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Background: Bleeding events are common complications of oral anticoagulant drugs, including both warfarin and the direct oral anticoagulants (DOACs). Some patients have their anticoagulant changed or discontinued after experiencing a bleeding event, while others continue the same treatment. Differences in anticoagulation management between warfarin- and DOAC-treated patients following a bleeding event are unknown. Methods: Patients with non-valvular atrial fibrillation from six anticoagulation clinics taking warfarin or DOAC therapy who experienced an International Society of Thrombosis and Haemostasis (ISTH)-defined major or clinically relevant non-major (CRNM) bleeding event were identified between 2016 and 2020. The primary outcome was management of the anticoagulant following bleeding (discontinuation, change in drug class, and restarting of same drug class). DOAC- and warfarin-treated patients were propensity matched based on the individual elements of the CHA2DS2-VASc and HAS-BLED scores as well as the severity of the bleeding event. Results: Of the 509 patients on warfarin therapy and 246 on DOAC therapy who experienced a major or CRNM bleeding event, the majority of patients continued anticoagulation therapy. The majority of warfarin (231, 62.6%) and DOAC patients (201, 81.7%) restarted their previous anticoagulation. Conclusion: Following a bleeding event, most patients restarted anticoagulation therapy, most often with the same type of anticoagulant that they previously had been taking.

Current guidelines recommend targeting an international normalized ratio (INR) of 2.5 to 3.5 for patients with mechanical aortic valve replacement (AVR) and additional risk factors for thromboembolic events. Available literature supporting the higher intensity (INR) goal is lacking. We aimed to evaluate the association of standard and higher intensity anticoagulation on outcomes in this patient population. The Michigan Anticoagulation Quality Improvement Initiative database was used to identify patients with mechanical AVR and at least one additional risk factor. Patients were classified into 2 groups based on INR goal: standard-intensity (INR goal 2.5) or higher-intensity (INR goal 3.0). Cox-proportional hazard model was used to calculate adjusted hazard ratios. One hundred and forty-six patients were identified of whom 110 (75.3%) received standard-intensity anticoagulation and 36 (24.7%) received higher intensity anticoagulation. Standard-intensity patients were older and more likely to be on aspirin. Atrial fibrillation was the most common additional risk factor for inclusion. The primary outcome of thromboembolic events, bleeding, or all-cause death was 13.9 and 19.5/100-person-years in the standard-intensity and higher intensity groups, respectively (adjusted HR 2.58, 95% confidence interval 1.28 to 5.18). Higher-intensity anticoagulation was significantly associated with any bleeding (adjusted HR 2.52, 95% confidence interval 1.27 to 5.00) and there were few thromboembolic events across both groups (5 events total). These results challenge current guideline recommendations for anticoagulation management of mechanical AVR in patients with additional risk factors., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Limited data is available on the rates of bleeding and thromboembolic events for patients undergoing low bleeding risk procedures while taking direct oral anticoagulants (DOAC)., Methods: Adults taking DOAC in the Michigan Anticoagulation Quality Improvement Initiative (MAQI 2 ) database who underwent a low bleeding risk procedure between May 2015 and Sep 2019 were included. Thirty-day bleeding (of any severity), thromboembolic events, and death were compared between DOAC temporarily interrupted and continued uninterrupted groups. Adverse event rates were compared using an inverse probability weighting propensity score., Results: There were 820 patients who underwent 1412 low risk procedures. DOAC therapy was temporarily interrupted in 371 (45.2%) patients (601 [42.6%] procedures) and continued uninterrupted in 449 (54.8%) patients (811 [57.4%] procedures). DOAC patients with temporary interruptions were more likely to have diabetes, prior stroke or TIA, prior bleeding, higher CHA2DS2-VASc, and higher modified HAS-BLED scores. DOAC interruption was common for gastrointestinal endoscopy, electrophysiology device implantation, and cardiac catheterization while it was less common for cardioversion, dermatologic procedures, and subcutaneous injection. After propensity score adjustment, bleeding risk was lower in the DOAC temporary interruption group (OR 0.62, 95% CI 0.41-0.95) as compared to the group with continuous DOAC use. Rates of thromboembolic events and death did not differ significantly between the two groups., Conclusions: DOAC-treated patients undergoing low bleeding risk procedures may experience lower rates of bleeding when DOAC is temporarily interrupted. Prospective studies focused on low bleeding risk procedures are needed to identify the safety DOAC management strategy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Use of bridging anticoagulation increases a patient's bleeding risk without clear evidence of thrombotic prevention among warfarin-treated patients with atrial fibrillation. Contemporary use of bridging anticoagulation among warfarin-treated patients with venous thromboembolism (VTE) has not been studied., Methods: We identified warfarin-treated patients with VTE who temporarily stopped warfarin for a surgical procedure between 2010 and 2018 at six health systems. Using the 2012 American College of Chest Physicians guideline, we assessed use of periprocedural bridging anticoagulation based on recurrent VTE risk. Recurrent VTE risk and 30-day outcomes (bleeding, thromboembolism, emergency department visit) were each assessed using logistic regression adjusted for multiple procedures per patient., Results: During the study period, 789 warfarin-treated patients with VTE underwent 1529 procedures (median, 2; interquartile range, 1-4). Unadjusted use of bridging anticoagulation was more common in patients at high risk for VTE recurrence (99/171, 57.9%) than for patients at moderate (515/1078, 47.8%) or low risk of recurrence (134/280, 47.86%). Bridging anticoagulation use was higher in high-risk patients compared with low- or moderate-risk patients in both unadjusted (P = .013) and patient-level cluster-adjusted analyses (P = .031). Adherence to American College of Chest Physicians guidelines in high- and low-risk patients did not change during the study period (odds ratio, 0.98 per year; 95% confidence interval, 0.91-1.05). Adverse events were rare and not statistically different between the two treatment groups., Conclusions: Bridging anticoagulation was commonly overused among low-risk patients and underused among high-risk patients treated with warfarin for VTE. Adverse events were rare and not different between the two treatment groups., (© 2020 International Society on Thrombosis and Haemostasis.)

Objective: Lateral C1-C2 puncture can be used for CSF collection, contrast agent injection for myelography, and access for cordotomy. The objective of this article is to describe the indications, technique, and potential complications of this procedure., Conclusion: Radiologists performing lumbar puncture or myelography should be comfortable gaining access to the subarachnoid space via the lateral C1-C2 approach when indicated. Familiarity with the technique and its potential complications is essential for a safe and efficient procedure.

Use of bridging anticoagulation has been shown to be harmful and without benefit in warfarin-treated patients with atrial fibrillation. We performed a quasi-experimental interrupted time series analysis between 2010 and 2017 in the Michigan Anticoagulation Quality Improvement Initiative (MAQI 2 ) collaborative before and after the BRIDGE trial publication (July 2015). Predicted use of bridging at the end of the study period was calculated with and without the effect of the BRIDGE trial after adjustment for patient-level clustering. Predictors of bridging anticoagulation use in the post-BRIDGE trial period were analyzed. In adjusted analyses, the use of bridging anticoagulation declined from a predicted 27.8% (95% confidence interval, 20.5%-35.1%) to 13.6% (95% confidence interval, 9.0%-18.2%) at the end of 2017 (P = .001) in response to the BRIDGE trial. Use of bridging anticoagulation declined similarly among atrial fibrillation patients at low risk for stroke (29.0% to 14.4%) and intermediate or high risk for stroke (38.0%-20.3%). Younger age and a prior history of stroke were independent predictors of bridging anticoagulation use following the BRIDGE trial publication. The BRIDGE trial publication is associated with a rapid and significant decline in the use of periprocedural bridging anticoagulation., (Copyright © 2019. Published by Elsevier Inc.)

OBJECTIVEPercutaneous vertebral augmentation procedures such as vertebroplasty and kyphoplasty are often performed in cancer patients to relieve mechanical axial-load pain due to pathological collapse deformities. The collapsed vertebrae in these patients can be associated with varying degrees of spinal canal compromise that can be worsened by kyphoplasty. In this study the authors evaluated changes to the spinal canal, in particular the cross-sectional area of the thecal sac, following balloon kyphoplasty (BKP) prior to stereotactic radiosurgery (SRS).METHODSThe authors retrospectively reviewed the records of all patients with symptomatic vertebral compression fractures caused by metastatic disease who underwent kyphoplasty prior to single-fraction SRS. The pre-BKP cross-sectional image, usually MRI, was compared to the post-BKP CT myelogram required for radiation treatment planning. The cross-sectional area of the thecal sac was calculated pre- and postkyphoplasty, and intraprocedural CT imaging was reviewed for epidural displacement of bone fragments, tumor, or polymethylmethacrylate (PMMA) extravasation. The postkyphoplasty imaging was also evaluated for evidence of fracture progression or fracture reduction.RESULTSAmong 30 consecutive patients, 41 vertebral levels were treated with kyphoplasty, and 24% (10/41) of the augmented levels showed a decreased cross-sectional area of the thecal sac. All 10 of these vertebral levels had preexisting epidural disease and destruction of the posterior vertebral body cortex. No bone fragments were displaced posteriorly. Minor epidural PMMA extravasation occurred in 20% (8/41) of the augmented levels but was present in only 1 of the 10 vertebral segments that showed a decreased cross-sectional area of the thecal sac postkyphoplasty.CONCLUSIONSIn patients with preexisting epidural disease and destruction of the posterior vertebral body cortex who are undergoing BKP for pathological fractures, there is an increased risk of further mass effect upon the thecal sac and the potential to alter the SRS treatment planning.

Most studies on the effects of glucocorticosteroid therapy in rhinitis relate to their inhibitory effect on activation and the number of inflowing cells that are involved in the development and maintenance of inflammation. It is also very important to determine the range of effect of budesonide on residing cells (epithelial cells). The purpose of this study was to evaluate the effect of local budesonide therapy on the cytological image of the nasal mucosa, with attention paid to columnar cells in patients with rhinitis. The in vivo results obtained were analyzed in correlation with changes in normal CHO-K1 cells exposed to budesonide at concentrations falling within the pharmacological dose range. Fifty patients diagnosed with rhinitis with suspected allergic background without nasal polyps were included in clinical trials. The control group were 10 healthy people without clinical signs of rhinitis. Only in patients with homogeneous cytological picture, exfoliative cytology was performed before treatment and after 4 weeks of therapy with budesonide used in aerosol form. Papanicolaou and Pappenheim - stained smears were evaluated qualitatively and quantitatively for changes in nasal mucosal cells. The nasal mucosal image of the patients before treatment clearly indicated the pathological state confirmed by the presence of numerous neutrophils, eosinophils, abundant bacterial flora and goblet or epithelial cells prevalence. In contrast, in smears of patients post-treatment budesonide observed a clear improvement in their nasal mucosa by reducing inflammation. There was a significant increase in the number of columnar cells and the appearance of very numerous epithelial cells with increased cytoplasmic vacuolization and visible leucophagocytosis. In vitro studies were performed on normal CHO-K1 cells that were treated with budesonide at concentrations of 0.5 μM - 45 μM. After 48 hours of incubation with the test agent, the samples were prepared for optical microscopy using the H&E method and transmission electron microscopy. Comparison of cells exposed to budesonide with control cells (without addition of test agent) revealed vacuolization changes with autophagy. Apoptotic changes have also been demonstrated, which occured to a lesser extent than vacuolization. The changes observed after budesonide treatment in the cytological picture of patients with allergic rhinitis indicate the therapeutic effect of this drug. On the other hand, the changes observed in the cytoplasm of epithelial cells, such as autophagy (clearly promoted in CHO-K1 cells) and leucophagocytosis, may indicate an additional mechanism of action for budesonide.

Background: Patients on chronic warfarin therapy require regular laboratory monitoring to safely manage warfarin. Recent studies have challenged the need for routine monthly blood draws in the most stable warfarin-treated patients, suggesting the safety of less frequent laboratory testing (up to every 12 weeks). De-implementation efforts aim to reduce the use of low-value clinical practices. To explore barriers and facilitators of a de-implementation effort to reduce the use of frequent laboratory tests for patients with stable warfarin management in nurse/pharmacist-run anticoagulation clinics, we performed a mixed-methods study conducted within a state-wide collaborative quality improvement collaborative., Methods: Using a mixed-methods approach, we conducted post-implementation semi-structured interviews with a total of eight anticoagulation nurse or pharmacist staff members at five participating clinic sites to assess barriers and facilitators to de-implementing frequent international normalized ratio (INR) laboratory testing among patients with stable warfarin control. Interview guides were based on the Tailored Implementation for Chronic Disease (TICD) framework. Informed by interview themes, a survey was developed and administered to all anticoagulation clinical staff (n = 62) about their self-reported utilization of less frequent INR testing and specific barriers to de-implementing the standard (more frequent) INR testing practice., Results: From the interviews, four themes emerged congruent with TICD domains: (1) staff overestimating their actual use of less frequent INR testing (individual health professional factors), (2) barriers to appropriate patient engagement (incentives and resources), (3) broad support for an electronic medical record flag to identify potentially eligible patients (incentives and resources), and (4) the importance of personalized nurse/pharmacist feedback (individual health professional factors). In the survey (65% response rate), staff report offering less frequent INR testing to 56% (46-66%) of eligible patients. Most survey responders (n = 24; 60%) agreed that an eligibility flag in the electronic medical record would be very helpful. Twenty-four (60%) respondents agreed that periodic, personalized feedback on use of less frequent INR testing would also be helpful., Conclusions: Leveraging information system notifications, reducing additional work load burden for participating patients and providers, and providing personalized feedback are strategies that may improve adoption and utilization new policies in anticoagulation clinics that focus on de-implementation.

Intraductal papillary mucinous neoplasms (IPMNs) are mucin-producing papillary neoplasms of the pancreatic or biliary ductal system that exhibit variable cellular atypia and cause ductal dilation. There are few reported cases of IPMN arising from the biliary tree in the literature. It has a higher propensity to undergo malignant transformation compared to IPMN arising from the pancreatic duct. An 80-year-old male underwent cross-sectional tomography (CT) imaging of the abdomen for evaluation of prostate adenocarcinoma, which revealed an incidental 2.3 × 2.7 cm soft tissue mass centered at the porta hepatis with diffuse dilatation of the left intrahepatic biliary ductal system and mild prominence of the right intrahepatic ductal system. Endoscopic ultrasound showed 2 adjacent hilar masses involving the common hepatic duct and the left hepatic duct with protrusion of the tissue into the lumen of the duct and upstream ductal dilatation. Endoscopic retrograde cholangiopancreatography revealed a large filling defect in the common hepatic duct extending into the left hepatic duct. A large amount of clot and soft tissue with a fish-egg appearance was retrieved. The patient underwent left hepatic lobectomy, radical resection of the common hepatic duct with Roux-en-Y hepaticojejunostomy to the right hepatic duct. Histopathological examination of the resected specimen revealed intraductal papillary mucinous neoplasm with diffuse high-grade dysplasia. Follow-up CT scan of the abdomen 2 months after the surgery was negative for any masses., Competing Interests: The authors have no conflicts of interest to disclose.

The diagnosis of leptomeningeal metastasis (LM) has increased in frequency, as new therapies have lengthened the survival of patients with cancer. Early diagnosis and intervention help improve quality of life and prevent further neurological deterioration in LM. The detection of LM is often established by magnetic resonance imaging examinations, cerebrospinal fluid analysis, or both. We present a series of cases where LM was identified on fluid-attenuated inversion recovery or T2-weighted image but was nonenhancing on the traditionally more sensitive postcontrast T1-weighted sequences. Nonenhancing LM is unusual and not yet fully understood but should be considered in the appropriate clinical context and may become more common with increased utilization of antiangiogenic therapies.

Background: Tumor-associated sacral insufficiency fractures (SIF) present a significant clinical challenge. As survival increases for many malignancies, sacral fractures associated with metastases, sacral or extended pelvic radiation, and paraneoplastic osteoporosis are increasingly common and yet remain difficult to treat in the setting of the potentially significant morbidity of open sacral surgery., Objective: To describe our prospective experience with sacroplasty for tumor-associated lesions, including the largest series to date of radiation-induced SIF., Methods: Twenty-five patients with symptomatic SIF underwent 31 percutaneous fluoroscopy-guided sacroplasties with a median 5.8 mL of polymethyl methacrylate or a ceramic-resin composite under fluoroscopic guidance and with concurrent biopsy acquisition. Eighteen patients had fractures related to previous sacral or pelvic radiation; 4 had viable lytic lesions; and 2 had oncology-related osteoporosis. Postoperative pain reduction, procedural morbidity, and functional outcomes were recorded., Results: Twenty of 25 patients (80%) had reduction in their visual analog pain score at a median follow-up of 6.5 months; no patients worsened. The mean visual analog scale score decreased from 8.8 to 4.7 postprocedurally (P < .001), with significant reductions regardless of the underlying pathology (P < .001 to P < .05). Six of 13 patients with pretreatment ambulatory impairment required fewer ambulatory aids and 3 were newly ambulatory. Extravertebral cement migration was noted in 18 procedures; however, no instance was clinically relevant. Six repeat or contralateral procedures were performed. No morbidity was encountered., Conclusion: Sacroplasty is a safe and effective option for the palliation of sacral fractures in the oncologic population.

Background and Purpose: Spinal instrumentation plays a key role in the treatment of spinal instability in patients with metastatic tumors. Poor bone quality, radiation, and diffuse osseous tumor involvement present significant challenges to spinal stabilization with instrumentation and occasionally result in postinstrumentation compression fractures. Vertebral cement augmentation has been effective in the treatment of painful tumor-related compression fractures. Our objective was to describe cement augmentation options in the treatment of vertebral compression fractures associated with spinal instrumentation in patients with metastatic tumors., Materials and Methods: Patients who underwent percutaneous vertebral cement augmentation in the treatment of instrumentation-associated vertebral compression fractures between 2005 and 2011 were included in the analysis. Only fractures that occurred within the construct or at an adjacent level were included. The change in Visual Analog Scale and need for further surgery were analyzed., Results: Eleven patients met the inclusion criteria, with 8 tumors located in the thoracic spine and 3 tumors in the lumbar spine. The median time between instrumented surgery and vertebral augmentation was 5 months (1-48 months) and the median follow-up after cement augmentation was 24 months (4-59 months). A total of 22 vertebrae that were either within or immediately adjacent to the surgical instrumentation underwent vertebral augmentation. All patients reported a decrease in their pain scores (mean decrease: 6 Visual Analog Scale points; P < .003). One patient required reoperation after cement augmentation. None of the patients experienced vertebral cement augmentation-related complications., Conclusions: Vertebral cement augmentation represents a safe and effective treatment option in patients with recurrent or progressive back pain and instrumentation-associated vertebral compression fractures., (© 2014 by American Journal of Neuroradiology.)

Introduction: There is little data on sacral insufficiency fracture(SIF) incidence following pelvic radiotherapy, with existing studies based on conventional fractionation. Stereotactic body radiotherapy (SBRT), characterized by dose escalation with hypofractionation, may pose even greater risks to sacral integrity. This study aims to define SIF incidence and risk factors following SBRT., Methods: Records of 43 consecutive patients who underwent sacral SBRT from September 2005-May 2009 were reviewed. Baseline patient information (age, gender, menopausal status, body mass index, use of bone-thinning agents, presence of osteoporosis), tumor characteristics (histology, lesion appearance and extent) and treatment parameters (dose/fractionation, prior radiation/surgery) were documented. Primary end-point was development of new fractures or progression of pre-existing fractures. Secondary end-points included pain scores, analgesic use, functional ability, and local tumor control., Results: Median follow-up was 17months. Common histologies included sarcoma, renal cell, and prostate carcinoma; 47% of lesions were lytic, 37% sclerotic and the remainder mixed. Doses ranged from 18-24Gy/1fraction to 30Gy/5fractions with 45% receiving single fractions.14% had prior radiation (median dose: 30Gy/10fractions).Five patients developed SIF. In four, fractures occurred in the context of controlled local disease. Median time to SIF was 8.2months. Symptoms varied from minimal pain requiring no intervention to severe pain impacting on function. Two patients underwent sacroplasty due to intractable pain, with both obtaining good analgesia. Low event numbers precluded meaningful univariate/multivariate analyses. One-year local tumor control rates were excellent (91.7%)., Conclusion: In this study, actuarial SIF incidence at one year was 8.2%, suggesting that SIF risk from sacral SBRT is low. However, larger prospective studies with longer follow-up are needed. In addition, novel therapies such as sacroplasty need further study to determine safety, efficacy and indications for use.

Purpose: Advances in stereotactic radiosurgery have improved local control of spine metastases, but local failure is still a problem and repeat irradiation is limited by normal tissue tolerance. A novel high-dose-rate (HDR) brachytherapy technique has been developed to treat these previously irradiated lesions., Methods and Materials: Five patients with progressive disease at previously irradiated sites in the spine who were not amenable to further external beam radiation were treated. Catheters were placed intraoperatively in 2 patients and percutaneously implanted in 3 patients with image-guided techniques. Conformal plans were generated to deliver dose to target tissues and spare critical structures. Patients received single-fraction treatment using HDR iridium-192 brachytherapy., Results: Median dose was 14 Gy (range, 12-18 Gy) with a median gross total volume D90 of 75% (range, 31-94%); spinal cord/cauda equina dose constraints were met. At a median followup of 9 months, no local progression of disease has been observed. Four patients had reduction in pain 1-4 weeks after treatment. No brachytherapy-related complications have been observed., Conclusions: Intraoperative and percutaneous iridium-192 HDR spine brachytherapy techniques were not associated with complications or acute toxicity. There has been no local progression at treated sites, and most patients experienced reduction in cancer-related pain., (Copyright © 2013 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Objective: To study risk factors for the development of postoperative neurological deficits after brain tumor resection and to define prognostic factors for recovery., Methods: We prospectively studied 82 brain tumor patients undergoing tumor resection. Pre- and postoperative neurological examination, functional and performance status, cancer treatment, cardiovascular risk factors, seizure history, and blood pressure and oxygen saturation were recorded perioperatively. Postoperative magnetic resonance imaging scans were obtained within 72 hours of surgery, and the radiologist was blinded to the patient's status. Abnormalities on magnetic resonance diffusion weighted images were classified as new if they extended beyond the tumor cavity margins and were absent before surgery., Results: Of the 80 assessable patients, 24 had a new or increased postoperative deficit by at least one point on the National Institutes of Health Stroke Scale. Presence of preoperative neurological deficits predicted development of postoperative deficits, whereas a new diffusion weighted imaging lesion after craniotomy predicted incomplete recovery of a new postoperative deficit., Conclusion: Postoperative diffusion magnetic resonance imaging is useful in predicting early functional recovery from new deficits after brain tumor surgery.

A 62-year-old man with progressive cerebellar and brainstem dysfunction had gadolinium-enhancing lesions in basal ganglia and occipital lobe on MRI suggestive of primary CNS lymphoma (PCNSL). The patient, who had been treated with high-dose steroid hormones for several months, developed respiratory failure and expired before a histological diagnosis could be obtained. The postmortem examination showed Pneumocystis cariniiwas the cause of death. Pathology of the brain showed a necrotizing vasculopathy affecting the white matter of the cerebrum and cerebellum with involvement of the basal ganglia and the periventricular gray matter. Other organs such as liver, lung, and kidneys were spared. Necrotizing vasculopathy is a novel entity that should be considered in the differential diagnosis of PCNSL.

Intrinsic biologic tumor features are critical prognosticators of survival in patients with neuroblastoma. Patients with localized neuroblastoma and favorable biologic parameters may be observed without treatment. Conversely, leptomeningeal metastases in patients with primary extracranial neuroblastoma are highly unusual and, despite aggressive multimodality therapies, invariably fatal. The authors describe a newly diagnosed infant with neuroblastoma and radiographic imaging suggestive of leptomeningeal metastases. The patient underwent partial surgical resection of the primary tumor. The primary tumor revealed favorable biologic characteristics. The patient was observed with no cytotoxic therapy and remained well with no evidence of disease progression more than 3 years since diagnosis. This case illustrates that some infants with favorable-biology neuroblastoma may be observed without treatment despite the advanced INSS stage.

Background and Purpose: CT-guided spinal biopsy (CTGSB) is considered a safe and accurate procedure. Our goal was to determine the accuracy of a CTGSB of osseous spinal lesions in patients with known or suspected underlying malignancy in reference to major variables such as the radiographic appearance of the biopsied lesion and its location within the spinal column., Methods: We retrospectively reviewed results of 410 consecutive percutaneous CTGSB procedures of osseous spinal lesions. Biopsy was determined to be adequate if diagnostic tissue was obtained (n = 401) or unsatisfactory (n = 9) if only blood without cellular elements was present on final pathologic-cytologic examination., Results: The level of spinal biopsy was cervical in nine patients (2%), thoracic in 123 (31%), lumbar in 164 (42%), and sacral in 96 (25%). The overall diagnostic accuracy of CTGSB was 89%, with a false-negative rate of 11%. Biopsy of lytic lesions yielded an accurate diagnosis in 93% (220 of 236). Despite technical challenges inherent to biopsy of sclerotic lesions, diagnostic accuracy was 76% (63 of 83), although more importantly, 24% (20 of 83) of the results in sclerotic lesions were falsely negative., Conclusion: CTGSB of osseous spinal lesions is an important tool in the workup of patients with known or suspected underlying neoplastic disease. However, a negative result must be confirmed with either close follow-up or, preferably, open biopsy, especially in cases of sclerotic lesions for which diagnostic accuracy is decreased and the false-negative rate is high., (Copyright American Society of Neuroradiology)

Background: We recently identified a novel mutation in large family characterised by premature nocturnal sudden death. In the present paper we provide an overview of the findings in this family., Methods: From 1958 onwards, when the first patient presented, we collected clinical data on as many family members as possible. After identification in 1998 of the underlying genetic disorder (SCN5A, 1795insD), genotyping was performed diagnostically., Results: Since 1905 unexplained sudden death occurred in 26 family members, 17 of whom died during the night. Besides sudden death, symptomatology was rather limited; only six patients reported syncopal attacks. In one of them, a 13-year-old boy, asystolic episodes up to nine seconds were documented. Until now, the mutation has been found in 114 family members (57 males, 57 females). Carriers of the mutant gene exhibited bradycardia-dependent QT-prolongation, intrinsic sinus node dysfunction, generalised conduction abnormalities, a paucity of ventricular ectopy, and the Brugada sign. Cardiomyopathy or other structural abnormalities were not found in any of the carriers. Electrophysiological studies showed that mutant channels were characterised by markedly reduced I Na amplitude, a positive shift of voltage-dependence of activation and a substantial negative shift of voltage-dependence of inactivation of I Na . From 1978 onwards, a pacemaker for anti-brady pacing was implanted for prevention of sudden death. In patients in whom a prophylactic pacemaker was implanted no unexplained sudden death occurred, whereas 5 sudden deaths occurred in the group of patients who did not receive a pacemaker., Conclusion: We have described a large family with a SCN5A-linked disorder (1795insD) with features of LQT 3 , Brugada syndrome and familial conduction system disease. Anti-brady pacing was successful in preventing sudden death. The mode of death is possibly bradycardic.

At the age of 4 years, a total cavopulmonary connection was performed in a boy with a complex congenital heart defect. On addition, a DDDR pacemaker was implanted for sick sinus syndrome. Atrial and ventricular leads were epicardially placed at the left atrium and left ventricle. At the age of 10 years, a new epicardial ventricular lead was placed because of malfunction of the existing lead. At the same operation the pulse generator was replaced by a Medtronic Kappa DR 731. After replacement, the boy experienced episodes of phrenic nerve stimulation associated with feelings of discomfort. Holter recordings revealed ventricular stimulation from the atrial stimulus for 2 consecutive beats. This phenomenon repeated exactly every 3 hours and was caused by the automatic lead impedance measurement that used a 5-V, 1-ms stimulus output.

Introduction: We recently identified a novel mutation of SCN5A (1795insD) in a large family with features of both long QT syndrome type 3 and the Brugada syndrome. The purpose of this study was to detail the clinical features and efficacy of pacemaker therapy in preventing sudden death in this family., Methods and Results: The study group consisted of 116 adult family members: 60 carriers (29 males) and 56 noncarriers (28 males) of the mutant gene. Investigations included 24-hour Holter monitoring, ergometry, and electrophysiologic studies. Mean, lowest, and highest heart rate were lower in the carriers, but heart rate variability was comparable. In carriers, disproportional QT prolongation was present during bradycardia. No complex ventricular ectopy was recorded, and there were fewer isolated premature beats (both ventricular and atrial) in carriers. All patients were asymptomatic, except for two individuals who experienced syncope; in one of these patients, asystolic episodes (up to 9 sec) were repeatedly recorded. Prolonged HV intervals were present in 5 of 6 patients. Thirty carriers received a prophylactic backup pacemaker. During median follow-up of 4.5 years (range 0.0 to 22.6), their survival rate was 100%. There were five sudden deaths among the remaining 30 carriers without a pacemaker (P = 0.019)., Conclusion: This family with a high incidence of nocturnal sudden death is characterized by bradycardia-dependent QT prolongation, intrinsic sinus node dysfunction, and generalized conduction abnormalities. There is a striking absence of complex ventricular ectopy, and pacemaker implantation was effective in preventing sudden death. These findings raise the possibility of a bradycardic rather than tachycardic mode of death.

In a previous study we found, after an overnight fast of 18 hours, a lower arterial glucose concentration and a depressed glycogenolysis in lambs with aortopulmonary left-to-right shunts. During exercise, glucose and free fatty acids (FFA) concentrations normally increase. The aim of this study was to investigate whether the shunt lambs could compensate for a depressed glycogenolysis by increasing gluconeogenesis and by increasing levels of blood substrates such as FFA and glycerol during exercise. Therefore, we investigated glucose kinetics, with [U-(13)C]glucose, in five 7-week-old shunt and 7 control lambs of a similar age, at rest and during moderate exercise (treadmill; 50% of VO(2) peak). The glucose production rate and the rate of disappearance of glucose were lower in shunt than in control lambs, both at rest and during exercise. We found no difference in metabolic clearance rate of glucose, glucose recycling, or gluconeogenesis between both groups of lambs. Glycogenolysis was at rest lower in shunt than in control lambs and tended to be lower during exercise. The arterial concentrations of pyruvate, lactate, FFA, and total and free glycerol increased during exercise in both groups of lambs. In conclusion, shunt lambs have lower arterial glucose concentrations than control lambs, both at rest and during moderate exercise. This was due to a lower glucose production rate, in particular a lower glycogenolysis. In addition, the reduced glycogenolysis rate was not offset by an increase in gluconeogenesis nor by an increase in other substrates that can be utilized by working muscles., (Copyright 2001 by W.B. Saunders Company)

Cardiac conduction disorders slow the heart rhythm and cause disability in millions of people worldwide. Inherited mutations in SCN5A, the gene encoding the human cardiac sodium (Na+) channel, have been associated with rapid heart rhythms that occur suddenly and are life-threatening; however, a chief function of the Na+ channel is to initiate cardiac impulse conduction. Here we provide the first functional characterization of an SCN5A mutation that causes a sustained, isolated conduction defect with pathological slowing of the cardiac rhythm. By analysing the SCN5A coding region, we have identified a single mutation in five affected family members; this mutation results in the substitution of cysteine 514 for glycine (G514C) in the channel protein. Biophysical characterization of the mutant channel shows that there are abnormalities in voltage-dependent 'gating' behaviour that can be partially corrected by dexamethasone, consistent with the salutary effects of glucocorticoids on the clinical phenotype. Computational analysis predicts that the gating defects of G514C selectively slow myocardial conduction, but do not provoke the rapid cardiac arrhythmias associated previously with SCN5A mutations.

Objective: To evaluate an integrated battery of preoperative functional magnetic resonance imaging (fMRI) tasks developed to identify cortical areas associated with tactile, motor, language, and visual functions., Methods: Sensitivity of each task was determined by the probability that a targeted region was activated for both healthy volunteers (n = 63) and surgical patients with lesions in these critical areas (n = 125). Accuracy of each task was determined by the correspondence between the fMRI maps and intraoperative electrophysiological measurements, including somatosensory evoked potentials (n = 16), direct cortical stimulation (n = 9), and language mapping (n = 5), and by preoperative Wada tests (n = 13) and visual field examinations (n = 6)., Results: For healthy volunteers, the overall sensitivity was 100% for identification of the central sulcus, visual cortex, and putative Wernicke's area, and 93% for the putative Broca's area (dominant hemisphere). For patients with tumors affecting these regions of interest, task sensitivity was 97% for identification of the central sulcus, 100% for the visual cortex, 91% for the putative Wernicke's area, and 77% for the putative Broca's area. These sensitivities were enhanced by the use of multiple tasks to target related functions. Concordance of the fMRI maps and intraoperative electrophysiological measurements was observed whenever both techniques yielded maps and Wada and visual field examinations were consistent with fMRI results., Conclusion: This integrated fMRI task battery offers standardized and noninvasive preoperative maps of multiple critical functions to facilitate assessment of surgical risk, planning of surgical routes, and direction of conventional, intraoperative electrophysiological procedures. Thus, a greater range of structural and functional relationships is brought to bear in the service of optimal outcomes for neurosurgery.

The pharmacokinetics, safety, and tolerability of oral moxifloxacin, a new 8-methoxy quinolone, were assessed in a randomized, double-blind, placebo-controlled study in which healthy male and female volunteers received either 400 mg of moxifloxacin once daily (n = 10) or a placebo once daily (n = 5) for 10 days. Plasma moxifloxacin concentrations on days 1 and 10 were measured by high-performance liquid chromatography and fluorometric detection. Standard pharmacokinetic parameters were estimated by noncompartmental methods. Natural logarithmic estimates for each pharmacokinetic variable of each subject were analyzed by a two-way analysis of variance. Hematology, blood chemistry, vital signs, and adverse events were monitored, and electrocardiograms (ECG) were performed. Plasma moxifloxacin concentrations of predicted therapeutic relevance were achieved in this study. For day 1, the mean maximum concentration of drug in serum (C(max)) and the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) were 3. 4 mg/liter and 30.2 mg. h/liter, respectively. Corresponding means on day 10 were 4.5 mg/liter and 48 mg. h/liter, respectively. On day 10, the mean elimination half-life was approximately 12 h. Plasma moxifloxacin concentrations exceeded the MIC for Streptococcus pneumoniae throughout the 24-h dosing period. The day 1 and day 10 mean AUC/MIC ratios were 121 and 192, respectively, and the mean C(max)/MIC ratios were 13 and 18, respectively. Moxifloxacin was well tolerated; no clinically relevant changes in the standard laboratory tests, vital signs, or ECG were observed. Pharmacokinetic parameters demonstrated linearity, and estimates of pharmacokinetic/pharmacodynamic ratios (AUC/MIC and C(max)/MIC) indicate that the regimen of 400-mg once daily should be effective for treating a variety of infections. Moxifloxacin was found to be safe and well tolerated in healthy volunteers when it was given as a single daily 400-mg dose for 10 days.

Spontaneously occurring hypoglycemia has been described in children with severe acute congestive heart failure. Hypoglycemia may be the result of an increase in glucose utilization in tissues, a decrease in glucose production, or a decrease in the dietary intake of nutrients. To determine whether hypoglycemia may also occur in congenital heart disease with volume overloading, we investigated glucose metabolism during and after an 18-hour fast in nine lambs with an aortopulmonary left-to-right shunt and nine control lambs. Plasma levels of hormones involved in the endocrine control of glucose metabolism were determined. The glucose production rate (rate of appearance [Ra]) was studied using [U-13C]glucose. Gluconeogenesis through the Cori cycle was estimated by measuring glucose 13C recycling. The arterial glucose concentration (3,409 +/- 104 v 4,338 +/- 172 micromol/L, P < .001) and Ra of glucose (16.97 +/- 0.89 v 25.49 +/- 4.28 micromol x min(-1) x kg(-1), P < .05) were lower in shunt versus control lambs. There were no differences in hormone levels between control and shunt lambs. Fractional glucose 13C recycling via the Cori cycle (6.9% +/- 2.8% v 7.1% +/- 2.5%) and gluconeogenesis from pyruvate and lactate (1.24 +/- 0.58 v 1.95 +/- 0.67 micromol x min(-1) x kg(-1)) were similar in both groups of lambs. The sum of glycogenolysis and gluconeogenesis from precursors other than pyruvate and lactate was lower in shunt versus control lambs (15.73 +/- 1.07 v 23.54 +/- 4.27 micromol x min(-1) x kg(-1), P < .05). In conclusion, after an 18-hour fast, the arterial glucose concentration is lower in lambs with aortopulmonary shunts. This lower glucose concentration is associated with a decreased glucose production rate. In shunt lambs, glycogenolysis is decreased, while there is no difference in gluconeogenesis or hormonal control.

Background: Around birth, myocardial substrate supply changes from carbohydrates before birth to primarily fatty acids after birth. Parallel to these changes, the myocardium is expected to switch from the use of primarily lactate before birth to fatty acids thereafter. However, myocardial lactate uptake and oxidation around birth has not been measured in vivo., Methods and Results: We measured myocardial lactate uptake, oxidation, and release with infusion of [1-13C]lactate and myocardial flux of fatty acids and glucose in chronically instrumented fetal and newborn (1 to 15 days) lambs. Myocardial lactate oxidation was the same in newborn (81.7+/-14.7 micromol. min-1. 100 g-1, n=11) as in fetal lambs (60.7+/-26.7 micromol. min-1. 100 g-1, n=7). Lactate uptake was also the same in newborn as in fetal lambs. Lactate uptake was higher than lactate flux, indicating lactate release simultaneously with uptake. In the newborn lambs, lactate uptake declined with age. Lactate uptake was strongly related to lactate supply, whereas lactate oxidation was not. The supply of fatty acids or glucose did not interfere with lactate uptake, but the flux of fatty acids was inversely related to lactate oxidation., Conclusions: We show that lactate is an important energy source for the myocardium before birth as well as in the first 2 weeks after birth in lambs. We also show that there is release of lactate by the myocardium simultaneously with uptake of lactate. Furthermore, we show that lactate oxidation may be attenuated by fatty acids but not by glucose, probably at the level of pyruvate dehydrogenase.

Objective: Because of either cardiac anatomy or small size, pacing in children often occurs by means of epicardial leads. The disadvantage of epicardial leads is the shorter longevity of these leads compared with endocardial leads. During short-term follow-up, improved stimulation thresholds were found for the newer steroid-eluting epicardial leads. The longevity of these leads may be better than that of conventional epicardial leads. An improved longevity of epicardial leads may influence the choice to either epicardial or endocardial pacing in children., Methods: We studied the longevity and the pacing and sensing characteristics of 33 steroid-eluting epicardial pacing leads (group I, 15 atrial, 18 ventricular) implanted between November 1991 and October 1996 in 20 children with a mean age of 7.6 +/- 6.5 years (mean +/- SD), and 29 endocardial pacing leads (group II, 15 atrial, 14 ventricular) implanted during the same period in 21 children with a mean age of 11.7 +/- 4.7 years., Results: The mean follow-up in group I was 2.9 +/- 1.6 years and in group II 3.1 +/- 1.7 years (P =.61). The 2-year survival of the leads in group I was 91% +/- 5% and in group II 86% +/- 7% (P =.97). Lead failure occurred in both groups in 4 leads (P =.85). Chronic stimulation and sensing thresholds were similar., Conclusions: Steroid-eluting epicardial leads have the same longevity as the conventional endocardial leads. Pacing and sensing thresholds were similar and did not change during follow-up. Therefore steroid-eluting epicardial pacing leads are a good alternative for endocardial leads in small children and in children with congenital heart disease.

In a previous study [G. C. M. Beaufort-Krol, J. Takens, M. C. Molenkamp, G. B. Smid, J. J. Meuzelaar, W. G. Zijlstra, and J. R. G. Kuipers. Am. J. Physiol. 275 (Heart Circ. Physiol. 44): H1503-H1512, 1998], a lower systemic O2 supply was found in lambs with aortopulmonary left-to-right shunts. To determine whether the lower systemic O2 supply results in increased anaerobic metabolism, we used [1-13C]lactate to investigate lactate kinetics in eight 7-wk-old lambs with shunts and eight control lambs, at rest and during moderate exercise [treadmill; 50% of peak O2 consumption (VO2)]. The mean left-to-right shunt fraction in the shunt lambs was 55 +/- 3% of pulmonary blood flow. Arterial lactate concentrations and the rate of appearance (Ra) and disappearance (Rd) of lactate were similar in shunt and control lambs, both at rest (lactate: 1, 201 +/- 76 vs. 1,214 +/- 151 micromol/l; Ra = Rd: 12.97 +/- 1.71 vs. 12.55 +/- 1.25 micromol. min-1. kg-1) and during a similar relative workload. We found a positive correlation between Ra and systemic blood flow, O2 supply, and VO2 in both groups of lambs. In conclusion, shunt lambs have similar lactate kinetics as do control lambs, both at rest and during moderate exercise at a similar fraction of their peak VO2, despite a lower systemic O2 supply.

Congenital long QT syndrome (cLQTS) is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncopes, seizure, or sudden death. LQTS can occur either as an autosomal dominant (Romano Ward) or as an autosomal recessive disorder (Jervell and Lange-Nielsen syndrome). Mutations in at least five genes have been associated with the LQTS. Four genes, encoding cardiac ion channels, have been identified. The most common forms of LQTS are due to mutations in the potassium-channel genes KCNQ1 and HERG. We have screened 24 Dutch LQTS families for mutations in KCNQ1 and HERG. Fourteen missense mutations were identified. Eight of these missense mutations were novel: three in KCNQ1 and five in HERG. Novel missense mutations in KCNQ1 were Y184S, S373P, and W392R and novel missense mutations in HERG were A558P, R582C, G604S, T613M, and F640L. The KCNQ1 mutation G189R and the HERG mutation R582C were detected in two families. The pathogenicity of the mutations was based on segregation in families, absence in control individuals, the nature of the amino acid substitution, and localization in the protein. Genotype-phenotype studies indicated that auditory stimuli as trigger of cardiac events differentiate LQTS2 and LQTS1. In LQTS1, exercise was the predominant trigger. In addition, a number of asymptomatic gene defect carriers were identified. Asymptomatic carriers are still at risk of the development of life-threatening arrhythmias, underlining the importance of DNA analyses for unequivocal diagnosis of patients with LQTS.