Three-dimensional optical coherence tomography of Barrett's esophagus and buried glands beneath neosquamous epithelium following radiofrequency ablation.

We report three-dimensional (3D) endoscopic microscopy findings in Barrett's esophagus, using an endoscopic optical coherence tomography (OCT) system in one patient before and in one patient after radiofrequency ablation (RFA). Findings were compared with those in a normal patient without Barrett's esophagus. In the normal patient,findings were of regular flat squamous mucosa with small subepithelial vessels and glands. In the Barrett's esophagus patient, findings were of large, densely packed glands with distortion of mucosal architecture. In the post-RFA case, findings were of a small number of isolated glands buried beneath 300-500 microm of neosquamous epithelium and lamina propria. Neosquamous epithelium is a marker of successful ablative therapy, while buried glands may have potential for dysplastic progression and are difficult to detect using conventional methods. These results indicate a potential role of 3D-OCT endoscopic microscopy for follow-up, including subsurface assessment, of ablative treatments for Barrett's esophagus.

Severe fetal hydrocephalus with and without neural tube defect: a comparative study.

OBJECTIVE: To describe the main perinatal and 1-year outcomes in babies with a prenatal ultrasonographic diagnosis of severe hydrocephalus according to the presence or absence of a neural tube defect (NTD) in a country where abortion is illegal. METHOD: The study population consisted of cases referred to and delivered at Hospital de Clínicas de Porto Alegre, diagnosed between January 1993 and December 2001. The diagnosis of severe hydrocephalus was based on a lateral ventricular atrium diameter > or =15 mm in at least one hemisphere. RESULTS: Sixty cases were ascertained: 28 with NTD (group 1) and 32 without NTD (group 2). The groups were similar in terms of maternal and child variables at birth and hospitalization days during the 1st year of life. The mortality (including intrauterine deaths and deaths of babies with malformations incompatible with life that characterize a very poor prognosis) until 1 year of age was 36% in group 1 and 59% in group 2 (p = 0.077). The rate of cardiac malformations was higher in the group without NTD (p = 0.015). The length of hospital stay after birth (1st admission) was significantly higher in the group with NTD (p = 0.007). CONCLUSIONS: The morbidity was higher in the group with NTD, possibly due to the higher number of surgical interventions in the central nervous system. However, the mortality was higher in the group without NTD, possibly due to the presence of other associated malformations, especially congenital heart disease. Further studies should focus on neurological function and quality of life of the children and their families at the end of the 1st year and after 2 or 6 years of age.

Ultrahigh resolution optical coherence tomography of Barrett's esophagus: preliminary descriptive clinical study correlating images with histology.

BACKGROUND AND STUDY AIMS: Endoscopic ultrahigh resolution optical coherence tomography (UHR OCT) achieves an axial image resolution of approximately 5 microm, which is 2 - 3 times finer than standard endoscopic OCT imaging. This study investigated the capability of endoscopic UHR OCT for imaging patients with Barrett's esophagus. PATIENTS AND METHODS: Fivty volunteers previously diagnosed with Barrett's esophagus underwent UHR OCT. Imaging was performed at 1.3 microm wavelengths with approximately 5 microm axial and approximately 15 microm transverse resolutions using a 1.8 mm/diameter linear-scanning catheter introduced through the accessory channel of a standard endoscope. OCT images were compared with endoscopic diagnosis and pinch biopsy histological appearances. RESULTS: UHR OCT images of normal esophagus, Barrett's esophagus, high grade dysplasia and esophageal adenocarcinoma were evaluated. UHR OCT images of the normal esophagus exhibited characteristic layered architecture with uniform epithelium, while images of Barrett's esophagus corresponded to crypt-like glandular structures. High grade dysplasia and esophageal adenocarcinoma images exhibited more heterogeneous structures corresponding to irregular, heterogeneous tissue morphology from distorted and cribriform or villiform glandular architecture. Fine features can be discerned more clearly with endoscopic UHR OCT. CONCLUSIONS: This study evaluated new endoscopic OCT technology and demonstrated the feasibility of carrying out UHR OCT imaging in conjunction with standard endoscopy for in vivo real-time imaging of Barrett's esophagus, dysplasia, and esophageal adenocarcinoma. A survey of normal and abnormal upper gastrointestinal tissues was performed using a research prototype OCT system with the highest axial resolution to date, and can serve as a baseline for future investigation.

Routes to the future German health economy.

A fundamental reorganisation of the health-care system to introduce a market orientation, more transparency and patient autonomy is proposed as the way to deliver the required high-quality care of the future.

Acute cor pulmonale in acute respiratory distress syndrome submitted to protective ventilation: incidence, clinical implications, and prognosis.

CONTEXT: The incidence of acute cor pulmonale (ACP), a frequent and usually lethal complication of acute respiratory distress syndrome (ARDS) during traditional respiratory support, has never been re-evaluated since protective ventilation gained acceptance. OBJECTIVE: We performed a longitudinal transesophageal echocardiographic (TEE) study to determine whether this incidence, and its severe implications for prognosis, might have changed in our unit as we altered respiratory strategy. DESIGN: Prospective open clinical study. SETTING: Medical intensive care unit of a university hospital. PATIENTS: Seventy-five consecutive ARDS patients given respiratory support with airway pressure limitation (plateau pressure < or =30 cm H2O). INTERVENTIONS: ACP was defined as a ratio of right ventricular end-diastolic area to left ventricular end-diastolic area in the long axis >0.6 associated with septal dyskinesia in the short axis during TEE examination. RESULTS: Normal right ventricular function was present in 56 patients, whereas right ventricular dysfunction was observed in 19 patients after 2 days of respiratory support. ACP was associated with pulmonary artery hypertension, increased heart rate, and decreased stroke index. Significant impairment of left ventricular diastolic function was also seen. All echo-Doppler abnormalities were reversible in patients who recovered, and the mortality rate was the same in both groups (32%). However, ACP patients who recovered required a longer period of respiratory support. A multivariate analysis individualized Paco2 level as the sole factor independently associated with ACP, suggesting that ACP development in ARDS is influenced by the severity of lung damage and/or the respiratory strategy. CONCLUSION: Evaluation of right ventricular function by TEE in a group of 75 ARDS patients submitted to protective ventilation revealed the persistence of a 25% incidence of ACP, resulting in detrimental hemodynamic consequences associated with tachycardia. However, ACP was reversible in patients who recovered and did not increase mortality.

Positive end-expiratory pressure titration in acute respiratory distress syndrome patients: impact on right ventricular outflow impedance evaluated by pulmonary artery Doppler flow velocity measurements.

OBJECTIVE: Positive end-expiratory pressure (PEEP) titration in acute respiratory distress syndrome patients remains debatable. We used two mechanical approaches, calculation of the compliance of the respiratory system and determination of the lower inflexion point of the pressure-volume curve of the respiratory system, to identify specific PEEPs (PEEPS and PEEPA) whose impact on right ventricular (RV) outflow was compared with Doppler analysis of pulmonary artery flow velocity. DESIGN: Prospective, open, clinical study. SETTING: Medical intensive care unit of a university hospital. PATIENTS: Sixteen consecutive ventilator-dependent acute respiratory distress syndrome patients. INTERVENTIONS: Two PEEPs were determined: PEEPS was the highest PEEP associated with the highest value of respiratory compliance, and PEEPA was the coordinate of the lower inflexion point of the inspiratory pressure-volume curve on the pressure axis plus 2 cm H2O. MEASUREMENTS AND MAIN RESULTS: We observed a large difference between the two PEEPs, with PEEPA (13 + 4 cm H2O) > PEEPS (6 + 3 cm H2O). Changes in RV outflow impedance produced by tidal ventilation with zero end-expiratory pressure (ZEEP) and after application of these two PEEPs were assessed by Doppler study of pulmonary artery flow velocity obtained by a transesophageal approach, with particular reference to the end-expiratory and end-inspiratory pulmonary artery velocity-time integral, as reflecting RV stroke output, and mean acceleration as reflecting RV outflow impedance during an unchanged flow period. A significant inspiratory reduction in pulmonary artery velocity-time integral (from 11.8 + 0.3 to 10.0 + 0.3 cm) and mean acceleration (from 11.9 + 0.9 to 8.0 + 0.9 m/sec2) was observed with ZEEP, showing a reduction in RV stroke index (from 29.0 + 0.9 to 26.0 + 0.6 cm3/m2) by a sudden increase in outflow impedance during tidal ventilation. Application of PEEPA, which improved Pao2 (102 + 40 vs. 65 + 18 torr with ZEEP), worsened the inspiratory drop in RV stroke index (21.6 + 0.8 cm3/m2), resulting in a significant reduction in cardiac index compared with ZEEP (from 3.0 + 1.0 to 2.7 + 1.1). Application of PEEPS, which also significantly improved Pao2 (81 + 21 torr), was associated with a lesser impact on RV outflow impedance (inspiratory mean acceleration: 9.5 + 1 m/sec2) and cardiac index (3.2 + 1.0) than PEEPA. CONCLUSION: RV outflow impedance evaluated by the Doppler technique appeared sensitive to PEEP titration. Application of PEEPA worsened RV systolic function impairment produced by tidal ventilation. Conversely, application of PEEPS reduced RV systolic function impairment, suggesting an association with a lower pulmonary vascular resistance.

Cyclic AMP-mediated inhibition of cell growth requires the small G protein Rap1.

In many normal and transformed cell types, the intracellular second messenger cyclic AMP (cAMP) blocks the effects of growth factors and serum on mitogenesis, proliferation, and cell cycle progression. cAMP exerts these growth-inhibitory effects via inhibition of the mitogen-activated protein (MAP) kinase cascade. Here, using Hek293 and NIH 3T3 cells, we show that cAMP's inhibition of the MAP kinase cascade is mediated by the small G protein Rap1. Activation of Rap1 by cAMP induces the association of Rap1 with Raf-1 and limits Ras-dependent activation of ERK. In NIH 3T3 cells, Rap1 is required not only for cAMP's inhibition of ERK activation but for inhibition of cell proliferation and mitogenesis as well.

Early preload adaptation in septic shock? A transesophageal echocardiographic study.

BACKGROUND: An accepted concept in septic shock is that preload adaptation by acute left ventricular dilatation, when occurring spontaneously or with the aid of volume loading, permits maintenance of an adequate cardiac output, leading to final recovery. From a physiologic point of view, this concept appears debatable because a normal pericardium exerts a restraining action on a normal heart. METHODS: During a 26-month period, the authors investigated, by transesophageal echocardiography, 40 patients hospitalized in their unit for an episode of septic shock. Transesophageal echocardiography was performed in the first hours after admission, proceeded by correction of any hypovolemia, and stabilization of arterial pressure by vasoactive agent infusion if necessary. Left ventricular dimensions were obtained in long- and short-axis views, permitting calculation of left ventricular ejection fraction (long axis) and fractional area contraction (short axis). Stroke index was simultaneously measured by the Doppler technique. RESULTS: Stroke index was strongly correlated with both echocardiographic left ventricle ejection fraction (r = 0.75; P < 0.0001) and left ventricle fractional area contraction (r = 0.76; P < 0.0001), whereas it was independent of echocardiographic left ventricle diastolic dimensions. CONCLUSIONS: The transesophageal echocardiography study was unable to confirm the reality of the concept of early preload adaptation by left ventricular dilatation in septic shock. Conversely, because left ventricular volume always remained in a normal range after correcting hypovolemia, systolic function was the unique determinant of stroke index in septic shock.

The Internal jugular veins are asymmetric. Usefulness of ultrasound before catheterization.

OBJECTIVE: To demonstrate an asymmetry of the internal jugular veins, a finding which will have consequences for catheterization. DESIGN: Prospective study. SETTING: The medical ICU of a university-affiliated teaching hospital. PATIENTS: Eighty critically ill consecutive patients. INTERVENTION: Measurement of the cross-sectional area of the internal jugular veins. Search for an asymmetry, defined as an area at least twice that of the contralateral vein. RESULTS: An asymmetry was noted in 62.5% of the patients. The dominant vein was the right in only 68 % of these cases. In addition, 23% of the 160 jugular internal veins had an area of 0.4 cm2 or less. CONCLUSIONS: Using a simple technique, ultrasound identifies the dominant internal jugular vein, thus indicating the safer side before blind catheterization.

Cabbage cryoprotectin is a member of the nonspecific plant lipid transfer protein gene family.

We have recently purified a protein (cryoprotectin) from the leaves of cold-acclimated cabbage (Brassica oleracea) to electrophoretic homogeneity, which protects thylakoids isolated from the leaves of nonacclimated spinach (Spinacia oleracea) from freeze-thaw damage. Sequencing of cryoprotectin showed the presence of at least three isoforms of WAX9 proteins, which belong to the class of nonspecific lipid transfer proteins. Antibodies raised against two synthetic peptides derived from the WAX9 proteins recognized a band of approximately 10 kD in western blots of crude cryoprotectin preparations. This protein and the cryoprotective activity could be precipitated from solution by the antiserum. We show further that cryoprotectin is structurally and functionally different from WAX9 isolated from the surface wax of cabbage leaves. WAX9 has lipid transfer activity for phosphatidylcholine, but no cryoprotective activity. Cryoprotectin, on the other hand, has cryoprotective, but no lipid transfer activity. The cryoprotective activity of cryoprotectin was strictly dependent on Ca(2+) and Mn(2+) and could be inhibited by chelating agents, whereas the lipid transfer activity of WAX9 was higher in the presence of ethylenediaminetetraacetate than in the presence of Ca(2+) and Mn(2+).

Germany health-care systems at the turning point.

How innovative medical technologies bring improved care and cost-effectiveness.

CD28 and the tyrosine kinase lck stimulate mitogen-activated protein kinase activity in T cells via inhibition of the small G protein Rap1.

Proliferation of T cells via activation of the T-cell receptor (TCR) requires concurrent engagement of accessory costimulatory molecules to achieve full activation. The best-studied costimulatory molecule, CD28, achieves these effects, in part, by augmenting signals from the TCR to the mitogen-activated protein (MAP) kinase cascade. We show here that TCR-mediated stimulation of MAP kinase extracellular-signal-regulated kinases (ERKs) is limited by activation of the Ras antagonist Rap1. CD28 increases ERK signaling by blocking Rap1 action. CD28 inhibits Rap1 activation because it selectively stimulates an extrinsic Rap1 GTPase activity. The ability of CD28 to stimulate Rap1 GTPase activity was dependent on the tyrosine kinase Lck. Our results suggest that CD28-mediated Rap1 GTPase-activating protein activation can help explain the augmentation of ERKs during CD28 costimulation.

beta 2-adrenergic receptor activates extracellular signal-regulated kinases (ERKs) via the small G protein rap1 and the serine/threonine kinase B-Raf.

G protein-coupled receptors can induce cellular proliferation by stimulating the mitogen-activated protein (MAP) kinase cascade. Heterotrimeric G proteins are composed of both alpha and betagamma subunits that can signal independently to diverse intracellular signaling pathways including those that activate MAP kinases. In this study, we examined the ability of isoproterenol, an agonist of the beta(2)-adrenergic receptor (beta(2)AR), to stimulate extracellular signal-regulated kinases (ERKs). Using HEK293 cells, which express endogenous beta(2)AR, we show that isoproterenol stimulates ERKs via beta(2)AR. This action of isoproterenol requires cAMP-dependent protein kinase and is insensitive to pertussis toxin, suggesting that Galpha(s) activation of cAMP-dependent protein kinase is required. Interestingly, beta(2)AR activates both the small G proteins Rap1 and Ras, but only Rap1 is capable of coupling to Raf isoforms. beta(2)AR inhibits the Ras-dependent activation of both Raf isoforms Raf-1 and B-Raf, whereas Rap1 activation by isoproterenol recruits and activates B-Raf. beta(2)AR activation of ERKs is not blocked by expression of RasN17, an interfering mutant of Ras, but is blocked by expression of either RapN17 or Rap1GAP1, both of which interfere with Rap1 signaling. We propose that isoproterenol can activate ERKs via Rap1 and B-Raf in these cells.

Interface between titanium miniplate/screw and human calvaria.

This study demonstrates interfacial changes of titanium miniplate/screw with normal calvaria and nonvascularized calvarial bone graft ensued from craniectomy in a 53-year-old female. In 18 months after operation, a right parietal bone containing an L-shaped miniplate with screws, 5 mm long and 2 mm in external diameter, was harvested, fixed, and embedded in methylmetacrylate. Fifteen micrometer thick sections were made by an EXAKT cutting-grinding system (Exakt Company, Hamburg, Germany), and reviewed under the bright field light microscope. The mean of the bone-contacting surface ratio (BCSR) in six screwed bone was 64.1%; 69.3% in normal bone, and 60.4% in grafted bone. The trabecular bone areas in 10 x 5 mm (50 mm2) rectangular area of diploe surrounding the screws was 43.02 mm2; 45.25 mm2 in normal calvaria; and 41.82 mm2 in grafted bone. The mean Ca/P peak-height ratio of the plated and screwed calvaria was 1.47 in a 9 mm wide zone around each screw; 1.37 in normal calvaria; and 1.51 in grafted calvaria. We concede that the effect of direct contact of titanium with screws onto the bone is as much as an osseous integration (osseointegration).

Cyclic changes in right ventricular output impedance during mechanical ventilation.

In a context such as acute respiratory distress syndrome, where optimum tidal volume and airway pressure levels are debated, the present study was designed to differentiate the right ventricular (RV) consequences of increasing lung volume from those secondary to increasing airway pressure during tidal ventilation. The study was conducted by combined two-dimensional echocardiographic and Doppler studies in 10 patients requiring mechanical ventilation in the controlled mode because of acute respiratory failure. Continuous monitoring of airway pressure on echocardiographic and Doppler recordings provided accurate timing of each cardiac event during the respiratory cycle, with particular attention being paid to end-expiratory and end-inspiratory atrial diameters, RV dimensions, and pulmonary artery and tricuspid flow estimated by the velocity-time integral (PA(VTI) and T(VTI), respectively). At baseline, lung inflation during the inspiratory phase of mechanical ventilation produced a drop in PA(VTI) from 14.3 +/- 2.6 cm at end expiration to 11.3 +/- 2.1 cm at end inspiration. This drop occurred without reduction in right atrial diameter or in RV diastolic dimensions. It was not preceded but was followed by a decrease in T(VTI), thus confirming an increase in RV outflow impedance. Manipulation of tidal volume without changing airway pressure and manipulation of airway pressure without changing tidal volume demonstrated that tidal volume, but not airway pressure, was the main determinant factor of RV afterloading during mechanical ventilation.

Acute, fatal, oral chromic acid poisoning.

CASE REPORT: We report a 35-year-old woman who developed severe acidosis, massive gastrointestinal hemorrhage, acute renal failure, and hepatic injury following ingestion of chromic acid (50 mL) and died 12 hours after ingestion. Postmortem liver biopsy revealed a fatty degeneration with chromium concentration 3.6 mumol/g. The kidney, with chromium concentration 2.6 mumol/g, had extensive necrosis and ischemic lesions. Erythrocyte chromium was 1903 mumol/L at 3 hours declining to 865 mumol/L at 11 hours.

Impact of nicotine on bone healing.

A limited number of experimental animal studies and in vitro data confirm that nicotine impairs bone healing, diminishes osteoblast function, causes autogenous bone graft morbidity, and decreases graft biomechanical properties. Therefore, our long-term goal is to develop an effective therapy to reverse the adverse impact of nicotine from tobacco products. However, before accomplishing this goal, we had to develop an animal model. Our hypotheses were nicotine administration preceding and following autogenous bone grafting adversely affected autograft incorporation and depressed donor site healing in a characterized animal wound model. Hypothesis testing was accomplished in bilateral, 4-mm diameter parietal bone defects prepared in 60 Long-Evans rats (male, 35-day-old). A 4-mm diameter disk of donor bone was removed from the left parietal bone and placed in the contralateral defect. The donor site served as a spontaneously healing bone wound. The rats were partitioned equally among three doses of nicotine administered orally in the drinking water (12.5, 25, and 50 mg/L). For each dose, the duration and sequence of nicotine treatment followed four courses, including no nicotine and designated combinations of nicotine administration and abatement prior to and following osseous surgery. Experimental sites were recovered on 14 and 28 days postsurgery, responses quantitated, and data analyzed by analysis of variance and post hoc statistics (p < or = 0.05). We developed a convenient and effective osseous model, and the results validated our hypothesis that nicotine negatively impacts on bone healing.

Tissue-engineered bone biomimetic to regenerate calvarial critical-sized defects in athymic rats.

A tissue-engineered bone biomimetic device was developed to regenerate calvaria critical-sized defects (CSDs) in athymic rats. Well-documented evidence clearly confirms that left untreated, CSDs will not spontaneously regenerate bone. To accomplish regeneration, four candidate treatments were assessed: porous poly(D,L-lactide) and type I collagen (PLC), PLC and human osteoblast precursor cells (OPCs) at 2 x 10(5) (PLC/OPCs), PLC and 50 microg of recombinant human bone morphogenetic protein-2 (PLC/rhBMP-2), and PLC/OPCs/rhBMP-2 (the bone biomimetic device). The hypotheses for this study were PLC/OPCs/rhBMP-2 would promote more new bone formation in CSDs than the other treatments and the amount of bone formation would be time dependent. To test the hypotheses, outcomes from treatments were measured at 2 and 4 weeks postoperatively by radiomorphometry for percent radiopacity and by histomorphometry for square millimeters of new bone formation. Data were analyzed by analysis of variance and Fisher's protected least significant difference for multiple comparisons with p < or = 0.05. At 2 and 4 weeks, radiomorphometric data revealed PLC/rhBMP-2 and PLC/OPCs/rhBMP-2 promoted significantly more radiopacity than either PLC or PLC/OPCs. Histomorphometry data at 2 and 4 weeks indicated significantly more new bone formation for PLC/rhBMP-2, PLC/OPCs/rhBMP-2, and PLC/OPCs compared to PLC. By 4 weeks, PLC/OPCs/rhBMP-2 and PLC/rhBMP-2 had regenerated the CSDs with more new bone than the other treatments; the quantity of bone at 4 weeks for these treatments was greater than at 2 weeks.

Bone morphogenetic proteins: an update on basic biology and clinical relevance.

The regeneration of bone is a remarkable, complex physiological process, and BMPs are a formidable clinical tool to promote its regeneration. By defining roles played by BMPs in developmental biology and bone regeneration, significant progress has been made to identify cell-signaling molecules and their regulators. For example, the regulators of BMPs that include noggin, chordin, cerberus, dan, and gremlin may be harnessed as therapies to offset calcification encountered after total hip arthroplasties. Furthermore, exploiting BMPs and Smads may generate new therapeutic options for bone repair. Another compelling clinical consideration is the trans-acting factor osteoblast-specific factor-2, which can promote osteoblast differentiation. Moreover, the affiliation of osteoblast-specific factor-2 with heritable disorders merits exploration. A recognized daunting challenge includes a carrier/delivery system for the powerful morphogenetic therapeutic tools, as well as osteoprogenitor cells and intracellular transduction and transcriptional factors. In addition, the long-term effects of administering superphysiological doses of rhBMPs to patients must be assessed systematically. A new generation carrier/delivery system may be the answer to offset dosing liabilities as well as to provide residence for exogenous, BMP-receptive osteoprogenitor cells (111,112). The areas highlighted in this review offer fertile territory for thought and research to develop rational clinical treatments to promote bone regeneration and to understand some of the biological roles of BMPs.

Speckle in optical coherence tomography.

Speckle arises as a natural consequence of the limited spatial-frequency bandwidth of the interference signals measured in optical coherence tomography (OCT). In images of highly scattering biological tissues, speckle has a dual role as a source of noise and as a carrier of information about tissue microstructure. The first half of this paper provides an overview of the origin, statistical properties, and classification of speckle in OCT. The concepts of signal-carrying and signal-degrading speckle are defined in terms of the phase and amplitude disturbances of the sample beam. In the remaining half of the paper, four speckle-reduction methods-polarization diversity, spatial compounding, frequency compounding, and digital signal processing-are discussed and the potential effectiveness of each method is analyzed briefly with the aid of examples. Finally, remaining problems that merit further research are suggested. © 1999 Society of Photo-Optical Instrumentation Engineers.