Side-to-side differences in bone strength in master jumpers and sprinters.

INTRODUCTION: This study evaluated side-to-side difference in tibial bone structure, calf muscle cross-sectional area (CSA) and hopping force in master athletes as a result of training for sports with different magnitudes of inter-leg loading difference. METHODS: Tibial bone parameters (at 4%, 14%, 38% and 66% tibial length proximal to distal end), muscle CSA (at 66% tibial length) and hopping forces of both legs of 51 master athletes (conditioned jumpers, conditioned triple jumpers, unconditioned jumpers, hurdlers and sprinters) were examined using pQCT. In epiphyseal 4% slice bone CSA (Ar.tot), total BMC (vBMC.tot), trabecular BMC (vBMC.tb) cortical BMC (vBMC.ct), and trabecular BMD (vBMD.tb) were measured. In diaphyseal slices, Ar.tot, vBMC.ct, cortical density (vBMD.ct), cross-sectional moment of inertia (CSMI) and calf muscle CSA (MuscA) were examined. RESULTS: In conditioned jumpers, side-to-side differences in favour of take-off leg were found in 4% slice in vBMC.tb (+4.1%) (P<0.05). A side-to-side difference was found in 66% slice vBMC.ct and CSMI (both P<0.05), with conditioned jumper (+2.8% and 6.6%) and triple jumper (+2.7% and 7.2%) values higher than other groups. CONCLUSION: The results suggest that regular training in high-impact sports with uneven lower limb loading results in side-to-side differences in skeletal adaptation independent of age and gender, suggesting that high-impact exercise is effective in maintaining bone strength throughout human lifespan.

[The clinical spectrum of urea cycle defects in adult patients]. / Das klinische Spektrum von Harnstoffzyklusdefekten im Erwachsenenalter.

Urea cycle defects belong to the most common metabolic disorders with a cumulative incidence of 1:8000. A common trait of urea cycle defects is a disturbed detoxification of ammonia leading to hyperammonemia in the event of a high nitrogen load. Most patients develop symptoms in the neonatal period or in infancy, e. g. vomiting, seizures and disturbed consciousness. Depending on the affected enzyme and its residual activity, patients differ in the age at first presentation, the character and severity of symptoms and in the susceptibility to metabolic derangement. The presence of hyperammonemia and an altered plasma amino acid profile give the essential diagnostic clues. Since modern therapeutic measures have prolonged the life expectancy of these patients and provided the possibility of a first presentation in adulthood, patients with urea cycle defects have become an increasing challenge in internal medicine. The reported case series illustrates the heterogeneous clinical course of these disorders from childhood to adulthood.

Domain structure of the simian virus 40 core origin of replication.

The simian virus 40 core origin of replication consists of nucleotides 5211 through 31. These 64 base pairs contain three functional domains with strict sequence requirements and two spacer regions with relaxed sequence specificity but precise positional constraints. The early domain extends for 10 contiguous base pairs between nucleotides 5211 and 5220. A 9-base pair spacer from sequences 5221 through 5229 separates the early domain from the 23-base pair central palindrome that directs the binding of T antigen. The late end of the core between nucleotides 12 and 31 also contains spacer and sequence-specific functions that are not yet completely mapped. We propose that the sequence-specific domains are interaction sites for viral and cellular proteins, determinants of DNA conformation, or both. The spacers would position these signals at required distances and rotations relative to one another.

Protein-DNA interactions at the simian virus 40 origin of replication.

Simian Virus 40 (SV40)-encoded large T antigen has an intrinsic ATP-dependent DNA-unwinding activity which is necessary for an early step in the activation of the viral origin of replication. Isolated T antigen unwinds any double-stranded DNA, regardless of whether it is linear or circularly closed. However, initiation of DNA replication depends on an intact origin of replication, and even minor deviations from the wild-type origin sequence abolish the template activity of an origin-bearing plasmid. This discrepancy suggests that T antigen may not be sufficient for origin activation and that other, probably cellular, functions are involved. We have isolated a cellular protein, the LOB protein, which specifically interacts with the AT-rich region of the SV40 origin and which induces a pronounced bending of the bound DNA.

Protein-induced bending of the simian virus 40 origin of replication.

A 3.5 S protein, isolated from mammalian nuclei, specifically binds to DNA fragments containing the simian virus 40 (SV40) origin of replication. Two distinct nucleoprotein complexes are formed, a complex with high electrophoretic mobility carrying probably only one protein molecule, and a complex with reduced electrophoretic mobility carrying probably two protein molecules per DNA fragment. Band shift competition as well as methylation interference assays locate the binding site of the protein in the A + T-rich "late" region of the origin between SV40 nucleotides 13 and 35. The late origin binding (LOB) protein and T antigen bind simultaneously to adjacent sites in the origin. Using circularly permuted DNA fragments of identical lengths we show that the LOB protein induces pronounced bending of the origin fragment. The bending center maps at the 5' end of the adenine tract with one bound protein molecule and at the 3' end when two LOB proteins are bound to one origin fragment.

A B cell-suppressive IgG-antiimmunoglobulin antibody induced by alloimmunization.

This study is an extension of our previous report that alloimmunization produces a serum factor that suppresses the lymphocytotoxic antibody response. The experiments presented herein show that: (1) serum and IgG of pretreated rats contain an antibody directed against the constant region of IgG; (2) the anti-IgG has strong anti-Fc-gamma and weak anti-Fab activity; (3) the antibody also reacts with IgM; (4) the antiimmunoglobulin is an autoantibody; and (5) the antiimmunoglobulin suppresses the primary B cell response in vitro.

Examination of the role of endopeptidase 3.4.24.15 in A beta secretion by human transfected cells.

1. We have taken advantage of our recent development of highly potent and specific phosphinic inhibitors of endopeptidase 3.4.24.15 to examine the putative contribution of the enzyme in the secretion of A beta by HK293 transfected cells overexpressing the wild type and the Swedish (Sw) double mutated form of beta APP751. 2. First, we showed that HK293 cells contain a peptidase activity, the inhibition profile of which fully matches that of purified endopeptidase 3.4.24.15. Second, we established that the treatment of HK293 cells with specific phosphinic inhibitors leads to about 80% inhibition of intracellular endopeptidase 3.4.24.15 activity, indicating that these inhibitors penetrate the cells. 3. Metabolic labelling of wild type and Sw beta APP751-expressing cells, followed by immunoprecipitation of A beta-containing peptides, revealed the secretion of A beta and the intracellular formation of an A beta-containing 12 kDa product. 4. A beta secretion by Sw beta APP751 transfected cells was drastically enhanced when compared to cells expressing wild type beta APP751. This production was not affected by endopeptidase 3.4.24.15 inhibitors in either cell type. This correlates well with the observation that endopeptidase 3.4.24.15 does not cleave recombinant baculoviral Sw beta APP751, in vitro. 5. Our previous data indicated that endopeptidase 3.4.24.15 activity was reduced in the parietal cortex of Alzheimer's disease affected brains and that the enzyme probably participated, in this brain area, to the catabolism of somatostatin 1-14. However, the present work indicates that endopeptidase 3.4.24.15 does not seem to behave as a beta-secretase in HK293 transfected cells. Therefore, it is suggested that endopeptidase 3.4.24.15 could participate in the symptomatology, but probably not in the aetiology of Alzheimer's disease.

The use of quinolones in respiratory tract infections.

In a prospective (and continuing) trial, a total of 271 patients with acute purulent exacerbations of chronic respiratory disease (bacteriologically confirmed) were treated with various new oral quinolones including enoxacin (26), pefloxacin (50), ciprofloxacin (80) and ofloxacin (115). Various therapeutic schedules were employed, with differing drug dosages, frequencies of administration and durations of treatment. All patients were investigated microbiologically during and immediately after treatment and after 7 days of follow-up. The best clinical results were noted after ofloxacin 800 mg once daily for 7 days, which showed excellent gastrointestinal absorption and rapid penetration through to the sputum. Some of the treatment failures with enoxacin and pefloxacin could be ascribed to the development of resistance during treatment, rises in minimal inhibitory concentrations (MICs) being noted with Streptococcus pneumoniae and Pseudomonas aeruginosa.

Penetration of ofloxacin from blood to sputum.

Serum and sputum concentrations of ofloxacin were measured by a microbiological agar-well diffusion assay in nearly 100 patients after single 400, 600 or 800 mg doses of ofloxacin. All patients were admitted to hospital because of acute purulent exacerbations of chronic respiratory disease, and the concentration studies were performed on the first treatment day while the sputum was still purulent. Both blood and sputum samples were tested at standardised time intervals after dosage, and concentration-time curves were constructed. Cmax values in serum and sputum were 3.7 and 2.7 mg/L after 400 mg ofloxacin, 7.1 and 6.1 mg/L after 600 mg and 8.8 and 6.3 mg/L after 800 mg. Penetration from blood to sputum, as judged from ratio of AUC values for sputum and serum, varied from 78 to 103%.

Transient post-renal obstruction may protect the kidney against nephrotoxic damage--a case report.

In critically ill patients, acute renal failure is mostly multifactorial in origin. In general, the simultaneous presence of several deleterious factors tends to aggravate the renal damage. The present case report describes a patient with multifactorial acute renal failure, in whom one of the factors contributing to the renal failure, i.e. transient unilateral post-renal obstruction, apparently protected the obstructed kidney against damage from other causes.

Cathepsin D displays in vitro beta-secretase-like specificity.

The formation of A beta and A beta-containing fragments is likely a key event in the process of neural degeneration in Alzheimer's disease. The N-terminal residue (Asp-1) of A beta and its C-terminally extended sequences is liberated from the beta-amyloid precursor protein (beta APP) by beta-secretase(s). This activity appears highly increased by the presence (N-terminally to Asp-1) of a double-mutation (KM-->NL) found in several Swedish families affected by early onset Alzheimer's disease. By means of synthetic peptides encompassing the "normal' (N peptide) and mutated (delta NL peptide) sequences targeted by beta-secretase(s), we have detected a human brain protease displaying preferred efficiency for the delta NL peptide than for the non-mutated analog. This activity is sensitive to pepstatin, maximally active at acidic pH and hydrolyses the two peptides at the expected M/D or L/D cleavage sites. Such acidic activity is also detected in rat brain, PC12 cells and primary cultured astrocytes. The pepstatin sensitivity and pH maximum of the brain activity that appeared reminiscent of those displayed by the acidic protease cathepsin D led us to examine this enzyme as a putative beta-secretase-like candidate. Purified cathepsin D displays higher catalytic parameters for the delta NL peptide than for the non-mutated peptide, cleaves these two substrates at the expected M/D or L/D sites, and is maximally active at acidic pH. However, cathepsin D does not cleave peptides bearing mutations that were previously shown to drastically lower or fully block A beta secretion by transfected cells. Furthermore, cathepsin D hydrolyses recombinant baculoviral delta NL beta APP751 at a 6-fold higher rate than beta APP751 and gives rise to a 12-kDa C-terminal product that is recognized by antibodies fully specific of the N-terminus of A beta. Altogether, our study indicates that cathepsin D displays several in vitro beta-secretase-like properties that suggests that this protease could fulfill such a role, at least in the Swedish genetic form of Alzheimer's disease.

A physiological toxicokinetic model for 1,3-butadiene in rodents and man: blood concentrations of 1,3-butadiene, its metabolically formed epoxides, and of haemoglobin adducts--relevance of glutathione depletion.

A physiological toxicokinetic (PT) model is presented describing disposition and metabolism of 1,3-butadiene (BU) and 1,2-epoxy-3-butene (BMO) in rat, mouse and man, and of 1,2:3,4-diepoxybutane (BDI) in mice. It contains formation of BMO and BDI, intrahepatocellular first-pass hydrolysis of BMO, conjugation of BMO with glutathione (GSH) and GSH-turnover in the liver. Tissue:air partition coefficients of BU and BMO were determined experimentally. Haemoglobin (HB) adducts of BMO in rodents following exposure to BU were simulated and compared with published data. The model is compared with those published earlier. An attempt was made to compare the carcinogenic potential of BU in mice and rats with respect to the carcinogenic potentials of both epoxides.

Intramural hematoma of the esophagus: appearance on magnetic resonance imaging.

A 73-yr-old woman on anticoagulant therapy experienced progressive dyspnea and dysphagia due to a large compressing mass in the posterior mediastinum. Because her clinical condition deteriorated rapidly surgery was performed. A large intramural hematoma along the full length of the esophagus with dissection of the muscular layers of the esophagus was found. MRI findings of this case are reported.

Lead in human bones. Investigations on an occupationally non-exposed population in southern Bavaria (F.R.G.). I. Adults.

The concentration of lead in three different bones (pelvic bone, cortical part of the mid-femur, petrous portion of the temporal bone) of 240 occupationally non-exposed adults who died between October 1983 and February 1985 was determined by electrothermal atomic absorption spectrometry. As far as sex, age and domicile (urban and rural) are concerned, a balanced distribution was achieved (for each age decade 10 urban females, 10 rural females, 10 urban males and 10 rural males). The predominantly cortical femur (geom. mean, 3.86 mg Pb/kg bone wet wt.) and temporal bones (5.59) showed higher Pb concentrations than the trabecular pelvic bone (1.65) (in each case n = 240). For each of the three types of bone, the mean lead content of the males (n = 120) was significantly higher than those of the females (n = 120): e.g. for pelvic bone by 38.3%, mid-femur by 51.3% and temporal bone by 24.8%. No statistically significant difference was obtained when comparing residents of Munich (population greater than 1 X 10(6] (n = 120) with people in the remaining parts of Southern Bavaria (n = 120). The Pb content of the temporal bone increased steadily with age. In contrast, in the mid-femur and the pelvic bone the Pb content reaches a plateau in middle age with a decrease at higher ages; this decline is more distinct for females. The mean lead body burden was calculated to be 41.4 +/- 24.2 mg for all males (n = 120) and 24.1 +/- 12.5 mg for all females (n = 120). We conclude that the lead burden, at least in the area investigated, has been reduced in the last decade, probably because of a reduction in the lead content of petrol.

A non-contact mouse for surgeon-computer interaction.

We have developed a system that uses computer vision to replace standard computer mouse functions with hand gestures. The system is designed to enable non-contact human-computer interaction (HCI), so that surgeons will be able to make more effective use of computers during surgery. In this paper, we begin by discussing the need for non-contact computer interfaces in the operating room. We then describe the design of our non-contact mouse system, focusing on the techniques used for hand detection, tracking, and gesture recognition. Finally, we present preliminary results from testing and planned future work.

VIRGY: a virtual reality and force feedback based endoscopic surgery simulator.

This paper describes the VIRGY project at the VRAI Group (Virtual Reality and Active Interface), Swiss Federal Institute of Technology (Lausanne, Switzerland). Since 1994, we have been investigating a variety of virtual-reality based methods for simulating laparoscopic surgery procedures. Our goal is to develop an endoscopic surgical training tool which realistically simulates the interactions between one or more surgical instruments and gastrointestinal organs. To support real-time interaction and manipulation between instruments and organs, we have developed several novel graphic simulation techniques. In particular, we are using live video texturing to achieve dynamic effects such as bleeding or vaporization of fatty tissues. Special texture manipulations allows us to generate pulsing objects while minimizing processor load. Additionally, we have created a new surface deformation algorithm which enables real-time deformations under external constraints. Lastly, we have developed a new 3D object definition which allows us to perform operations such as total or partial object cuttings, as well as to selectively render objects with different levels of detail. To provide realistic physical simulation of the forces and torques on surgical instruments encountered during an operation, we have also designed a new haptic device dedicated to endososcopic surgery constraints. We are using special interpolation and extrapolation techniques to integrate our 25 Hz visual simulation with the 300 Hz feedback required for realistic tactile interaction. The fully VIRGY simulator has been tested by surgeons and the quality of both our visual and haptic simulation has been judged sufficient for training basic surgery gestures.

Force feedback for virtual reality based minimally invasive surgery simulator.

This paper presents ongoing research towards an endoscopic surgery simulation system. Our specific application of interest is laparoscopic surgery. The goal is to conceive an endoscopic surgical training tool which allows to realistically simulate the interactions between one or several surgical instruments and the gastrointestinal organs in a virtual reality based environment. An artificial patient is being developed into which endoscopic surgical instruments can be inserted to operate upon virtual organs displayed on a video monitor. In order to achieve a faithful and precise simulation, not only a realistic graphical representation of the organic tissue and its behavior is needed, but also the forces and moments on the surgical instruments encountered during an operation are required to be simulated. The laparoscopic surgery simulator must therefore provide force feedback through the endoscopic instruments manipulated by the surgeon. This paper details the mechanical design of the force feedback mechanisms and addresses some of the technical challenges of this project.

Robotic system for cervical spine surgery.

BACKGROUND: In contemporary surgical clinical practice, spinal instability is often treated with mechanical stabilization techniques in order to protect the spinal cord and nerve roots. These techniques involve placing screws in defined regions of the vertebrae, typically the pedicle, where the strongest bone is found. The challenge for the surgeon is the accurate placement of screws for good mechanical purchase and to avoid damage to surrounding vital anatomical structures. This is especially critical in the cervical region, where the target bone mass is smaller and the spinal cord, nerve roots and vertebral arteries are all at risk. A robotic system enabling the surgeon to precisely place implants into the vertebrae should enhance safety and may potentially improve surgical results. METHODS: We describe such a system, which consists of a compact robot positioned using a passive structure, an optical tracking system, a surgical input device and planning and navigational software. The implant trajectory in each vertebra is planned preoperatively, using fine-cut computerized tomography (CT) scans. During surgery, registration matching between the CT scan and the patient's anatomy is achieved using point to point registration, refined with a surface merge technique. Approximate robot positioning is done passively by the surgeon. Final precise instrument positioning is performed by the robot according to the planned trajectory through the target vertebra. Implants (screws) are then placed through the robot-guided working channel. RESULTS: Six cadaver experiments, consisting of placing transarticular (i.e. crossing the joints between the vertebrae) screws in the upper two vertebrae of the human cervical spine, were performed. Implant placement accuracy was comparable with that achieved using freehand image-guided techniques by an experienced surgeon. CONCLUSIONS: These results confirm the utility and applicability of the system. It is currently in redesign to improve accuracy and to render it compatible with on-line planning.

A navigation system for open liver surgery: design, workflow and first clinical applications.

BACKGROUND: The surgical treatment of liver tumours relies on precise localization of the lesions and detailed knowledge of the patient-specific vascular and biliary anatomy. Detailed three-dimensional (3D) anatomical information facilitates complete tumour removal while preserving a sufficient amount of functional liver tissue. METHODS: We present an easy to use, clinically applicable navigation system for efficient visualization and tool guidance during liver surgery. Accurate instrument guidance within 3D planning models was achieved with a fast registration procedure, assuming a locally rigid and temporarily static scenario. After deformations occurring during the procedure, efficient means for registration updates are provided. Special focus was given to workflow integration and the minimization of overhead time. The navigation system was validated with nine clinical cases. RESULTS: Navigated surgical interventions were performed with a median time overhead of 16.5 min. The navigation technology had a median accuracy of 6.3 mm, improving anatomical orientation and the detection of structures at risk. CONCLUSIONS: Successful application of the navigation technology to open liver surgery was achieved by minimizing the procedural complexity and optimizing integration within the existing surgical environment. The assumption of locally rigid patient registration was validated, and clinical evaluation shows clear benefits for the surgeon.