Measurement of the reflectivity of the intima-medial layer of the common carotid artery improves the discriminatory value of intima-medial thickness measurement as a predictor of risk of atherosclerotic disease

Our aim was to assess the predictive value of a measurement of intima-medial layer (IML) reflectivity in the differentiation of pathological from physiological increases in intima-medial thickness (IMT). Both common carotid arteries (CCA) of familial hypercholesterolemia (FH) patients and age- and sex-matched controls (no cardiovascular risk factors) were imaged using a 10- to 15-MHz linear array transducer (n = 30). Images of the CCA far wall were analyzed in the IMT "plug-in" of "HDI Lab." The IML reflectivity, averaged over an 8- to 12-mm length of arterial wall, was expressed as a ratio of reflectivity at a point 0.21-mm deep to the intima-medial interface divided by the reflectivity at the intima-medial interface, termed the intima-medial reflectivity index (IMRI). The risk of atherosclerosis was assessed in terms of IMT alone and IMT coupled with IMRI. Defining high risk of atherosclerosis in FH, in terms of both IMT alone and IMT coupled with IMRI, produced an appropriate, when compared with cholesterol-years score, statistically significant stratification (p < 0.01 and p < 0.005). Analysis of the low-risk subjects revealed a tendency to define a subject as "high risk" based on a physiological increase in IMT, but when IMRI is included in the assessment, all controls are correctly identified as low risk. This method of quantifying the reflectivity of the IML improved the discriminatory performance of IMT increase as an indicator of atherosclerotic risk by enabling a smaller, therefore earlier, increase in IMT to be considered pathologic when accompanied by an increase in IMRI.     

An inducible autocrine cascade regulates rat hepatocyte proliferation and apoptosis responses to tumor necrosis factor-alpha

Tumor necrosis factor-alpha (TNF) is an inflammatory cytokine that induces context-dependent proliferation, survival, and apoptosis responses in hepatocytes. TNF stimulates and enhances growth factor-mediated hepatocyte proliferation and survival following partial hepatectomy, but also acts in concert with other inflammatory cytokines of the innate immune response during viral infection to induce apoptosis in hepatocytes. In other epithelial cell types, TNF has recently been shown to stimulate autocrine release of transforming growth factor-alpha (TGF-alpha) and interleukin-1 (IL-1) family ligands. Here, we examine the role of these autocrine ligands in modulating TNF-induced proliferation and apoptosis in primary hepatocytes. We show that TNF-induced hepatocyte proliferation is regulated by an inducible, coupled, and self-antagonizing autocrine cascade involving the pro-proliferative TGF-alpha and IL-1 receptor antagonist (IL-1ra) ligands and antiproliferative IL-1alpha/beta ligands. Moreover, cooperative stimulation of hepatocyte proliferation by combined TNF and TGF-alpha treatment is self-limited through antiproliferative autocrine IL-1alpha/beta feedback. We show that TNF potently induces apoptosis of adenovirus-infected hepatocytes in a manner similarly determined through the integrated activity of a coupled TGF-alpha-IL-1alpha/beta-IL-1ra autocrine cascade. Exogenous TGF-alpha can either enhance or diminish apoptosis in adenoviral vector-treated and TNF-treated hepatocytes, in a biphasic relationship also mediated by autocrine IL-1alpha/beta feedback. CONCLUSION: We demonstrate that TNF-induced hepatocyte proliferation and apoptosis are both governed by a self-antagonizing TGF-alpha-IL-1alpha/beta-IL-1ra autocrine cascade in vitro, and thus identify multiple molecular targets for control of TNF-regulated hepatocyte phenotypic responses related to liver regeneration and adenoviral gene therapy.     

Improvement in severe self-mutilation following limbic leucotomy: a series of 5 consecutive cases.

BACKGROUND: The efficacy of neurosurgical intervention for self-mutilation behavior associated with severe, intractable psychiatric disorders remains undetermined. We report the effects of limbic leucotomy in 5 consecutive patients with severe self-mutilation behaviors. METHOD: After unsolicited referrals from their psychiatrists and careful consideration by the Massachusetts General Hospital Cingulotomy Assessment Committee (MGH-CAC), 5 patients were treated with limbic leucotomy. Their primary DSM-IV psychiatric diagnoses were either obsessive-compulsive disorder or schizoaffective disorder. Comorbid severe, treatment-refractory self-mutilation was an additional target symptom. Outcome was measured by an independent observer using the Clinical Global Improvement. Current Global Psychiatric-Social Status Rating, and DSM-IV Global Assessment of Functioning scales in addition to telephone interviews with patients, families, their psychiatrists, and treatment teams. The mean postoperative follow-up period was 31.5 months. RESULTS: All measures indicated sustained improvement in 4 of 5 patients. In particular, there was a substantial decrease in self-mutilation behaviors. Postoperative complications were transient in nature. and postoperative compared with preoperative neuropsychological assessments revealed no clinically significant deficits. CONCLUSION: In carefully selected patients as described in this report, limbic leucotomy may be an appropriate therapeutic consideration for self-mutilation associated with severe, intractable psychiatric disorders.     

Modified quadrangular resection for mitral valve repair

Posterior leaflet quadrangular resection is the most commonly performed mitral valve repair procedure for patients with degenerative mitral valve disease. After resection, the remaining leaflet edges must be approximated. When the two leaflet edges are of different heights, modifications are necessary to create a tension-free repair. We present two techniques for posterior leaflet reconstruction when resection results in leaflet edges of different heights.     

Safety and efficacy of intraarterial thrombolysis for perioperative stroke after cardiac operation

Background. Acute ischemic stroke after cardiac operations is a devastating complication with limited therapeutic options. As clinical trials of thrombolysis for acute ischemic stroke exclude patients with recent major surgery, the safety of intraarterial thrombolysis in this setting is unknown.

Methods. Thirteen patients with acute ischemic stroke within 12 days of cardiac operation underwent intraarterial thrombolysis within 6 hours of stroke symptom onset. The National Institutes of Health Stroke Scale was used to assess neurologic recovery.

Results. The mean age was 69 years (standard deviation ±5 years) and 62% were men. Cardiac procedures included valve operations in 6 patients, coronary artery bypass grafting in 4, valve and coronary artery bypass grafting in 2, and left ventricular assist device in 1 patient. Atrial fibrillation occurred in 5 patients (38%). The mean time from operation to stroke was 4.3 days (standard deviation ± 3 days). Thrombolysis was initiated within 3.6 hours (standard deviation ±1.6 hours) of stroke symptom onset. Recanalization was complete in 1 patient, partial in 5, and 7 patients had low flow. Neurologic improvement occurred in 5 patients (38%). One patient needed a chest tube for hemothorax, 2 others were transfused for low hemoglobin. No operative intervention for bleeding was necessary.

Conclusions. In select patients with acute ischemic stroke after recent cardiac operation, intraarterial thrombolysis appears to be reasonably safe and may lead to neurologic recovery.     

Clinical experience with 202 adults receiving extracorporeal membrane oxygenation for cardiac failure: survival at five years.

OBJECTIVES: We sought to determine 5-year survival after extracorporeal membrane oxygenation for cardiac failure and its predictors, to assess survival and its predictors after bridging to transplantation or weaning from extracorporeal membrane oxygenation, and to identify factors influencing the likelihood of these outcomes. METHODS: Two hundred two adults (mean age, 55 +/- 14 years) were supported with extracorporeal membrane oxygenation between 1992 and July 1999 after cardiac failure. Follow-up extended to 7.5 years (mean, 3.8 +/- 2 years). Multivariable hazard function analysis identified predictors of survival, and logistic regression identified the determinants of bridging or weaning. RESULTS: Survival at 3 days, 30 days, and 5 years was 76%, 38%, and 24%, respectively. Patients surviving 30 days had a 63% 5-year survival. Risk factors (P <.1) included older age, reoperation, and thoracic aorta repair. Forty-eight patients were bridged to transplantation, and 71 were weaned with intent for survival. Survival was similar after either outcome (44% vs 40% 5-year survival, respectively). Failure to bridge or wean included (P <.03) renal and hepatic failure on extracorporeal membrane oxygenator support, occurrence of a neurologic event, and absence of infection. The dominant modes of death were cardiac failure and multisystem organ failure. CONCLUSIONS: Extracorporeal membrane oxygenation is versatile and salvages some patients who would otherwise die. Improvement in intermediate-term outcome will require a multidisciplinary approach to protect organ function and limit organ injury before and during this support.     

Optimisation of radiotherapy for carcinoma of the parotid gland: a comparison of conventional, three-dimensional conformal, and intensity-modulated techniques.

BACKGROUND AND PURPOSE: To compare external beam radiotherapy techniques for parotid gland tumours using conventional radiotherapy (RT), three-dimensional conformal radiotherapy (3DCRT), and intensity-modulated radiotherapy (IMRT). To optimise the IMRT techniques, and to produce an IMRT class solution. MATERIALS AND METHODS: The planning target volume (PTV), contra-lateral parotid gland, oral cavity, brain-stem, brain and cochlea were outlined on CT planning scans of six patients with parotid gland tumours. Optimised conventional RT and 3DCRT plans were created and compared with inverse-planned IMRT dose distributions using dose-volume histograms. The aim was to reduce the radiation dose to organs at risk and improve the PTV dose distribution. A beam-direction optimisation algorithm was used to improve the dose distribution of the IMRT plans, and a class solution for parotid gland IMRT was investigated. RESULTS: 3DCRT plans produced an equivalent PTV irradiation and reduced the dose to the cochlea, oral cavity, brain, and other normal tissues compared with conventional RT. IMRT further reduced the radiation dose to the cochlea and oral cavity compared with 3DCRT. For nine- and seven-field IMRT techniques, there was an increase in low-dose radiation to non-target tissue and the contra-lateral parotid gland. IMRT plans produced using three to five optimised intensity-modulated beam directions maintained the advantages of the more complex IMRT plans, and reduced the contra-lateral parotid gland dose to acceptable levels. Three- and four-field non-coplanar beam arrangements increased the volume of brain irradiated, and increased PTV dose inhomogeneity. A four-field class solution consisting of paired ipsilateral coplanar anterior and posterior oblique beams (15, 45, 145 and 170 degrees from the anterior plane) was developed which maintained the benefits without the complexity of individual patient optimisation. CONCLUSIONS: For patients with parotid gland tumours, reduction in the radiation dose to critical normal tissues was demonstrated with 3DCRT compared with conventional RT. IMRT produced a further reduction in the dose to the cochlea and oral cavity. With nine and seven fields, the dose to the contra-lateral parotid gland was increased, but this was avoided by optimisation of the beam directions. The benefits of IMRT were maintained with three or four fields when the beam angles were optimised, but were also achieved using a four-field class solution. Clinical trials are required to confirm the clinical benefits of these improved dose distributions.     

Growing Pains: a Simulation-Based Curriculum for Improving the Transition to Hematology/Oncology Fellowship

Trainee exposure to clinical oncology during residency training is heterogeneous and often modest. The steep learning curve upon entry into fellowship can result in undue stress for fellows and their patients. Simulation-based training has been shown to be superior to classical didactic approaches. We have introduced several innovative simulation-based workshops into the curriculum for the Johns Hopkins Hematology/Oncology Fellowship Training Program in order to address this unmet need. During the first months of training, fellows were engaged in activities emphasizing essential clinical and procedural skills. Specific workshops included the following: (1) chemotherapy writing, (2) cadaveric and simulation-based bone marrow biopsy and intrathecal chemotherapy administration, and (3) simulation-based communication skills training. All first-year fellows in our program participated in these exercises. Pre- and post-workshop surveys were administered to assess knowledge, attitudes, and behaviors; additional distant post-workshop evaluations were disseminated to assess the durability/impact of the curricula and for program evaluation. Overall, participating fellows indicated that the workshops improved patient care and comfort with procedures and patient-centered communication. Continued implementation of these workshops was recommended for program improvement. To the best of our knowledge, ours is amongst the first oncology fellowship training programs to systematically implement simulation-based curricula into our schema for fellowship training. We hypothesize that proactively introducing fellows to these high-yield activities will translate into improved patient care and reduced stress for trainees. Additional investigation into the long-term impact of such curricula remains an area of ongoing need.