bluuebunny/crossref_metadata_2025 huggingface dataset:
Harvesting the middle hepatic vein with a right hepatectomy does not increase the risk for the donor
Authors: Scatton Olivier , Belghiti Jacques , Dondero Federica , Goere Diane , Sommacale Daniele , Plasse Marylène , Sauvanet Alain , Farges Olivier , Vilgrain Valérie , Durand Francois
Published: January 2004

The harvesting of the middle hepatic vein (MHV) with a right hepatectomy for living-donor liver transplantation allows an optimal venous drainage for the recipient but can also have adverse effects for the donor. This study compares morbidity, early liver function, and volume regeneration in 2 groups of donors who underwent right hepatectomy with (MHV+, n = 21) or without (MHV−, n = 20) MHV harvesting during 2 successive periods. The operative time was 401 ± 60 minutes in the MHV+ group compared with 392 ± 63 minutes in the MHV− group, and the transection time was 152 ± 53 minutes in the MHV+ group compared with 131 ± 30 minutes in the MHV− group (not significant). Blood loss in the MHV+ group was 773 ± 343 mL compared with 613 ± 361 mL in the MHV− group (not significant). The graft weight and remnant liver volume ratio were similar in the MHV+ and MHV− groups (763 ± 200 gm vs. 832 ± 156 gm and 42% ± 9.5% vs. 43% ± 8.3%, respectively). Postoperative biologic liver function tests showed that prothrombin time (PT) ratio on postoperative days 1 and 3 were significantly lower in the MHV+ group compared with the MHV− group (53% vs. 65% and 63% vs. 72%, respectively, P < .05). There were no differences in postoperative alanine aminotransferase and aspartate aminotransferase peak levels between the MHV+ and MHV− groups (319 ± 198 IU /L vs. 310 ± 110 IU /L and 317 ± 226 IU /L vs. 296 ± 125 IU /L, respectively). Bilirubin maximal blood level was similar in the 2 groups (32 ± 17 μmol/L in the MHV+ group vs. 43 ± 16 μmol/L in the MHV− group, P < .05). No donor died. The overall morbidity was lower in the MHV+ group compared with the MHV− group (36% vs. 55%; P > .05, not significant). The donor’s remnant liver volume regeneration, evaluated by computed tomography (CT) volumetric study on day 7, was similar in the 2 groups (97% ± 29% in the MHV+ group and 103% ± 39% in the MHV− group, P > .05). The results of this comparative study show that right hepatectomy with the MHV neither affects morbidity nor impairs early liver function and regeneration in donors. (Liver Transpl 2004;10:71-76.)
Impact of pretransplant diagnosis of hepatocellular carcinoma on cadveric liver allocation in the era of MELD
Authors: Hayashi Paul H. , Trotter James F. , Forman Lisa , Kugelmas Marcelo , Steinberg Tracy , Russ Paul , Wachs Michael , Bak Thomas , Kam Igal , Everson Gregory T.
Published: January 2004

The allocation system based on the Model for End-stage Liver Disease (MELD) has led to more patients diagnosed with hepatocellular carcinoma (HCC) being transplanted. We hypothesized that more patients misdiagnosed with HCC are also being transplanted, leading to inappropriate organ allocation. Therefore, we retrospectively analyzed all liver transplants at our center from July 14, 2000, to October 22, 2002 (N = 172; 129 pre-MELD, 43 post-MELD), comparing pretransplant HCC diagnosis to explant histology. Thirty patients met the United Network for Organ Sharing (UNOS) diagnostic criteria for pretransplant HCC diagnosis. There were 25 men (median age, 52.5 yr), and 80% had hepatitis C. The proportion of patients transplanted who had an HCC diagnosis increased from 12% (15/129) pre-MELD to 35% (15/43) post-MELD implementation (P < 0.01). Three of 15 (20%) transplanted pre-MELD and 5 of 15 (33%) transplanted post-MELD lacked HCC in the explant (P = 0.10). Of the three false-positives pre-MELD, one was Status 2B already, and two received living-donor livers. Of the 5 false-positives post-MELD, three had score upgrades that led to early transplantation (13 to 29, 20 to 29, and 9 to 24) while two had MELD scores of 35 and 36 already. The percentage of organs that could have gone to patients with more advanced liver disease without HCC increased from 0% (0/129) pre-MELD to 7% (3/43) post-MELD (P < 0.01). Since the implementation of MELD, the proportion of patients transplanted who had an HCC diagnosis nearly tripled, and a small but significant proportion of organs are now going to patients misdiagnosed with HCC. More stringent HCC diagnostic criteria will be required to decrease the effect that misdiagnosis has on organ allocation. (Liver Transpl 2004;10:42-48.)
Laparoscopic iatrogeny of the hepatic hilum as an indication for liver transplantation
Authors: Fernández Juan Angel , Robles Ricardo , Marín Caridad , Sánchez-Bueno Francisco , Ramírez Pablo , Parrilla Pascual
Published: January 2004

The introduction of biliary laparoscopic surgery led to an increase in the incidence of liver hilum injuries. These types of lesions are very serious, because they can lead to secondary biliary cirrhosis or fulminant hepatic failure and the need for liver transplantion (LT). We present three cases of liver hilum injuries, which were treated with LT; one case was due to severe and persistent cholangitis, and two cases were due to fulminant hepatic failure. The world literature is also reviewed, and published cases of iatrogenic lesions of the liver hilum caused by laparoscopic surgery and requiring LT are presented. These iatrogenic lesions of the hepatic hilum are complex and technically demanding, due to their high morbidity and mortality and even the need for LT. In conclusion, these lesions must be always managed in centers with experience in hepatobiliary surgery. (Liver Transpl 2004;10:147-152.)
Results of the first year of the new liver allocation plan
Authors: Freeman Richard B. , Wiesner Russell H. , Edwards Erick , Harper Ann , Merion Robert , Wolfe Robert
Published: January 2004

Liver allocation policy in the U.S. was recently changed to a continuous disease severity scale with minimal weight given to time waiting in an effort to better prioritize deceased donor liver transplant candidates. We compared rates of waiting list registrations, removals, transplants, and deaths during the year prior to implementation of the new liver allocation policy (2/27/01-2/26/02, Era 1) with the first year’s experience (2/27/02-2/26/03, Era 2) under this new policy. Rates were adjusted for 1,000 patient years on the waiting list and compared using z-tests. A 1-sided test was used to compare death rates; 2-sided tests were used to compare transplant rates. Overall and subgroup analyses were performed for demographic, geographic, and medical strata. In Era 2, we observed a 12% reduction in new liver transplant waiting list registrations, with the largest reductions seen in new registrants with low MELD/PELD scores. In Era 2, there was a 3.5% reduction in waiting list death rate (P = .076) and a 10.2% increase in cadaveric transplants (P < .001). The reduction in waiting list mortality and increase in transplantation rates were evenly distributed across all demographic and medical strata, with some variation across geographic variables. Early patient and graft survival after deceased donor liver transplantation remains unchanged. In conclusion, by eliminating the categorical waiting list prioritization system that emphasized time waiting, the new system has been associated with reduced registrations and improved transplantation rates without increased mortality rates for individual groups of waiting candidates or changes in early transplant survival rates. (Liver Transpl 2004;10:7-15.)
De novo breast cancer in patients with liver transplantation: University of Pittsburgh’s experience and review of the literature
Authors: Oruc Tahir M. , Soran Atilla , Jain Ashok K. , Wilson John W. , Fung John
Published: January 2004

De novo malignancies are one of the current problems in patients with organ transplantation. The incidence has been considered to be higher as a result of increases of oncogenic viruses in immunosuppressed organ recipients. Published reports have shown increased incidence of de novo tumors such as malignant lymphomas and cutaneous neoplasms but decreased incidence of breast cancer. A variety of factors affect de novo breast cancer development in organ recipients, including immunosuppression, viruses, and underlying disease. The aims of this review are to evaluate the incidence and management of patients with de novo breast cancer by giving the University of Pittsburgh’s data, and to evaluate the incidence of de novo breast cancer in published reports in light of an age-adjusted rate. According to age-adjusted rates presented by the National Cancer Institute’s Surveillance, Epidemiology and End Results data, we found increased incidence rate of de novo breast cancer in the previously published series. The University of Pittsburgh’s incidence rate of de novo breast cancer was determined in a fashion similar to that for the Surveillance, Epidemiology and End Results data. Eighty-three percent of all patients were diagnosed at early stages, and it appeared to take longer for de novo breast cancer to develop in patients treated with tacrolimus than in patients treated with cyclosporine. In conclusion, surgical treatment of breast cancer in liver recipients is the same as treatment of breast cancer in patients without transplantation. However, the effects of chemotherapy, radiotherapy, and/or tamoxifen remain unclear in transplanted patients and need to be evaluated in larger studies. (Liver Transpl 2004;10:1-6.)
Syndromic incidence of ovarian cancer after liver transplantation: Is breast cancer an antecedent risk?
Authors: Buell Joseph F. , Woodle Steve E.
Published: January 2004

Ovarian cancer is the gynecologic malignancy with the highest number of deaths in the United States. Previous studies had found a decreased incidence of female gynecological malignancies after liver transplantation. In order to estimate the incidence of ovarian carcinoma after liver transplantation, we evaluated 1,708 consecutive liver transplant recipients from 1984 to 2001. Of them, 770 (43%) were female. Routine follow-ups were performed at 1, 2, 5, and 10 years after transplantation. There were two cases of ovarian carcinoma. Both occurred in recipients with a previous history of breast cancer. Based on these data, we conclude that the incidence of ovarian cancer is 1:385 among all female liver transplant recipients, and 1:6.5 among those with a history of pretransplant breast cancer. We recommend that regular checkups be undertaken, especially in the population at highest risk. (Dig Dis and Sci 2003;48:187-189.)
Impaired regeneration of biliary cells in human chronic liver allograft rejection. Special emphasis on the role of the finest branches of the biliary tree
Authors: van den Heuvel Marius C. , de Jong Koert P. , van der Horst Marian L.C. , Poppema Sibrand , Slooff Maarten J.H. , Gouw Annette S.H.
Published: January 2004

Severe loss of bile ducts is a hallmark of chronic liver rejection. We hypothesize that loss of the finest branches of the biliary tree, including the intralobular segments, contributes to an impaired regenerative response of bile ducts in chronic rejection. The number and proliferative response of bile ducts, intraportal ductules, and extraportal biliary cells were studied in graft biopsies of 12 chronic-rejection patients. Twenty-two long-term-surviving patients who experienced acute rejection without chronic rejection served as controls. Reperfusion, 1-week, 1-month, and 1-year biopsies were studied. Monochlonal antibody Ki67 was applied to assess proliferation, and cytokeratin 7 antibody to identify bile ducts, intraportal ductules, and extraportal biliary cells. Progressive loss of bile ducts, intraportal ductules, and extraportal biliary cells was observed in the chronic-rejection group. In controls, all of these structures remained well preserved. Additionally, a significant increase of intraportal ductules was present at 1 week in controls, which was not the case in the chronic-rejection group. Proliferative activity of intraportal ductules and extraportal biliary cells was significantly increased at 1 week in controls. This proliferative activity was higher in the intraportal ductules of controls, compared with the chronic-rejection group. After 1 week, proliferative activity was virtually absent in both groups. In conclusion, our results showed that a deficient proliferative response of the finer branches of the biliary tree, including its intralobular segments, might contribute to bile-duct loss in chronic rejection. This finding supports the postulation that these structures represent a regenerative compartment of the biliary unit in the liver. (Liver Transpl 2004;10:28-35.)
The role of surface zeta potential and substratum chemistry for regulation of dermal fibroblasts interaction
Authors: Altankov G. , Richau K. , Groth Th.
Published: January 2004

Synthetic materials considered for biohybrid skin or other tissue engineering applications have to support cellular interaction and colonisation of implants. However, despite the number of studies reported in the literature, there is no agreement on the principal factors applicable to modulate the interaction with cells, such as the wettability of biomaterials, their surface potential and chemistry of the surface. Particularly, in this study we were interested on the impact of surface chemistry and net surface (zeta) potential on dermal fibroblasts. To address this question self assembled monolayers of silanes on glass, further derivatized with different functional groups, were used to study the adhesion and proliferation of human skin fibroblasts in response to these factors. The model surfaces were characterized using streaming potential (zeta potential) and water contact angle measurements. All samples were found to be negatively charged at physiological pH (regardless of the different chemistry) increasing (or equal ∼) the magnitude of the negative potential in the following order: hydroxy (OH) < amine (NH2) ∼ epoxy (EPOXY) < carboxyl (COOH) < three‐fluorocarbon (CF3) < sulfonic (SO3) functionalities. The interaction of fibroblast characterized by the effectiveness of cell adhesion, spreading and actin stress fibres formation decreased almost in the opposite order: NH2 > OH > EPOXY > SO3 > COOH > CF3 functions. The surfaces were found also to be highly wettable, except CF3. Interestingly, the best cellular interaction was found on the moderately wettable NH2 surface representing water contact angle (CA) of 65°, and the worst, on the least wettable CF3 surface (CA 85°) indicating that not only the surface potential but also the type of functional groups may play an important role. The organisation of α5 and β3 integrins generally followed the same trend of less clustering in focal adhesion plaques when the negative potential increased, except on SO3 surface, where β3 but not α5 integrins were greatly expressed. Cell growth however, showed a significant decrease on highly charged COOH and SO3 surfaces, as well as, on non‐polar CF3 functions. The best proliferation response was obtained on surfaces with primary amine groups. The results indicate that the surface (zeta) potential might be a critical parameter for cellular interactions, but also the substratum wettability and the type of functional groups have to be controlled in order to improve the biocompatibility of material surfaces.
In‐vitro preparation of nanocrystalline calcium phosphates as bone substitution materials in surgery
Authors: Tadic D. , Veresov A. , Putlayev V.I. , Epple M.
Published: January 2004

A continuous preparation method for nanoscopic calcium phosphate ceramics is presented. The influence of processing parameters (temperature, time) on the properties of calcium phosphates was studied. Crystallinity, structure, and morphology are important for an application as biodegradable implant material in bone contact. The samples were studied in detail using X‐ray powder diffraction, infrared spectroscopy, atomic absorption spectroscopy, photometry, scanning electron microscopy, and transmission electron microscopy. All calcium phosphate precipitates are non‐stoichiometric, calcium‐deficient hydroxyapatites.
Statistical Mechanical Modeling of Protein Adsorption
Authors: Van Tassel P. R.
Published: January 2004

We present rationale for and a derivation of a statistical mechanical model of protein adsorption. Proteins are modeled as rigid geometric objects adsorbing initially in a reversible manner and subsequently undergoing an irreversible change in shape to a permanently adsorbed state. Both adsorption and shape change occur subject to energetic interactions with previously adsorbed proteins. We evaluate the model quantitatively for proteins with disk‐shaped projections within the scaled particle theory and compare the predictions to experimental measurements taken via optical waveguide lightmode spectroscopy.
Biomaterials for ossicular chain reconstruction. A review
Authors: Neumann A. , Jahnke K.
Published: January 2004

This review gives a survey of biomaterials used for ossicular chain reconstruction. The survey is focussed on application, biophysical requirements, properties and goals for future developments. The implantation site middle ear differs from others due to aeration and potential bacterial colonization. As a consequence, implant materials must exhibit excellent biocompatibility, biostabilty and sound conducting properties. In vitro and in vivo biocompatibility investigations and clinical observations determine the choice of material. Additionally the implants must provide the possibilty of intraoperative shaping or should be available in different variations in order to allow reconstruction appropriate to the individual conditions. Ceramics, metals and plastics are materials in current use. Based on thorough experimental and long term clinical experiences, the bioinert aluminum oxide is favorable amoung the ceramics. Bioactive ceramics may have minor biostability and the risk of fixation to surrounding bone which impairs sound conduction. This is also true for hydroxyapatite although biodegradation occurs only rarely. Today, titanium is the metal best established in middle ear implantation, reflected by excellent biocompatibility in vitro and in vivo, and good clinical results. Titanium is preferred by many surgeons, considering that sound transmission properties are mainly dependent on the implant weight. In stapes surgery, when the implant has direct contact to inner fluids, gold was accused to cause granuloma formation with subsequent inner ear damage in selected cases. In frequent past and present use, plastics (porous polyethylene and teflon) have proven to be of limited value in ossicular chain replacement because of high extrusion rates and the observation of material desintegration and bacterial colonization. In order to individually manage the pathological conditions in the middle ear, the implant design is of crucial importance. It is dependent on the ossicle to be replaced and the implant material. Future investigations have to minimize implant extrusions possibly by modifying and improving implant surfaces.
Laser‐Raman and Nuclear Magnetic Resonance (NMR) studies on plasma‐sprayed hydroxylapatite coatings: Influence of bioinert bond coats on phase composition and resorption kinetics in simulated body fluid
Authors: Heimann R. B. , Tran H. V. , Hartmann P.
Published: January 2004

The structure and phase composition of HAp coatings deposited onto Ti6Al4V coupons (50x20x2mm) by atmospheric plasma spraying (APS) were studied by laser‐Raman spectroscopy, 31P‐ and 1H‐MAS‐NMR and 2D‐31P/1H HETCOR‐CP‐NMR spectroscopy, and XRD with Rietveld refinement. The samples investigated comprised APS HAp coatings with and without a TiO2 bond coat as well as coatings incubated for different lengths of time (up to 12 weeks) in simulated body fluid (SBF) under physiological conditions. In APS coatings the presence of a bond coat increased the proportion of well‐ordered crystalline HAp at the expense of distorted apatite‐like structures such as oxyHAp and oxyapatite, and thermal decomposition products such as tricalcium phosphate (TCP) and tetracalcium phosphate (TTCP), and also decreased the amount of amorphous calcium phosphate (ACP). Incubation in SBF further advanced the proportion of crystalline HAp since the disordered structures, the thermal decomposition products, and ACP exhibit substantially higher solubility.
Surface modification of a novel porous titanium dioxide/glass composite
Authors: Erli H. J. , von Walter M. , Ragoß C. , Steffens G. C. M. , Paar O. , Maier H. R.
Published: January 2004

A novel technique is used to produce an open porous titanium dioxide/glass composite, named Ecopore, with promising structural and biological properties for the development as a bone graft. This study aims at a fast and lasting integration of the new material by means of biochemical surface modification. Surface etching of Ecopore, aminosilanization and covalent coupling of the cellular attachment mediator fibronectin was employed as modification strategy. In a comparison of different etching procedures, alkaline etching led to the highest density of amino functions after subsequent aminosilanization. Fibronectin was immobilized using a bifunctional aminoreactive PEG‐linker. This protein coating improved the attachment of human osteoblast‐like cells (HOB) on non‐porous Ecopore as displayed by vital staining. XTT metabolism assays indicated an enhanced HOB growth in the initial phase of cultivation on fibronectin‐coated versus non‐coated specimens. In a first feasibility study, cultivation of HOB on coated porous Ecopore cylinders with a median pore size diameter of 130 μm showed that cellular growth was uniform and dense on the external surface of the specimen, but was sparse in the interior pore system. Ecopore batches with larger pores will be modified and investigated in vitro and in vivo in the next step of the study.
Nano‐porous Alumina Coatings for Improved Bone Implant Interfaces
Authors: Walpole A. R. , Briggs E. P. , Karlsson M. , Pålsgård E. , Wilshaw P. R.
Published: January 2004

A new method is proposed for coating implants that produces a metal implant covered in a layer of nano‐porous alumina ceramic. These layers are produced by first depositing a layer of aluminium on the implant surface and then anodising it in phosphoric acid to produce the nano‐porous structure. This process results in the conversion of the aluminium to alumina containing 6‐8wt% phosphate ions. The surface alumina layer is bonded to the substrate via an interfacial layer of fully dense anodised titanium oxide. Mechanical measurements have shown that the shear and tensile strength of this coating are in excess of 20MPa and 10MPa, respectively.

The biological performance of nano‐porous alumina material has been assessed and shown to be highly favourable, supporting normal osteoblastic activity and maintaining the osteoblastic phenotype. The filling of the nano‐porous coating with bioactive material to achieve enhanced biological performance has been investigated using colloidal silica as an analogue for a Bioglass sol. The coating has been loaded with silica by dipping in colloidal silica with a pH of 5.6. Pore filling equivalent to 1.3 wt% SiO2 in the coating as a whole has been achieved in this way.
A TiO2‐Binding Protein isolated from Rhodococcus Strain GIN‐1 (NCIMB 40340) – Purification, Properties and Potential Applications
Authors: Gertler G. , Brudo I. , Kenig R. , Fleminger G.
Published: January 2004

A Rhodocuccus strain (Rh. GIN1, NCIMB 40340), which is capable of adsorption to titanium dioxide (TiO2) and TiO2‐containing coal fly ash particles, has been isolated previously in our Lab. Selectivity experiments showed that the bacterium is capable of adsorption to other metal oxides as well (e.g. magnetite and Al2O3) but at lower affinities. The bacterium binds tightly both to rutile and anatase TiO2. In electronmicrograms the formation of “bridge‐like” structures between the bacterium and the oxide is observed. A specific protein fraction, located on the cell wall of the bacterium was isolated from the bacterium. This protein was found to adhere strongly to TiO2 particles at high salt concentrations, similarly to the binding to TiO2 of the intact bacteria. TiO2 (rutile) was found to bind the protein faster, stronger and at a higher capacity than the anatase isoform. The 55 kDa Ti‐Binding Protein (TiBP) was isolated from the bacteria after homogenization by French Press. It was purified by affinity chromatography on TiO2 particles, hydrophobic chromatography on a Fractogel‐propyl column and gel filtration on a Superdex G‐200 column. The same protein was isolated from the bacteria by treatment with mutanolysin, an enzyme which is commonly used to retrieve cell‐wall proteins from Gram‐positive bacteria, demonstrating the outer cell location of the protein in Rh. GIN1. TiBP exhibits metal oxide binding selectivity similar to that of the intact bacterium, namely TiO2>ZnO>Al2O3 >Fe2O3(magnetite). Hydrophobic forces seem to dominate the interactions of the protein with TiO2 as its binding capability is greatly enhanced in the presence of high concentrations of NaCl and its desorption requires high concentrations of urea and SDS. These features differentiate TiBP from other proteins known to adsorb TiO2 (such as hemoglobin, cytochrome c and bovine serum albumin), mainly by weak, charge‐based interactions.
Stability of Surface‐Enhanced Ultrahydrophilic Metals as a Basis for Bioactive rhBMP‐2 Surfaces
Authors: Chatzinikolaidou M. , Zumbrink T. , Jennissen H. P.
Published: January 2004

For several years the treatment of metals like cp titanium and 316L stainless steel with concentrated chromosulfuric acid at high temperatures (230‐240 °C) has formed the basis for preparing ultra‐hydrophilic priming coats on these metals (Jennissen et al. Materialwiss. Werkstofftech. 30, 838‐845, 1999). Metals treated in this way have been called surface‐enhanced, displaying a characteristic ultrastructure, and can be easily modified to carry a biocoat of recombinant human bone morphogenetic protein 2 (rhBMP‐2). The major oxide on surface enhanced titanium is TiO2. Thus this TiO2‐layer could be responsible for the ultra‐hydrophilic properties of the priming coat. Irradiation of TiO2 layers by ultraviolet light (Wang et al., Nature 388, 431‐432, 1997) has been shown to endow these layers with ultra‐hydrophilic properties (i.e. contact angles of ∼ 0°). However the ultra‐hydrophilic TiO2‐layers produced by irradiation are unstable and revert to the original high contact angles of ∼ 70° within several days. The question of whether the ultra‐hydrophilic surfaces prepared by the chromosulfuric acid method show long‐term stability was therefore important to answer. In addition the question if rhBMP‐2 immobilized on such a surface will retain its biological activity was of great interest. In this paper it will be shown that ultrahydrophilic titanium mini‐plates retain their ultra‐hydrophilicity with contact angles of 0‐8° unchanged for at least 50 days and support the immobilization of rhBMP‐2 in a biologically active form.
Identification of the anthelix motif in the TGF‐β superfamily by molecular 3D‐Rapid Prototyping
Authors: Laub M. , Jennissen H. P.
Published: January 2004

3D‐Rapid Prototyping (3D‐RP) is a novel technique for the construction of highly accurate three‐dimensional polyamide models of biomolecules. This method has been shown to be a valuable tool in the modeling of protein‐protein‐interactions as well as in the analysis of surface topography. Using this technique we were recently able to identify a so far unknown structure on the concave side of bone morphogenetic protein 2 (BMP‐2). Since this structure is the imprint of a left‐handed helix we have called this negative an unthelix. Obviously this novel structural feature of BMP‐2 may act as a binding side for endogenous ligands.

BMP‐2 belongs to the highly conserved Transforming Growth Factor‐β (TGF‐β) superfamily, a large group of multifunctional peptides controlling differentiation, proliferation and repair in multicellular organism. The protomer structures of all members share a cystine‐knot motif as a characteristic feature. The question therefore arose whether a) the novel anthelical motif found in BMP‐2 is a common structural feature of this family and b) if there are any differences in terms of pitch and radius of the anthelix. As anthelical structures are difficult to visualize and nearly impossible to quantify using 3D molecular visualization software we constructed models of BMP‐2, BMP‐7 and TGF‐β2 from X‐ray crystallographic data by 3D‐Rapid Prototyping (3D‐RP).

The anthelix motif was found in BMP‐2, BMP‐7 and TGF‐β2 with similar values for pitch (ca. 8‐10 nm) and radius (ca. 0.5‐0.7 nm). In contrast the anthelical motif was not found in a 3D‐RP model of human chorionic gonadotropin (HCG) which is also a member of the cystine‐knot family but doesn’t belong to the TGF‐β superfamily. These results were corroborated by measurements of the intersubunit angle of these dimeric proteins (141‐149°) and the distances between the center of mass (1.68‐1.96 nm) of the subunits both of which appear to be determinants of the anthelical pitch.

We conclude that the anthelical groove on the concave side is a common structural motif of BMP‐2, BMP‐7 and TGF‐β2 and maybe of the whole group of the TGF‐β superfamily.
Modified cemented stem fixation in hip arthroplasty with computer based analysis – Experimental results
Authors: Barden B. , Weßkamp B. , Löer F. , Michiels I.
Published: January 2004

27 cemented stems were implanted in fresh‐frozen human cadaver femora with third generation antegrade cementing technique and with prechilled vacuum‐mixed and pre‐pressurized Palacos R bone cement. 3 groups with different implantation techniques were compared according to the achieved cement mantle thickness distribution. Group 1 (modified stem fixation): 7 canulated stems inserted over guidetubes that were fixed in distal synthetic plugs (3 Willert CF‐30 and 4 flanged Charnley stems). The guidetubes served simultaneously for stem centralization and evacuation of the intramedullary cavity. Group 2: 12 stems with distal centralizers with fins (4 flanged Charnley, 8 anatomic cemented AC), and Group 3: 8 stems without centralizer (4 Willert CF‐30 and 4 flanged Charnley). For analysis, each femur was cut into mean 25 cross‐sections (range, 22 ‐ 31). Contact radiographs were taken and digitized with a sampling distance of 0.12mm (204.8 dpi). Using a custom‐made computer program (FemStat 1.001), the cement mantle thickness was determined at mean 650 implant surface points per cross section. Results: The percentage of critical cement mantle thickness was lower for the canulated stems with guidetube. Here 14.1 % of the measurements were smaller than 2mm. For the stems with distal centralizer and without centralizer this was 28.3 % and 28.2 % (p = 0.003 and p = 0.002, U‐test). Cement mantles smaller than 1mm were also reduced for group 1 (2.8 % compared with 4.7 % and 7.5 %) but this was not significant (p = 0.384 and p = 0.094). The stems without centralizers had only slightly inferior cement mantles if compared to stems with distal centralizers with fins (for < 2mm p = 0.571, for < 1mm p = 0.305). Comparing different cementing techniques for one constant type of prosthesis (Charnley) the canulated stems with guide tubes provided a significantly better cement mantle thickness than the stems with distal centralizers (for < 2mm 10.3 % compared with 26.6 %, p = 0.029; for < 1mm 1.5 % compared with 3.4 %, p = 0.343). Distal centralizers failed, as the intramedullary cavity is elliptic in cross section and the gaps between the wings caused malposition. For all stems in group 3 improvement of the cement mantle thickness was predominantly achieved in the distal and middle third of the femur. Conclusion: The implantation technique with canulated stems inserted over a guidetube allows superior stem positioning leading to a more favourable cement mantle.
Biological Multi‐layer Systems as Implant Surface Modification
Authors: Willumeit R. , Feyerabend F. , Kamusewitz H. , Schossig M. , Clemens H.
Published: January 2004

In living organisms the natural contact areas between cells are the cell membranes. These membranes separate the individual cells or build reaction compartments in an aqueous environment. Beside their structural role they also have specific functions that are due to the great variety of their components which are lipids (about 40 %) and proteins (about 60 %).

In terms of implant development the next neighbors of the cells are artificial materials which do not belong to the natural cellular environment. Therefore, a biocompatible implant surface is needed which is achieved by either the correct choice of the material and surface roughness or a functionalization of the surface.

To date little is known of the role lipids could play in this context. However, from literature we know that phospholipids can cause calcification and that modified phosphorylcholine polymers ('MPC polymers') are used to decrease cell adhesion and to improve blood compatibility. In the last few years it became obvious that the lipid contribution in the membrane is not only important as support for proteins but that the lipid membrane itself can also be a target for drug design and its structure can influence the function of the proteins. We therefore focused our interest on this class of amphiphilic molecules. In this work we present initial observations on the modification of metallic implant surfaces of Ti‐6Al‐7Nb (in mass percent) by phospholipid multilayers, using contact angle measurements and surface sensitive characterization techniques such as scanning electron microscopy (SEM) and scanning force microscopy (SFM). Preliminary data concerning cell adhesion experiments are also presented.
Wirkungs‐ und Resistenzmechanismen: Was ist neu an Ketoliden und Oxazolidinonen?
Authors: Heisig Peter
Published: January 2004

Mit Ketoliden und Oxazolidinonen stehen seit kurzem zwei neue Antibiotikaklassen zur Verfügung, die zur Behandlung von Atemwegsinfektionen und Infektionen durch resistente grampositive Erreger eingesetzt werden. Beide greifen an jeweils anderen Stellen im bakteriellen Ribosom an und hemmen die Proteinsynthese. Dabei zeigen sie einen bakteriostatischen Wirkungstyp. Fortschritte in der Aufklärung der 3D‐Struktur des Ribosoms haben detaillierte Vorstellungen zu den molekularen Wirkungs‐ und Resistenzmechanismen dieser neuen Wirkstoffklassen erbracht, die für eine Weiterentwicklung beider Klassen eine wichtige Voraussetzung darstellen.
Zur Pharmakokinetik von Linezolid und Telithromycin: Zwei neue Antibiotika mit besonderen Eigenschaften
Authors: Sörgel Fritz , Landersdorfer Cornelia , Bulitta Jürgen
Published: January 2004

Mit Linezolid und Telithromycin stehen zwei neue Antibiotika zur Verfügung, die sich in ihren pharmakokinetischen Eigenschaften von anderen Substanzklassen unterscheiden. Beim Linezolid fällt auf, dass es trotz seiner chemisch eher neutralen Eigenschaften sehr gut in Gewebe penetriert und ansonsten aufgrund seiner vollständigen oralen Resorption, seiner parenteralen Applizierbarkeit und seiner bisher nicht bekannten Neigung zu pharmakokinetischen Interaktionen eine gut überschaubare Substanz darstellt.

Telithromycin zeigt sich als eine konsequente Weiterentwicklung aus dem Bereich der Makrolide, die zu besonderen pharmakokinetischen Eigenschaften geführt hat. Hier stehen ebenfalls sehr gute Penetrationseigenschaften in das Gewebe und die mittel bis lange Halbwertszeit im Vordergrund. Diese erlaubt eine einmal tägliche Dosierung.

Zusammen mit den antimikrobiellen Eigenschaften stellen diese beiden Substanzen eine wichtige Erweiterung des antibiotischen Arzneimittelschatzes dar.
Linezolid in der Therapie: Wirkung bei nosokomialer Pneumonie und schweren Haut‐ und Weichteilinfektionen
Authors: Bodmann Klaus‐Friedrich
Published: January 2004

Zusammenfassend ist festzustellen, dass Linezolid unter Berücksichtigung der heutigen Studienlage bei schweren Haut‐und Weichteilinfektionen dem Vancomycin wenigstens gleichzustellen ist. Bei durch MRSA verursachter nosokomialer Pneumonie ist Linezolid als Mittel der ersten Wahl anzusehen, da statistisch signifikant höhere Heilungsraten und niedrigere Letalitätsraten in doppelblinden Studien nachgewiesen worden sind. Vor dem Hintergrund der Einführung der DRG‐Richtlinien kann zudem die orale Verfügbarkeit von Linezolid und die damit verbundene kürzere Krankenhausverweildauer einen eigenen Vorteil darstellen.
Neuer Therapieansatz gegen AIDS: Fusionshemmstoffe
Authors: Holzgrabe Ulrike
Published: January 2004

Die Behandlung HIV‐infizierter Patienten beschränkt sich im Augenblick auf den Einsatz von nukleosidischen und nicht‐nukleosidischen Reverse‐Transkriptase‐Hemmstoffen und Inhibitoren der HIV‐Protease. Da weder die Therapie noch die Prophylaxe des AIDS‐Ausbruches zufriedenstellend sind, wird nach weiteren Therapieansätzen gefahndet.
Neuer Ansatz zur Therapie chronisch‐entzündlicher Erkrankungen
Authors: Winckler Thomas
Published: January 2004

Ein Forscherteam der amerikanischen Firma Xencor nutzte ein Verfahren des computergestützten Proteindesigns zur Entwicklung negativer TNF‐α‐Mutanten.
Farbenspiel im Spinnennetz: Spielwiese
Authors: Schlichting Hans Joachim
Published: January 2004

In Spinnennetzen kann man unter günstigen Bedingungen ein prächtiges Farbenspiel beobachten, das aus physikalischer Sicht hoch interessant ist. Wahrscheinlich hat es seine Ursache in einem Beugungseffekt an den dünnen Spinnenfäden und anschließender Interferenz.
Biegen und Brechen im Supercomputer: Duktile Verformungen und spröde Brüche von Kristallen
Authors: Buehler Markus J. , Gao Huajian
Published: January 2004

Ob sich ein Material unter Krafteinwirkung duktil verformt oder spröde bricht, hängt davon ab, wie sich in ihm Defekte ausbreiten. Um das zu untersuchen, „zerstören”︁ wir in Supercomputer‐Simulationen Nanokristalle, die bis zu einer Milliarde virtueller Atome enthalten. Die Simulationen zeigen zum Beispiel, wie sich Risse an der Grenzfläche zwischen einem härteren und einem weicheren Material ausbreiten. Sie erlauben auch nie zuvor gesehene Einblicke in die mikroskopischen Prozesse während der duktilen Verformung eines Metalls: Das kollektive Verhalten von vielen tausend Versetzungen führt zu einer Kaltverfestigung des Kristalls. Er wird spröde und bricht.
Physics on Stage III
Authors: Vollmer Michael
Published: January 2004

Vom 8. bis 15. November 2003 fand in Nordwijk, Holland, auf dem Gelände des europäischen Satelliten‐Testzentrums ESTEC zum dritten Mal das europäische Wissenschaftsfestival Physics on Stage [1] statt. Über 300 Teilnehmer aus 22 europäischen Ländern nahmen an diesem Ereignis teil.
Vom Arbeitshaus zur Supernova
Authors: Heering Peter
Published: January 2004

In der letzten Ausgabe stellten wir einige Arbeiten des Grafen von Rumford vor. Unter seinen vielfältigen Entwicklungen findet sich auch die Beschreibung eines der ersten Photometer. Diese Arbeiten aus dem Jahre 1792 führten letztlich zu einer Definition der Lichtstärke, die lange Zeit gebräuchlich war. Rumfords Konzept der Standardkerze findet sich heute unter anderem in der Astronomie wieder.
Auch Mesonen erfüllen Bellsche Ungleichung
Authors: Ziegler Thomas
Published: January 2004

Teilchenphysikern bei Belle am KEKB‐Beschleuniger in Tsukuba, Japan, ist es erstmals gelungen eine Verletzung der Bellschen Ungleichung bei Elementarteilchen nachzuweisen [1]. Damit konnten sie die Vollständigkeit der Quantenmechanik erneut bestätigen.
Zeitdilatation erneut bestätigt
Authors: Saathoff Guido
Published: January 2004

Eine der weitreichendsten Konsequenzen der Speziellen Relativitätstheorie ist das Phänomen der Zeitdilatation. Diese wurde nun am Max‐Planck‐Institut für Kernphysik mit der bisher höchsten Genauigkeit gemessen [1].
Genetic association studies in Alzheimer's disease research: challenges and opportunities
Authors: Edland Steven D. , Slager Susan , Farrer Matthew
Published: January 2004

Genetic association studies have identified important risk factors for Alzheimer's disease and other diseases. However, the ease with which these methods can be applied and the shear number of polymorphisms in the human genome has led to a well‐characterized multiple comparison problem—given the number of genetic variants being tested, it is likely that many of the positive findings reported in the literature to date will prove to be false positive findings explained simply by random fluctuation in data and type I error. The disparity of findings in initial positive reports versus subsequent negative replication studies observed in the Alzheimer's disease literature underscores this problem. The problem of a high false positive rate can be addressed in part by using statistical correction for multiple comparisons in larger and statistically more powerful samples and in meta‐analyses of smaller samples. National initiatives are now being considered to address this problem by encouraging sharing of genetic material. Of equal concern in planning future initiatives are methodological issues that are the domain of the epidemiologist. In fact, it is possible that disparate findings across case–control studies reported to date may be explained in part by problems in the design, analysis and interpretation of these studies. The involvement of epidemiologists may improve the situation in this regard. For example, population stratification bias, control selection bias and prevalent case bias can be minimized by careful study design and by appropriate statistical analysis. Regarding interpretation of case–control studies, a more careful consideration of the strength of evidence for a given genetic variant may help to temper enthusiasm for, or appropriately qualify, positive findings. Epidemiologists have well‐developed causal criteria for this purpose. This paper reviews the current state of case–control studies of genetic variants in Alzheimer's disease from the epidemiological perspective. The problem of multiple comparisons and a high false positive rate is reviewed. The potential for bias in case–control studies of Alzheimer's disease is reviewed by way of example. Future initiatives to promote case–control studies of genetic variants in Alzheimer's disease can only benefit from increased awareness the tools of epidemiology. Copyright © 2004 John Wiley & Sons, Ltd.
Family‐based association tests for survival and times‐to‐onset analysis
Authors: Lange Christoph , Blacker Deborah , Laird Nan M.
Published: January 2004

In this paper, we discuss family‐based association test (FBATs) relating genetic data to survival and time‐to‐onset data. We show how the standard logrank and Wilcoxon statistics can be used with family data to develop tests of association. We prove that the FBAT‐logrank approach can be identical to the proportional hazard approach discussed in Mokliatchouk et al. (2000). Further, using simulation studies, we compare the power of the logrank, Wilcoxon and an approach developed for censored exponential data (Euro J Hum Gen 2001; 9:301–306). Based on the results of the simulation study, we suggest rules of thumb about which statistics to use in a given situation. An application of all three tests to an Alzheimer study illustrates the practical relevance of our discussion. Copyright © 2004 John Wiley & Sons, Ltd.
Population‐based studies of AD: message and methods: an epidemiologic view
Authors: Launer L. J. , Brock D. B.
Published: January 2004

Dementia is a growing public health problem because the numbers suffering the disease is increasing rapidly as the population ages. Over the past decade several longitudinal population‐based studies were initiated and are still on‐going. These studies will provide valuable insight into the risk factors for, and progression of dementia. However, there are several design and statistical challenges that are unique to studying dementia in the population and that need to be addressed. These challenges include aspects of both ascertainment of disease and definition of exposure. To reduce bias from prospective epidemiologic studies, not only are new approaches to definition of disease and exposure needed, but new epidemiologic or statistical methods may be required as well. Published in 2004 by John Wiley & Sons, Ltd.
Incidence and mortality of Alzheimer's disease or dementia using an illness‐death model
Authors: Commenges D. , Joly P. , Letenneur L. , Dartigues JF.
Published: January 2004

We present an illness‐death model for studying the incidence and the prevalence of Alzheimer's disease or dementia. We argue that the illness‐death model is better than a survival model for this purpose. In this model the best choice for the basic time‐scale is age. Then we present extensions of this model for incorporating covariates and taking account of a possible effect of calendar time. Calendar time is introduced via a proportional intensity model. We give the likelihood for a mixed discrete‐continuous observation pattern from this model: clinical status is observed at discrete visit‐times while the date of death is observed exactly or right‐censored. The penalized likelihood approach allows to non‐parametrically estimate the transition intensities. Application on the data of the Paquid study allows to produce estimates of the age‐specific incidence of dementia together with mortality rates of both demented and non‐demented subjects. Then the effect of calendar time and educational level are studied. Low educational level increases the risk of dementia. The risk of dementia increases with calendar time while the mortality of demented subjects decreases. The most likely explanation of this result seems to be in a shift in the diagnosis of dementia towards earlier stages of the disease prompted by a change in the perception of dementia and the arrival of new drugs. Copyright © 2004 John Wiley & Sons, Ltd.
A shared random effect parameter approach for longitudinal dementia data with non‐ignorable missing data
Authors: Gao Sujuan
Published: January 2004

A significant source of missing data in longitudinal epidemiologic studies on elderly individuals is death. It is generally believed that these missing data by death are non‐ignorable to likelihood based inference. Inference based on data only from surviving participants in the study may lead to biased results. In this paper we model both the probability of disease and the probability of death using shared random effect parameters. We also propose to use the Laplace approximation for obtaining an approximate likelihood function so that high dimensional integration over the distributions of the random effect parameters is not necessary. Parameter estimates can be obtained by maximizing the approximate log‐likelihood function. Data from a longitudinal dementia study will be used to illustrate the approach. A small simulation is conducted to compare parameter estimates from the proposed method to the ‘naive’ method where missing data is considered at random. Copyright © 2004 John Wiley & Sons, Ltd.
Adjusting for non‐ignorable verification bias in clinical studies for Alzheimer's disease
Authors: Zhou Xiao‐Hua , Castelluccio Pete
Published: January 2004

A common problem for comparing the relative accuracy of two screening tests for Alzheimer's disease (AD) in a two‐stage design study is verification bias. If the verification bias can be assumed to be ignorable, Zhou and Higgs have proposed a maximum likelihood approach to compare the relative accuracy of screening tests in a two‐stage design study. However, if the verification mechanism also depends on the unobserved disease status, the ignorable assumption does not hold. In this paper, we discuss how to use a profile likelihood approach to compare the relative accuracy of two screening tests for AD without assuming the ignorable verification bias mechanism. Copyright © 2004 John Wiley & Sons, Ltd.