATPase activity as a possible peripheral marker for the neurotoxic effects of phenylalanine in phenylketonuria

Thein vitro effects of phenylalanine or alanine alone or combined on Na⁺,K⁺-ATPase activity in membranes from human platelets were investigated. The enzyme activity was assayed in membranes prepared from platelet-rich plasma of healthy donors. Phenylalanine or alanine were added to the assay to final concentrations of 0.3 to 1.2 mM, similar to those found in plasma of phenylketonuric patients. Phenylalanine inhibited Na⁺,K⁺-ATPase activity by 20–50% [F(4,25)=11.47; p<0.001]. Alanine had no effect on Na⁺,K⁺-ATPase activity but when combined with phenylalanine prevented the enzyme inhibition. These results, allied to others previously reported on brain Na⁺,K⁺-ATPase activity, may reflect a general inhibitory effect of phenylalanine on this important enzyme activity. Therefore, it is possible that measurement of Na⁺,K⁺-ATPase activity in platelets from PKU patients may be a useful peripheral marker for the neurotoxic effects of phenylalanine.     

Isolated thrombocytopenia after allogeneic bone marrow transplantation: existence of transient and chronic thrombocytopenic syndromes

Isolated thrombocytopenia after bone marrow transplantation was investigated in 65 fully engrafted patients surviving at least 60 days posttransplant. Twenty-four patients (37%) developed this complication, which occurred most frequently in patients receiving pretransplant preparation with total body irradiation or busulfan. Two distinct thrombocytopenic syndromes were identified: (1) transient thrombocytopenia (nine patients), in which a normal platelet count (greater than 100,000/microL) was initially established by day +40 but then diminished to less than 10,000 to 45,000/microL on day +40 to +70, with subsequent resolution of the thrombocytopenia by day +90; (2) chronic thrombocytopenia (15 patients), in which a platelet count greater than 100,000/microL was not achieved at any time during the first four months posttransplant, despite the simultaneous presence of normal granulocyte and reticulocyte counts. Although the transient syndrome did not adversely affect prognosis, the chronic syndrome carried a high mortality (21% actuarial survival at 1,000 days posttransplant compared with 67% survival for all patients, P less than .01) and had a high association with both severe (grades 3 to 4) acute graft-versus-host disease (GVHD) and chronic GVHD. In three of nine patients with transient thrombocytopenia, a temporal association with trimethoprim-sulfamethoxazole administration was observed, whereas in all other patients, no drug association could be found. Bone marrow biopsies in those patients with drug-associated thrombocytopenia showed decreased numbers of megakaryocytes, whereas biopsies in the remainder of the transiently thrombocytopenic patients demonstrated adequate numbers of platelet precursors, suggesting peripheral platelet destruction or ineffective thrombopoiesis. Biopsies in the chronic thrombocytopenic patients included those with and without adequate numbers of platelet precursors, although the association with chronic GVHD was strongest in patients demonstrating normal numbers of megakaryocytes. We conclude that isolated thrombocytopenia represents a significant complication of bone marrow transplantation, particularly in patients receiving hematopoietic ablative preparatory regimens, and that it is the chronic, not the transient, thrombocytopenic syndrome that is associated with an adverse patient prognosis.     

Clinical and electrophysiologic predictors of ventricular tachyarrhythmia recurrence in patients with implantable cardioverter defibrillators

INTRODUCTION: Not all patients experience recurrent sustained ventricular tachyarrhythmias after placement of an implantable cardioverter defibrillator (ICD). We evaluated the clinical and electrophysiologic predictors of ventricular tachycardia (VT) and ventricular fibrillation (VF) recurrence following ICD implantation. METHODS AND RESULTS: Consecutive patients (n = 133) underwent 4 +/- 3 serial electrophysiologic studies (EPS) over 50 +/- 26 months following ICD implantation. Sustained VT/VF could always be induced during follow-up EPS in 49 patients; sustained VT/VF was sometimes induced during follow-up EPS in 47 patients; and sustained VT/VF could never be induced during follow-up EPS in 37 patients. Spontaneous VT/VF requiring ICD therapy occurred in 107 patients during follow-up. Patients with sustained VT/VF that was always inducible or sometimes inducible during follow-up experienced more frequent episodes of VT/VF following ICD implant (20.5, 95% CI 12.7-33.0; and 17.8, 95% CI 11.3-28.1 episodes/patient respectively; vs 3.0, 95% CI 2.0-4.6 episodes/patient for patients with VT/VF never induced, P < 0.001). Inducibility of sustained VT/VF post-ICD implant (P < 0.001) and sustained VT as the presenting arrhythmia (P = 0.02) were independent predictors of spontaneous VT/VF recurrence. CONCLUSION: Reproducibly inducible VT/VF following ICD implantation predicts a high probability of VT/VF recurrence and identifies a cohort of patients who experience frequent episodes of VT/VF over time. Persistent noninducibility of sustained VT/VF identifies a group of patients who experience no or very few episodes of VT/VF recurrence.     

Monitoring the ACTIVE-W trial: some issues in monitoring a noninferiority trial

Noninferiority comparisons of new to current therapies and the use of composite outcomes represent significant advances in the design of clinical trials. They increasingly characterize trials of new cardiovascular agents, posing new challenges to Data Safety Monitoring Boards (DSMB) and principal investigators. The ACTIVE-W study was a noninferiority comparison of the combination of clopidogrel and acetylsalicylic acid versus oral anticoagulant among patients with atrial fibrillation. When unexpectedly high rates of stroke and then of the composite outcome of stroke, non-central nervous system systemic embolism, myocardial infarction, and vascular death emerged, the DSMB modified its monitoring plan and conducted its first formal interim analysis much earlier than had been planned in the DSMB charter. The study was terminated when only 27% of the anticipated outcomes had occurred. This paper discusses issues of appropriate stopping guidelines for noninferiority trials and the early emergence of significant harm in relation to one component (stroke) of a composite outcome. Conditional power was not determined concurrently with the HRs during the monitoring of ACTIVE-W; however, the members of the DSMB now believe that such calculations should be considered as useful adjuncts to the calculation of HRs and could lead to earlier termination of noninferiority trials whose interim results suggest futility, without the need for convincing proof of harm.     

Normal Venous Phase Documented during Angiography in Patients with Spinal Vascular Malformations: Incidence and Clinical Implications

BACKGROUND AND PURPOSE:A key angiographic sign observed in patients with spinal vascular malformations is the absence of a normal venous phase. While this finding alone is often believed to rule out a lesion impacting the perimedullary venous drainage, the observation of a venous phase in several patients with vascular malformations led us to reconsider the validity of that sign.MATERIALS AND METHODS:Eighty-one patients with 6 spinal arteriovenous malformations, 16 perimedullary arteriovenous fistulas, 61 spinal epidural or dural AVFs, and 1 paravertebral AVF (2 patients had multiple lesions) were reviewed. The venous phase was defined as normal, absent, or indeterminate. The venous phase timing was analyzed in patients with spinal dural or epidural AVFs.RESULTS:The existence of a venous phase could not be determined for technical reasons in 23 patients. A venous phase was documented in 25 of 58 patients (43%), including 16 of 49 vascular malformations (40.0%) with perimedullary venous drainage. Twelve of the 30 patients (40.0%) with dural or epidural AVFs had a normal venous phase, appearing, on average, 10.1 seconds and best visualized 15.0 seconds after opacification of the artery of Adamkiewicz.CONCLUSIONS:A normal venous phase was observed in 43% of patients with spinal vascular malformations, and within an acceptable delay (<18 seconds) in 40% of slow-flow AVFs. While it remains an important angiographic sign, the observation of a normal venous phase cannot be used to exclude the presence of a vascular malformation or justify interrupting a diagnostic spinal angiogram.

Spinal digital subtraction angiography (SpDSA) is the criterion standard imaging technique for the evaluation of the spinal vasculature and remains essential for the diagnosis and management of spinal vascular malformations (SVMs).¹ The practice of SpDSA requires a sound understanding of the vascular anatomy of the spinal cord, notably its venous system.^2,3 A key angiographic sign observed in patients with SVMs is the absence of a normal venous phase, a phenomenon first reported in 2 cases of spinal dural arteriovenous fistulas (SDAVFs).² It was later suggested that a spinal angiogram could be terminated when “a normal venous phase is visualized and the veins correspond to the defects on the myelogram,” an approach based on the assumption that “if the venous phase of the spinal circulation is normal, this alone rules out DAVF [dural AVF] as the cause of the patient''s symptoms.”⁴ While MR imaging has now supplanted myelography in the work-up of spinal vascular anomalies, the notion that the angiographic pursuit of an SVM can stop after the documentation of a normal venous phase is still widely accepted, though at times more cautiously. Some authors have, for example, suggested that a normal venous phase “usually”⁵ or “reportedly”⁶ allows terminating a diagnostic angiogram or that it only makes the “diagnosis of a fistula less likely.”⁷ To our knowledge, there is, so far, only 1 reported instance of a normal venous phase associated with a vascular malformation draining into the perimedullary system, but this case involved a cranial dural arteriovenous fistula rather than an SVM.⁸Several observations of a morphologically normal venous phase associated with lesions involving the perimedullary venous system have pushed us to reconsider the validity of this angiographic sign. The spinal venous phase was, therefore, evaluated in 81 patients diagnosed with an SVM in our practice during a 5-year period, with particular attention paid to SDAVFs and spinal epidural arteriovenous fistulas (SEAVFs).