Five fraction stereotactic radiotherapy after brain metastasectomy: a single-institution experience and literature review.

PURPOSE: The outcomes of five fraction stereotactic radiotherapy (hfSRT) following brain metastasectomy were evaluated and compared with published series. METHODS: 30 Gy in 5 fractions HfSRT prescribed to the surgical cavity was reduced to 25 Gy if the volume of 'brain-GTV' receiving 20 Gy exceeded 20 cm3. Endpoints were local recurrence, nodular leptomeningeal recurrence, new brain metastases and radionecrosis. The literature was searched for reports of clinical and dosimetric outcomes following postoperative hfSRT in 3-5 fractions. RESULTS: 39 patients with 40 surgical cavities were analyzed. Cavity local control rate at 1 year was 33/40 (82.5%). 3 local failures followed 30 Gy/5 fractions and 4 with 25 Gy/5 fractions. The incidence of leptomeningeal disease (LMD) was 7/40 (17.5%). No grade 3-4 toxicities, particularly no radionecrosis, were reported. The incidence of distant brain metastases was 15/40 (37.5%). The median overall survival was 15 months. Across 13 published series, the weighted mean local control was 83.1% (adjusted for sample size), the mean incidence of LMD was 14.9% (7-34%) and the mean rate of radionecrosis was 10.3% (0-20.6%). CONCLUSION: Postoperative hfSRT can be delivered with 25-30 Gy in 5 fractions with efficacy in excess of 82% and no significant toxicity when the dose to 'brain-GTV' does not exceed 20 cm3.

Intraoperative high frequency ultrasound in intracerebral high-grade tumors.

PURPOSE: To demonstrate the utility of a new concept of intraoperative use of high frequency ultrasound (hfioUS) in maximizing the extent of resection (EOR) of intracerebral high-grade tumors. MATERIALS AND METHODS: 22 Patients harboring an intracerebral high-grade tumor were retrospectively included in this study (14 primary tumors, 8 metastasis). 14 of them had a perilesional edema equal or greater to lesion volume, 3 had previously received radiotherapy. Following macroscopic tumor debulking, the small (11 × 31 mm) L15 - 7io (Philips, Bothell, USA) high-frequency probe (7 - 15 MHz) was introduced into the resection cavity and its walls were meticulously scanned to search for tumor remnants. Postoperative MR scan was evaluated by a board-certified independent neuroradiologist, who assessed the EOR. RESULTS: Gross total resection was achieved in 21 patients (95.5 %). One patient had a small tumor remnant (6 × 4 × 3 mm) of a very large (80 × 60 × 74 mm) anaplastic astrocytoma, detected in the postoperative MR scan. A permanent postoperative hemiparesis was diagnosed in one patient with a metastasis in the motor area, while the other patients recovered without permanent neurological deficits from the surgery. CONCLUSION: The hfioUS probe allowed in this study a precise detection of the tumor and a detailed discrimination between normal, pathological and edematous tissue in all 22 cases.

The N-terminal anchor sequences of 11beta-hydroxysteroid dehydrogenases determine their orientation in the endoplasmic reticulum membrane.

11beta-Hydroxysteroid dehydrogenase enzymes (11beta- HSD) regulate the ratio of active endogenous glucocorticoids to their inactive keto-metabolites, thereby controlling the access of glucocorticoids to their cognate receptors. In this study, the topology and intracellular localization of 11beta-HSD1 and 11beta-HSD2 have been analyzed by immunohistochemistry and protease protection assays of in vitro transcription/translation products. 11beta-HSD constructs, tagged with the FLAG epitope, were transiently expressed in HEK-293 cells. The enzymatic characteristics of tagged and native enzymes were indistinguishable. Fluorescence microscopy demonstrated the localization of both 11beta-HSD1 and 11beta-HSD2 exclusively to the endoplasmic reticulum (ER) membrane. To examine the orientation of tagged 11beta-HSD enzymes within the ER membrane, we stained selectively permeabilized HEK-293 cells with anti-FLAG antibody. Immunohistochemistry revealed that the N terminus of 11beta-HSD1 is cytoplasmic, and the catalytic domain containing the C terminus is protruding into the ER lumen. In contrast, the N terminus of 11beta-HSD2 is lumenal, and the catalytic domain is facing the cytoplasm. Chimeric proteins where the N-terminal anchor sequences of 11beta-HSD1 and 11beta-HSD2 were exchanged adopted inverted orientation in the ER membrane. However, both chimeric proteins were not catalytically active. Furthermore, mutation of a tyrosine motif to alanine in the transmembrane segment of 11beta-HSD1 significantly reduced V(max). The subcellular localization of 11beta-HSD1 was not affected by mutations of the tyrosine motif or of a di-lysine motif in the N terminus. However, residue Lys(5), but not Lys(6), turned out to be critical for the topology of 11beta-HSD1. Mutation of Lys(5) to Ser inverted the orientation of 11beta-HSD1 in the ER membrane without loss of catalytic activity. Our results emphasize the importance of the N-terminal transmembrane segments of 11beta-HSD enzymes for their proper function and demonstrate that they are sufficient to determine their orientation in the ER membrane.

The Embryonics Project: a machine made of artificial cells.

It is possible to trace the origins of biological inspiration in the design of electronic circuits to the very dawn of the field of computer engineering, with the work of John von Neumann in the 1940s. To his brilliance we owe not only the first methodical attempts to define the electronic equivalents of many fundamental biological process, but also the development of the first self-replicating computing machines. Unfortunately, the electronic technology of the time would not allow a physical realization of von Neumann's machines, and it was not until the introduction of new programmable circuits in the 1980s that the field of bio-inspired machines gained new momentum. In this article, we describe the Embryonics (embryonic electronics) Project, an attempt to draw inspiration from the ontogenetic processes that determine the growth of multicellular organisms in the design of new, massively parallel arrays of processors (the artificial cells). Our cells are simple processors, all based on an identical hardware structure and all containing the same program (our artificial genome), but executing different parts of the genome depending on their spatial coordinates within the array. As in living beings, the presence of the genome in every cell allows the introduction of features such as self-replication and self-repair (cicatrization). In addition, the cells are implemented using an array of programmable elements (the artificial molecules), which allows their structure to be adapted to a given application. Through the parallel operation of many of these simple processors, we hope to realize highly complex systems, the equivalent of multicellular organisms in the natural world.

Self-replicating and self-repairing multicellular automata.

Biological organisms are among the most intricate structures known to man, exhibiting highly complex behavior through the massively parallel cooperation of numerous relatively simple elements, the cells. As the development of computing systems approaches levels of complexity such that their synthesis begins to push the limits of human intelligence, engineers are starting to seek inspiration in nature for the design of computing systems, both at the software and at hardware levels. We present one such endeavor, notably an attempt to draw inspiration from biology in the design of a novel digital circuit: a field-programmable gate array (FPGA). This reconfigurable logic circuit will be endowed with two features motivated and guided by the behavior of biological systems: self-replication and self-repair.

Increased expression of erbB3 in colorectal cancer is associated with concomitant increase in the level of erbB2.

ErbB3 is a transmembrane signaling molecule that shares close structural homology with epidermal growth factor receptor (EGFR), erbB2, and erbB4. They have all been implicated in cell transformation and tumor pathogenesis, but very little is known about the role of erbB3 in normal colon and colorectal cancer. Therefore, in the current study, we determined whether erbB3 is found in normal human colon and whether its expression is altered in colorectal cancer. Because of some evidence that erbB3 might interact with erbB2 and EGFR, respectively, by heterodimerization, we also included erbB2 and EGFR analysis with special regard to coexpression. The study was performed on 35 patients operated on for colorectal carcinoma. The normal human colon showed weak erbB3 and erbB2 immunostaining, predominantly in surface epithelial cells. EGFR immunoreactivity in normal colon varied from weak to strong. In contrast, in 31 of 35 (89%) and in 29 of 35 (83%) colonic cancers, moderate to strong immunoreactivity for erbB3 and erbB2, respectively, was present in most epithelial cancer cells. A concomitant erbB3 and erbB2 immunostaining advantage could be found in 77% of cancerous tissues in comparison with the normal colon. No difference in EGFR immunostaining was evident between normal colon and cancer. Northern blot analysis showed an increase in erbB3 and erbB2 mRNA levels in 64% of cancers in comparison with normal colon samples. By densitometry, 2.3-fold and a 1.5-fold significant increases in erbB3 and erbB2 mRNA levels, respectively, were calculated in the cancerous tissues. Eighty-five percent of cancers with erbB3 mRNA overexpression showed an increase in erbB2 mRNA. Southern blot analysis did not indicate any gene amplification or rearrangement responsible for erbB2 or erbB3 overexpression. EGFR, however, was decreased in cancer on mRNA level. These findings indicate that erbB2 and erbB3, but not EGFR, may contribute to tumor growth and disease progression in colon cancer. The correlation between increased erbB2 and erbB3 expression in both Northern blots and immunohistochemical analysis suggests a co-overexpression of erbB2 and erbB3 and might support the hypothesis that these two growth factor receptors act together by heterodimer formation.

Ontogenetic hardware.

Ontogeny is the process by which a single mother cell, the zygote, gives rise, through successive divisions, to a complete organism, possibly containing trillions of cells (e.g. in humans). This paper describes research whose inspiration is drawn from the process of ontogenetic development. By adopting certain features of cellular organization, and by transposing them to the world of integrated circuits on silicon, we show that certain properties unique to the living world, such as self-replication, self-repair, and growth, can also be attained in artificial objects (integrated circuits). Specifically, we identify and describe three classes of ontogenetic hardware: (1) self-replicating hardware; (2) embryonic hardware; and (3) L-systems based hardware, dubbed L-hardware. For each class we present an example of a hardware realization, along with a discussion of possible applications. Continued research on ontogenetic hardware may yield novel bio-inspired systems endowed with replicative, growth, and regenerative capabilities.

Humeral avulsion of the anterior shoulder stabilizing structures after anterior shoulder dislocation: demonstration by MRI and MR arthrography.

OBJECTIVE: To demonstrate the MRI findings of an anterior shoulder capsular avulsion from the humerus, with or without subscapularis rupture, after anterior dislocation or severe abduction external rotation injury. DESIGN AND PATIENTS: We retrospectively reviewed the MRI and MR arthrographic examinations of seven patients who were identified at surgery with avulsion of the anterior shoulder stabilizers from the humerus. MRI was correlated with clinical history and surgical results. RESULTS: MRI findings included: inhomogeneity or frank disruption of the anterior capsule at the humeral insertion (all), fluid intensity anterior to the shoulder (six patients), tear of the subscapularis tendon (six patients), dislocation of the biceps tendon (four patients), and a Hill-Sachs deformity (four patients). MR arthrography additionally found extravasation of contrast through the capsular defect (two patients). CONCLUSIONS: Our findings suggest that MRI is helpful for diagnosing humeral avulsion of the anterior glenohumeral capsule, especially when a tear of the subscapularis tendon insertion is present. MR arthrography may be of benefit for diagnosing capsular avulsion without associated subscapularis tendon abnormality.

Psychogenic seizures: video telemetry observations in 27 patients.

Psychogenic seizures are unusual during the first decade of life. To compare the clinical features of psychogenic seizures in young children with those of teenagers, the long-term electroencephalographic and video monitoring studies of all patients younger than 18 years of age with recorded episodes diagnosed as psychogenic seizures were reviewed from a single hospital during the past 7 years. The 27 patients were divided into 2 age groups: group A, 6-9 years (n = 5), and group B, 10-17 years (n = 22). All patients had habitual episodes recorded during monitoring. Although the adolescents displayed clinical patterns similar to adult patients with psychogenic seizures, the children demonstrated a clinical pattern characterized mainly by prolonged staring and unresponsiveness. The most common behaviors in the adolescent group were tremor (45%), intermittent stiffening (41%), and out-of-phase movements of the extremities (36%). Fifteen percent of the patients had a history of seizures. This study suggests that young children with psychogenic seizures have clinical profiles different from that of teenagers.

Magnetic resonance arthrography of the shoulder.

Recently, there have been attempts to improve the accuracy of MR imaging by distending the glenohumeral joint with fluid prior to imaging. This article reviews the techniques employed in performing MR arthrography, imaging characteristics of MR arthrography, and diagnostic use of the procedure.

Saline magnetic resonance arthrography in the evaluation of glenohumeral instability.

Sixty-five patients underwent magnetic resonance (MR) shoulder arthrography. Forty-eight of these patients underwent examination under anesthesia (EUA). MR images were retrospectively evaluated for signs felt to be imaging indicators of shoulder instability, including evaluation of various capsular measurements and the presence of glenoid labral tears, as well as Hill-Sachs fractures. Statistical analysis of the results showed that no correlation between capsular indicators with EUA-documented instability was found. However, there was a statistically significant correlation between the presence of a Bankart cartilaginous deformity (p = 0.000) and Hill-Sachs fractures (p = 0.022) with EUA-documented instability. Sensitivity to labral tears was 89% and specificity was 98%, whereas Hill-Sachs fracture detection was 69% and 87%, respectively. We believe that MR saline arthrography is of benefit in the evaluation of the anterior labrum when unenhanced MR imaging is inconclusive, and we speculate on the role of MR arthrography as a primary investigative tool.

MR imaging in the evaluation of SLAP injuries of the shoulder: findings in 10 patients.

OBJECTIVE: Injuries to the superior portion of the glenoid labrum, called SLAP (superior labrum, anterior and posterior) injuries, are recently recognized injuries consisting of tears of the long head of the biceps tendon anchor/superior labral complex. The purpose of this study was to determine if the MR imaging findings in patients with surgically proved SLAP injuries correspond to the abnormalities found at arthroscopy. MATERIALS AND METHODS: Four variants of SLAP lesions have been described; they are based on the degree of compromise of the superior portion of the glenoid labrum, biceps tendon, and labral-biceps anchor. A type I lesion has superior labral fraying in the region of the biceps anchor. A type II lesion has superior labral fraying and stripping of the superior part of the glenoid labrum and attached biceps off the underlying glenoid fossa. A type III lesion has a bucket-handle tear of the superior portion of the glenoid labrum in the region of the biceps anchor. A type IV lesion has a bucket-handle tear of the superior part of the glenoid labrum with extension of the tear into the proximal biceps tendon. Standard spin-echo MR imaging studies in 10 patients with surgically proved SLAP lesions were evaluated retrospectively. Correlations were made between MR imaging findings and the SLAP injury type determined from descriptions in the surgical report. MR imaging studies in a control group of seven symptomatic patients surgically proved not to have SLAP injuries also were evaluated. RESULTS: MR imaging examinations of two patients with type I lesions showed irregularity of the labral contour and a slight increase in signal intensity on all imaging sequences. MR imaging examinations of two patients with type II lesions showed globular high signal interposed between the superior part of the glenoid labrum and the superior portion of the glenoid fossa. One case showed high signal in the labral-biceps anchor. The other case showed paired cleavages in the superior and inferior aspects of the superior part of the glenoid labrum at the labral-biceps anchor. MR imaging examinations of two patients with type III lesions showed superior labral tears identified as high signal intensity within the superior part of the labrum separate from the normal superior part of the labral cavity. MR imaging examinations of the four patients with type IV lesions showed diffuse high signal intensity within the superior part of the glenoid labrum with marked abnormal high signal intensity extending into the proximal high signal intensity within the superior part of the labrum separate from the normal superior part of the labral cavity. MR imaging examinations of the four patients with type IV lesions showed diffuse high signal intensity within the superior part of the glenoid labrum with marked abnormal high signal intensity extending into the proximal biceps tendon. None of the MR imaging studies of patients in the control group showed findings seen on MR imaging studies of patients with surgically proved SLAP lesions. CONCLUSION: Although prospective data are required to document accuracy, these preliminary data suggest that an MR examination can be useful in detecting SLAP abnormalities and establishing the type of SLAP lesion before surgery, thereby permitting better operative planning.

[Mucin histochemistry of the digestive tract in the human fetus]. / Histochimie des mucines du tube digestif chez le foetus humain.

Mucin secretion was studied in the gastric, intestinal, left colic and/or rectal mucosa of 42 human fetuses ranging in age from 10 to 41 weeks of gestation (menstrual age). Several histochemical techniques were used at different pH to demonstrate neutral mucins, sialomucins and sulphomucins (Periodic Acid Shiff (PAS) with and without amylase, Alcian Blue (BA) pH 2.5, pH 1 with and without hyaluronidase, BA/PAS pH 2.5 and High Iron Diamine (HID)/BA). The gastric mucosa showed mixed neutral/acid secretions during the second term. The neutral mucins increased during the 3rd term when acid mucins fell and represented only 20 percent of the secretions by the end of gestation, as during the neonatal period. These mixed secretions closely reassembled the intestinal metaplasia described in inflammatory or tumoral lesions of the stomach. The intestinal mucosa secreted mucins as early as 10 weeks before the gastric and rectal mucosa. There were neutral and acid mucins, but unlike in adults, the sulphomucins were secreted by the goblet cells of the villous and crypt epithelia. The secretions of the rectal mucosa were acid and the sulphomucins increased in quantity from 14 to 26 weeks of gestation. The HID positive sulphomucins diffused into the meconium, and probably modified the physical and chemical properties of meconium and influenced anal continence.

Comparison of conventional and computed arthrotomography with MR imaging in the evaluation of the shoulder.

To compare conventional arthrography and computed arthrotomography (CAT) with magnetic resonance (MR) imaging in the evaluation of the shoulder, we studied 18 patients who underwent conventional double contrast arthrography and CAT, and T1-, balanced, and T2-weighted MR imaging. The arthrograms were independently reviewed by two of the authors and the MR images were independently reviewed by three other authors in a systematic fashion with the aid of a prewritten evaluation form. The findings were compared among reviewers and between imaging methods. We found MR comparable to conventional arthrography in the evaluation of the rotator cuff; however, MR also enabled evaluation of tendonitis, which could not be accomplished with conventional arthrography. Because of MR's superior soft tissue imaging capability, we were able to stage the impingement syndrome. Magnetic resonance also allowed evaluation of the glenoid labrum and capsuloligamentous structures and assessment of instability in a fashion similar to CAT. In most cases, information obtained from MR equaled or exceeded that obtained from conventional arthrography and CAT. With refinement in technique and increased experience, we believe that MR may replace arthrography in the evaluation of the shoulder.

Anticonvulsant and antiarrhythmic actions of the beta blocking agent timolol.

Cats were anesthetized with alpha-chloralose and pentylenetetrazol, 10 and/or 20 mg were administered intracerebroventricularly (i.c.v.) to elicit epileptiform activity, including both interictal and ictal discharges. Timolol, 10, 100, 500 micrograms/kg i.c.v. and 1, 5, 10 and/or 20 mg/kg i.v., was administered at 5 min intervals to determine whether it suppressed the epileptiform activity. Mean arterial blood pressure and heart rate increased after the administration of pentylenetetrazol; these increases were associated with the development of epileptiform activity and cardiac arrhythmias. All doses of timolol caused a decrease in the blood pressure and heart rate elevated by pentylenetetrazol and suppressed the epileptiform activity. Similar findings were obtained in cats that received the same doses of timolol administered at different time intervals. The data indicate that the central administration of timolol reverses the epileptiform activity of pentylenetetrazol in the brain and suppresses the associated increases in blood pressure, heart rate and cardiac arrhythmias.

The relationship of the lock-step phenomenon and precipitous changes in mean arterial blood pressure.

The lock-step phenomenon (LSP) is the occurrence of postganglionic cardiac sympathetic discharge (PCSD) and cortical epileptiform activity (EA) in a time-locked fashion. The relationship between the LSP and precipitous changes in blood pressure (PCBP: greater than 23 mm Hg in 10 sec) was determined in 9 cats after EA was induced with pentylenetetrazol following pretreatment with phenobarbital (20 mg/kg, i.v.). Electrocorticogram (ECoG), PCSD, lead II EKG, and mean arterial blood pressure (MAP) were monitored. Since an interspike interval of 2.8 sec was frequently found to exist between ECoG spikes when the LSP was present, 4 categories of LSP were defined: LSP absent; stable LSP with 2.8 sec interval; stable LSP without 2.8 sec interval; and unstable LSP with increasing or decreasing rates of discharge. The duration of each LSP pattern and the proportion of time spent in PCBP were determined. A one-way repeated measures ANOVA and the Newman-Keuls post-hoc test showed that a higher mean proportion of time spent in PCBP was associated with the unstable LSP pattern (P less than 0.05). The LSP and associated patterns as related to precipitous changes in MAP are indicators of changes in autonomic function. Autonomic dysfunction with EA, causing cardiac arrhythmias, has been postulated as a cause of sudden unexplained death (SUD) in persons with epilepsy. Thus, an understanding of the autonomic changes, as indicated by PCBP associated with LSP, may contribute to the understanding and prevention of SUD in persons with epilepsy.

Early developmental progress of preterm twins discordant for birthweight and risk.

Studies of developmental progress in high-risk twins have disparate findings. In this study, we report the outcome of 45 twin pairs born between 26 and 37 weeks gestation, and whose birthweights ranged from 840 to 2000 g. No significant differences were found for weight, risk and birth order. However, earlier preterm infants were found to have significantly lower mental scores on the Bayley Scales of Infant Development at 24 months, and lower IQ scores on the Stanford Binet Intelligence Scale at 36 months. These findings imply that gestational age is a powerful variable in determining developmental outcome.

Preoperative evaluation of abdominal aortic aneurysms by computed tomography.

A prospective, preoperative study was conducted of 50 electively repaired abdominal aortic aneurysms comparing the CT and angiographic findings with those described at surgery. CT demonstrated all 50 aneurysms and correctly identified their proximal extent in relation to the takeoff of the renal arteries in 47 patients (94%), while angiography detected 48 aneurysms (96%) and their correct relation to the renal arteries in all (100%). CT correctly identified 40 (98%) of 41 patients with two renal arteries, but only two (29%) of seven with three and none of two patients with four arteries. Common iliac artery involvement or lack thereof was accurately predicted in 42 (84%) of the 50 patients and internal iliac artery aneurysms found in one (33%) of three patients. It was concluded that CT is not sufficiently accurate for documenting location and patency of the renal arteries to allow its routine substitution for angiography in patients undergoing preoperative assessment of abdominal aortic aneurysms.

Complicated pancreatic inflammatory disease: diagnostic and therapeutic role of interventional radiology.

Diagnostic and therapeutic interventional radiology techniques in 41 patients with complications of pancreatic inflammatory disease (noninfected pseudocyst, infected pseudocyst, phlegmon, abscess, hemorrhagic pancreatitis) are described. Computed tomography or ultrasound-guided aspiration or percutaneous pancreatic ductography enabled specific diagnoses in 43 of 45 patients (96%). In almost half the patients, diagnostic aspiration with 22-gauge needles was unsuccessful due to viscous contents or firm cavity walls. Single-step needle aspiration of noninfected pseudocysts was successful in only three of ten patients (30%). Catheter drainage cured six of seven noninfected pseudocysts (85.7%) and seven of nine infected pseudocysts (77.7%). Pancreatic phlegmons were aspirated in five patients to exclude secondary infection and help determine the need for surgery. Pancreatic abscesses were drained successfully in nine of 13 patients (69.2%); temporizing benefit was achieved in the other four who eventually underwent surgery in improved condition. Early diagnosis of the complications of pancreatitis may be established almost uniformly, and at least 70% of patients with infected or noninfected pseudocysts and pancreatic abscesses may be cured by nonoperative drainage.