MRI of the axial skeletal manifestations of ankylosing spondylitis.

Magnetic resonance imaging (MRI) is a valuable tool in the imaging and assessment of patients with ankylosing spondylitis. MRI can demonstrate the acute and chronic changes of sacroiliitis, osteitis, discovertebral lesions, disc calcifications and ossification and arthopathic lesions, which characterize the disease, as well as the complications, which include fracture and the rare cauda equina syndrome. This article reviews the range of MRI findings commonly seen within the axial skeleton in patients with this condition.

Predictors of progression in Barrett's esophagus II: baseline 17p (p53) loss of heterozygosity identifies a patient subset at increased risk for neoplastic progression.

OBJECTIVES: Most patients with Barrett's esophagus do not progress to cancer, but those who do seem to have markedly increased survival when cancers are detected at an early stage. Most surveillance programs are based on histological assessment of dysplasia, but dysplasia is subject to observer variation and transient diagnoses of dysplasia increase the cost of medical care. We have previously validated flow cytometric increased 4N fractions and aneuploidy as predictors of progression to cancer in Barrett's esophagus. However, multiple somatic genetic lesions develop during neoplastic progression in Barrett's esophagus, and it is likely that a panel of objective biomarkers will be required to manage the cancer risk optimally. METHODS: We prospectively evaluated endoscopic biopsies from 325 patients with Barrett's esophagus, 269 of whom had one or more follow-up endoscopies, by a robust platform for loss of heterozygosity (LOH) analysis, using baseline 17p (p53) LOH as a predictor and increased 4N, aneuploidy, high-grade dysplasia, and esophageal adenocarcinoma as outcomes. RESULTS: The prevalence of 17p (p53) LOH at baseline increased from 6% in negative for dysplasia to 57% in high-grade dysplasia (p < 0.001). Patients with 17p (p53) LOH had increased rates of progression to cancer (relative risk [RR] = 16, p < 0.001), high-grade dysplasia (RR = 3.6, p = 0.02), increased 4N (RR = 6.1, p < 0.001), and aneuploidy (RR = 7.5, p < 0.001). CONCLUSIONS: Patients with 17p (p53) LOH are at increased risk for progression to esophageal adenocarcinoma as well as high-grade dysplasia, increased 4N, and aneuploidy. 17p (p53) LOH is a predictor of progression in Barrett's esophagus that can be combined with a panel of other validated biomarkers for risk assessment as well as intermediate endpoints in prevention trials.

Predictors of progression in Barrett's esophagus III: baseline flow cytometric variables.

OBJECTIVES: Barrett's esophagus develops in 5-10% of patients with gastroesophageal reflux disease and predisposes to esophageal adenocarcinoma. We have previously shown that a systematic baseline endoscopic biopsy protocol using flow cytometry with histology identifies subsets of patients with Barrett's esophagus at low and high risk for progression to cancer. In this report, we further examined cytometric variables to better define the characteristics that best enable DNA cytometry to help predict cancer outcome. METHODS: Patients were prospectively evaluated using a systematic endoscopic biopsy protocol, with baseline histological and flow cytometric measurements as predictors and with cancer as the outcome. RESULTS: A receiver operating curve analysis demonstrated that a 4N fraction cut point of 6% was optimal to discriminate cancer risk (relative risk [RR] = 11.7, 95% CI = 6.2-22). The 4N fractions of 6-15% were just as predictive of cancer as were fractions of >15%. We found that only aneuploid DNA contents of >2.7N were predictive of cancer (RR = 9.5, CI = 4.9-18), whereas those patients whose sole abnormality was an aneuploid population with DNA content of < or =2.7 had a low risk for progression. The presence of both 4N fraction of >6% and aneuploid DNA content of >2.7N was highly predictive of cancer (RR = 23, CI = 10-50). S phase was a predictor of cancer risk (RR = 2.3, CI = 1.2-4.4) but was not significant when high-grade dysplasia was accounted for. CONCLUSIONS: Flow cytometry is a useful adjunct to histology in assessing cancer risk in patients with Barrett's esophagus. Careful examination of cytometric variables revealed a better definition of those parameters that are most closely associated with increased cancer risk.

An introduction to the minimally invasive osteosynthesis of intra-articular calcaneal fractures.

The approach to the treatment of intra-articular calcaneal fractures has often been the subject of discussion. The results achieved with both operative and non-operative management remain to some extent unpredictable. Minimally invasive osteosynthesis offers an alternative approach, especially in those cases in which open reduction would be hazardous and non-operative treatment inadequate. This technique requires minimal dissection and preserves subtalar motion almost completely. The authors believe that displaced intra-articular calcaneal fractures are best treated through operative intervention. Restoration of articular congruity is an integral, though not necessarily sufficient, component of a successful long-term outcome following calcaneal fracture. The extra-articular dimensions of the calcaneus must be restored in order to tolerate standard shoe-wear, maintain a functional range of talocalcaneal motion and avoid subsequent tibiotalar arthrosis. However, in certain circumstances open reduction may be associated with an unacceptably high complication rate. In these cases, the authors have found a "minimally invasive" osteosynthesis technique useful in dealing with competing goals. In our experience, this technique can, when used appropriately, result in a functional recovery of the patient suffering a calcaneal fracture.

Optimizing endoscopic biopsy detection of early cancers in Barrett's high-grade dysplasia.

OBJECTIVE: The of high-grade dysplasia management (HGD) in Barrett's esophagus remains controversial, in part, because of uncertainty about the ability of endoscopic biopsies to consistently detect early, curable cancers. METHODS: Here we report cancers we have diagnosed in 45 patients with Barrett's HGD using a protocol involving serial endoscopies with four-quadrant biopsies taken at 1-cm intervals. We compare these results to a modeled endoscopic biopsy protocol in which four-quadrant biopsies are taken every 2 cm in the Barrett's segment. RESULTS: Thirteen cancers were detected at the baseline endoscopy and 32 in surveillance. In 82% of patients, cancer was detected at a single 1-cm level of the esophagus, and in 69% the cancer was detected in a single endoscopic biopsy specimen. A 2-cm protocol missed 50% of cancers that were detected by a 1-cm protocol in Barrett's segments 2 cm or more without visible lesions. The maximum depth of cancer invasion was intramucosal in 96% of patients. Only 39% of patients who had endoscopic biopsy cancer diagnoses had cancer detected in the esophagectomy specimen. Adverse outcomes included the development of regional metastatic disease during surveillance (1 of 32), operative mortality (3 of 36), including two patients who had their primary surgeries at other institutions, and death from metastatic disease after endoscopic ablation performed at another institution (1 of 3). CONCLUSIONS: A four-quadrant, 1-cm endoscopic biopsy protocol performed at closely timed intervals consistently detects early cancers arising in HGD in Barrett's esophagus and should be used in patients with HGD who do not undergo surgical resection.

Predictors of progression to cancer in Barrett's esophagus: baseline histology and flow cytometry identify low- and high-risk patient subsets.

OBJECTIVE: Barrett's esophagus develops in 5-20% of patients with gastroesophageal reflux disease and predisposes to esophageal adenocarcinoma. The value of endoscopic biopsy surveillance is questioned because most patients do not develop cancer. Furthermore, observer variation in histological diagnosis makes validation of surveillance guidelines difficult because varying histological interpretations may lead to different estimated rates of progression. Thus, objective biomarkers need to be validated for use with histology to stratify patients according to their risk for progression to cancer. METHODS: We prospectively evaluated patients using a systematic endoscopic biopsy protocol with baseline histological and flow cytometric abnormalities as predictors and cancer as the outcome. RESULTS: Among patients with negative, indefinite, or low-grade dysplasia, those with neither aneuploidy nor increased 4N fractions had a 0% 5-yr cumulative cancer incidence compared with 28% for those with either aneuploidy or increased 4N. Patients with baseline increased 4N, aneuploidy, and high-grade dysplasia had 5-yr cancer incidences of 56%, 43%, and 59%, respectively. Aneuploidy, increased 4N, or HGD were detected at baseline in all 35 patients who developed cancer within 5 yr. CONCLUSIONS: A systematic baseline endoscopic biopsy protocol using histology and flow cytometry identifies subsets of patients with Barrett's esophagus at low and high risk for progression to cancer. Patients whose baseline biopsies are negative, indefinite, or low-grade displasia without increased 4N or aneuploidy may have surveillance deferred for up to 5 yr. Patients with cytometric abnormalities merit more frequent surveillance, and management of high-grade dysplasia can be individualized.

A neural network theory of proportional analogy-making.

A neural network model that can simulate the learning of some simple proportional analogies is presented. These analogies include, for example, (a) red-square:red-circle :: yellow-square:?, (b) apple:red :: banana: ?, (c) a:b :: c:?. Underlying the development of this network is a theory for how the brain learns the nature of association between pairs of concepts. Traditional Hebbian learning of associations is necessary for this process but not sufficient. This is because it simply says, for example, that the concepts "apple" and "red" have been associated, but says nothing about the nature of this relationship. The types of context-dependent interlevel connections in the network suggest a semilocal type of learning that in some manner involves association among more than two nodes or neurons at once. Such connections have been called synaptic triads, and related to potential cell responses in the prefrontal cortex. Some additional types of connections are suggested by the problem of modeling analogies. These types of connections have not yet been verified by brain imaging, but the work herein suggests that they may occur and, possibly, be made and broken quickly in the course of working memory encoding. These working memory connections are referred to as differential, delayed and anti-Hebbian connections. In these connections, one can learn transitions such as "keep red the same"; "change red to yellow"; "turn off red"; "turn on yellow," and so forth. Also, included in the network is a kind of weight transport so that, for example, red to red can be transported to a different instance of color, such as yellow to yellow. The network instantiation developed here, based on common connectionist building blocks such as associative learning, competition, and adaptive resonance, along with additional principles suggested by analogy data, is a step toward a theory of interactions among several brain areas to develop and learn meaningful relationships between concepts.

Waist-to-hip ratio, weight gain, and dietary and serum selenium are associated with DNA content flow cytometry in Barrett's esophagus.

This cross-sectional study reports associations between anthropometric measures, serum antioxidant concentrations, and present diet with measures of elevated cell proliferation in 51 patients with Barrett's esophagus. Cell proliferation was assessed as fractions of cells in the S and G2 phases, measured in biopsies of Barrett's tissue and analyzed by DNA content flow cytometry. Elevated proportions in the S and G2 phases predict progression to adenocarcinoma. The percentage of cells in the S phase was positively associated with waist-to-hip ratio (r = 0.33, p < 0.05) and negatively associated with serum and dietary selenium (r = -0.34 and -0.32, respectively, p < 0.05). The percentage of cells in the G2 phase was positively associated with weight change from age 25 (r = 0.39, p < 0.01) and negatively associated with dietary selenium (r = -0.31, p < 0.05). Selenium from breads and grains was negatively associated with the percentage of cells in the S phase (r = -0.41, p < 0.01) and the percentage of cells in the G2 phase (r = -0.41, p < 0.01). These results suggest that increasing weight gain in adulthood, increasing waist-to-hip ratio, and decreasing dietary selenium intake and serum levels increase the risk of progression of Barrett's esophagus to adenocarcinoma.

Safety of a systematic endoscopic biopsy protocol in patients with Barrett's esophagus.

OBJECTIVE: Widespread implementation of rigorous, systematic endoscopic biopsy protocols for patients with Barrett's esophagus may be hindered by concerns about their safety. This report describes the safety experience of a large series of patients with gastroesophageal reflux disease and Barrett's esophagus who underwent such procedures. METHODS: Patients in the Seattle Barrett's Esophagus Project undergo biopsy surveillance in a research-based clinical setting, using large channel endoscopes and "jumbo" biopsy forceps. After visual inspection, multiple biopsies are obtained from lesions and at 1- to 2-cm intervals throughout the Barrett's esophageal segment. RESULTS: From 1983 to 1997, 1,458 consecutive endoscopies were performed on 705 patients and 50,833 biopsies (average, 35; maximum, 120 per procedure) were taken. Procedures lasted from 15 to 90 min during which one to two biopsies were obtained per minute. Eleven patients experienced 18 significant adverse events, five of which led to overnight hospitalizations: two for bleeding attributed to concomitant esophageal stricture dilation; two for cardiac dysrhythmias; and one for respiratory arrest. Events managed in outpatient settings included chest pain during seven endoscopies (all accounted for by two patients), chest or epigastric pain developing after five endoscopies, and one tonsillar abrasion. All patients recovered completely, and no deaths, perforations, aspiration, or esophageal stricturing resulted from the procedures. CONCLUSIONS: A rigorous, systematic endoscopic biopsy protocol in patients with Barrett's esophagus does not produce esophageal perforation or bleeding when performed by an experienced team of physicians, nurses, and technicians.

Effect of segment length on risk for neoplastic progression in patients with Barrett esophagus.

BACKGROUND: The increased risk for esophageal adenocarcinoma associated with long-segment (> or =3 cm) Barrett esophagus is well recognized. Recent studies suggest that short-segment (<3 cm) Barrett esophagus is substantially more common; however, the risk for neoplastic progression in patients with this disorder is largely unknown. OBJECTIVE: To examine the relation between segment length and risk for aneuploidy and esophageal adenocarcinoma in patients with Barrett esophagus. DESIGN: Prospective cohort study. SETTING: University medical center in Seattle, Washington. PATIENTS: 309 patients with Barrett esophagus. MEASUREMENTS: Patients were monitored for progression to aneuploidy and adenocarcinoma by repeated endoscopy with biopsy for an average of 3.8 years. Cox proportional hazards analysis was used to calculate adjusted relative risks and 95% Cls. RESULTS: After adjustment for histologic diagnosis at study entry, segment length was not related to risk for cancer in the full cohort (P > 0.2 for trend). When patients with high-grade dysplasia at baseline were excluded, however, a nonsignificant trend was observed; based on a linear model, a 5-cm difference in segment length was associated with a 1.7-fold (95% CI, 0.8-fold to 3.8-fold) increase in cancer risk. Among all eligible patients, a 5-cm difference in segment length was associated with a small increase in the risk for aneuploidy (relative risk, 1.4 [CI, 1.0 to 2.1]; P = 0.06 for trend). A similar trend was observed among patients without high-grade dysplasia at baseline. CONCLUSIONS: The risk for esophageal adenocarcinoma in patients with short-segment Barrett esophagus was not substantially lower than that in patients with longer segments. Although our results suggest a small increase in risk for neoplastic progression with increasing segment length, additional follow-up is needed to determine whether the patterns of risk occurred by chance or represent true differences. Until more data are available, the frequency of endoscopic surveillance should be selected without regard to segment length.

Complete resolution of heartburn symptoms and health-related quality of life in patients with gastro-oesophageal reflux disease.

BACKGROUND: Medical treatments for gastro-oesophageal reflux disease (GERD) vary in their ability to completely resolve heartburn and other symptoms. Although GERD reduces health-related quality of life (HRQL) little is known about the relationship between resolution of heartburn symptoms with medical therapy and HRQL. We evaluated the association between complete resolution of heartburn symptoms and functioning and well-being in three samples of patients with GERD. METHODS: We analysed baseline and follow-up assessments of heartburn symptoms and HRQL scores from three clinical trials (total n=1351) comparing omeprazole and ranitidine for acute symptomatic treatment of GERD. Heartburn symptoms were measured using patient diaries and/or patient self-report. HRQL was assessed using the Psychological General Well-Being Index (PGWB) in all three clinical trials and the SF-36 Health Survey in two clinical trials. Resolution of heartburn symptoms was defined as no heartburn reported during the assessment period. RESULTS: We observed statistically significant differences favouring patients with no heartburn symptoms on the PGWB total score (P=0.018 to P < 0.0001) and anxiety (P=0.002 to P < 0.0001), general health (P=0.05 to P < 0. 0001), positive well-being (P=0.028 to P < 0.0001) and vitality (P=0. 05 to P < 0.0001) sub-scale scores at 4-14 weeks. Patients with no heartburn reported better SF-36 pain (P=0.005 to P < 0.0001) and general health perceptions (P=0.032 to P < 0.0001) compared with patients still experiencing heartburn symptoms at 4-24 weeks. SF-36 physical component summary scores were significantly better in patients with no heartburn symptoms compared with patients with heartburn symptoms at 4-24 weeks (P=0.013 to P=0.009), while mental component summary scores were only significantly different at 24 weeks (P=0.0005) in one of the two studies where the SF-36 was utilized. CONCLUSIONS: Complete resolution of heartburn symptoms was consistently associated with improvement in HRQL; the greatest impact was observed on measures of psychological well-being and physical functioning and well-being. Effective treatment of GERD that completely resolves heartburn results in clinically significant improvement in patient HRQL.

Histological and anatomic changes in Barrett's esophagus after antireflux surgery.

OBJECTIVE: The best treatment approach for patients with documented Barrett's esophagus remains controversial. There is currently no well designed prospective study examining the effect of successful antireflux surgery on Barrett's esophagus. METHODS: Fourteen patients with histologically proven Barrett's esophagus underwent standard antireflux surgery followed by careful endoscopic, histological, and symptomatic follow-up beginning at 2-4 wk after surgery. Pre- and postoperative symptoms, patient functional assessment scores, lower esophageal sphincter pressure, and 24-h pH studies were compared, in addition to monitoring patients for evidence of squamous re-epithelialization and dysplasia. RESULTS: Patients demonstrated statistically significant improvement in symptoms, functional assessment scores, lower esophageal sphincter pressure, and 24-h pH assessments after antireflux surgery. Two patients had complete disappearance of short segments (2 and 3 cm) of Barrett's esophagus. Ten additional patients demonstrated evidence of squamous re-epithelialization, although biopsies often showed mixed components of squamous and columnar epithelium. No patients showed progression of dysplastic change, and four patients demonstrated the disappearance of low grade dysplasia throughout the period of the study. CONCLUSION: Successful antireflux surgery can produce at least partial squamous re-epithelialization in Barrett's metaplasia and stabilization or apparent improvement in dysplasia in some patients without the need for long term medication. Continued long term endoscopic and histologic follow-up is still required in all patients with Barrett's esophagus after antireflux surgery.

Oral beclomethasone dipropionate for treatment of intestinal graft-versus-host disease: a randomized, controlled trial.

BACKGROUND & AIMS: Beclomethasone dipropionate (BDP), a topically active steroid, seemed to be an effective treatment for intestinal graft-versus-host disease (GVHD) in a phase I study. The aim of this study was to compare the effectiveness of oral BDP to that of placebo capsules in treatment of intestinal GVHD. METHODS: Sixty patients with anorexia and poor oral intake because of intestinal GVHD were randomized to receive prednisone (1 mg.kg-1.day-1) plus either oral BDP (8 mg/day) or placebo capsules. Initial responders who were eating at least 70% of caloric needs at evaluation on day 10 continued to take study capsules for an additional 20 days while the prednisone dose was rapidly tapered. The primary end point was the frequency of a durable treatment response at day 30 of treatment. RESULTS: The initial treatment response at day 10 was 22 of 31 (71%) in the BDP/prednisone group vs. 16 of 29 (55%) for the placebo/prednisone group. The durable treatment response at day 30 was 22 of 31 (71%) vs. 12 of 29 (41%), respectively (P = 0.02). CONCLUSIONS: The combination of oral BDP capsules and prednisone was more effective than prednisone alone in treating intestinal GVHD. Oral BDP allowed prednisone doses to be rapidly tapered without recurrent intestinal symptoms.

Immunosuppression during spaceflight deconditioning.

Spaceflight results in immunosuppression which is likely due mainly to neurohumoral factors released in response to intermittent stress effects during flight. However, no major non-physiological health problems have been reported during or following spaceflight, but diseases resulting from immunosuppression could occur on long-duration missions and would include bacterial, fungal, and viral infections in addition to increased incidence of neoplasia and autoimmunity. Pharmacokinetics and pharmacodynamics appear to be altered during spaceflight and, as a consequence, alternative drug administration and dosing procedures will need to be developed. Moderate exercise training enhances immune function, but in-flight exercise may affect immunological parameters and immunity in ways not yet ascertained. Hyperosmolality may enhance some immune parameters, and attenuate others especially when associated with dehydration and exercise. Reducing in-flight stress may attenuate flight-induced immunosuppression, but pharmacological interventions may be essential to prevent undesirable immune responses which may occur on long-duration missions to Mars.

Chance fracture after pedicle screw fixation. A case report.

STUDY DESIGN: A case of a Chance fracture through an instrumented pedicle is presented. The radiographic and intraoperative findings and management of this complication are reported. OBJECTIVE: To increase awareness of the complications of transpedicular screw fixation and to suggest a form of management of this unusual complication. SUMMARY OF BACKGROUND DATA: To the authors' knowledge, this is the first reported case of such a vertebral fracture occurring after pedicle screw fixation. METHODS: A 44-year-old man with athetoid cerebral palsy and a progressive thoracic kyphosis sustained a Chance fracture at the caudal end of the segmental instrumentation construct. RESULTS: Surgical intervention, including fracture reduction and extension of the instrumented fusion to the pelvis, provided effective restoration of physiologic sagittal alignment. CONCLUSION: Chance fracture after pedicle screw fixation can be successfully managed with surgical intervention.

Management of dysplasia in the columnar-lined esophagus.

The management of patients with high-grade dysplasia in Barrett's esophagus is complex and controversial with regard to electing continued endoscopic biopsy surveillance until an early adenocarcinoma is detected or proceeding with partial esophagogastrectomy. Clinical recommendations to patients for either option should be individualized and based on several parameters reflecting patient and clinician factors. Available data on interpretational variation in the diagnosis of dysplasia; limitation of diagnostic errors with the use of a rigorous, systematic endoscopic biopsy protocol; new information on the apparent benign natural history of high-grade dysplasia in some patients; and the morbidity and mortality of esophageal resection all suggest that recommendation for continued endoscopic biopsy surveillance is an appropriate clinical practice in selected patients. Ongoing research investigations on high-grade dysplasia in Barrett's esophagus aim to reduce the potential for diagnostic errors, simplify cancer surveillance, and develop therapeutic interventions that are safer than but as effective as surgery.