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PubMed1982

Histology of the islets of Langerhans following administration of human lymphocytes into athymic mice.

Lymphocytes from seven newly diagnosed insulin-dependent (Type 1) diabetics, five islet cell antibody positive unaffected children and five normal subjects were injected i.p. into athymic nude mice. A further six mice were injected with medium and six control mice received no injection. Blood was taken from the tail vein before injection for glucose determination. After 10 days blood was again obtained from the tail vein; the pancreas was removed under deep ether anaesthesia and the mice sacrificed by exsanguination. Routine histological sections of the pancreas were prepared. There was no difference between groups in respect of the initial blood glucose. However, final blood glucose levels were raised in all mice that had received an injection including medium only, the rise being statistically significant both after injection of lymphocytes from normal subjects (P less than 0.05) and from newly diagnosed diabetics (P less than 0.001). Histology did not reveal any evidence of 'insulitis' or islet cell damage although enlarged, hyperplastic islets could be found in each group of treated mice. We conclude that passive transfer of diabetes was not achieved in this animal model. Elevation of blood glucose levels and islet hyperplasia may simply reflect a non-specific 'stress' reaction.

Animals↗
PubMed2005

SPE dose prediction using locally weighted regression.

When astronauts are outside Earth's protective magnetosphere, they are subject to large radiation doses resulting from solar particle events. The total dose received from a major solar particle event in deep space could cause severe radiation poisoning. The dose is usually received over a 20-40 h time interval but the event's effects may be reduced with an early warning system. This paper presents a method to predict the total dose early in the event. It uses a locally weighted regression model, which is easier to train, and provides predictions as accurate as the neural network models that were used previously.

Algorithms↗
PubMed1990

Stereochemical mechanism of action for thymidylate synthase based on the X-ray structure of the covalent inhibitory ternary complex with 5-fluoro-2'-deoxyuridylate and 5,10-methylenetetrahydrofolate.

The structure of the Escherichia coli thymidylate synthase (TS) covalent inhibitory ternary complex consisting of enzyme, 5-fluoro-2'-deoxyuridylate (FdUMP) and 5,10-methylene tetrahydrofolate (CH2-H4PteGlu) has been determined at 2.5 A resolution using difference Fourier methods. This complex is believed to be a stable structural analog of a true catalytic intermediate. Knowledge of its three-dimensional structure and that for the apo enzyme, also reported here, suggests for the first time how TS may activate dUMP and CH2-H4PteGlu leading to formation of the intermediate and offers additional support for the hypothesis that the substrate and cofactor are linked by a methylene bridge between C-5 of the substrate nucleotide and N-5 of the cofactor. By correlating these structural results with the known stereospecificity of the TS-catalyzed reaction it can be inferred that the catalytic intermediate, once formed, must undergo a conformational isomerization before eliminating across the bond linking C-5 of dUMP to C-11 of the cofactor. The elimination itself may be catalyzed by proton transfer to the cofactor's 5 nitrogen from invariant Asp169 buried deep in the TS active site. The juxtaposition of Asp169 and bound tetrahydrofolate in TS is remarkably reminiscent of binding geometry found in dihydrofolate reductase where a similarly conserved carboxyl group serves as a general acid for protonating the corresponding pyrazine ring nitrogen of dihydrofolate.

Binding Sites↗
PubMed1999

Applying risk assessment models in orthopaedic surgery: overview of our clinical experience.

Major joint surgery (elective hip or knee replacement, or hip fracture) carries a high risk of postoperative deep vein thrombosis (DVT) and pulmonary embolism. DVT prophylaxis has become an essential part of routine management, since several preventive methods, including low-molecular-weight heparins (LMWHs) and oral anticoagulants, are effective and safe in major joint surgery. Clinically important questions remain about the best way to use LMWHs for DVT prevention. The need for preoperative dosing, whether to give LMWHs once or twice daily, and the most suitable duration of prophylaxis remain issues of debate. Reports of local bleeding after spinal or epidural anaesthesia/analgesia in orthopaedic surgery patients given LMWH may make anaesthetists more reluctant to combine regional anaesthesia with LMWH prophylaxis, especially if a preoperative dose is required. The worldwide trend towards early transfer of postoperative patients from hospital to a convalescent facility or home has increased the need for formal recommendations about the optimal duration of prophylaxis. Ever shorter hospital admissions after elective surgery mean that prophylaxis given only in hospital may not be sufficient.

Anticoagulants↗
PubMed2026

Deep learning reveals genomic regions introgressed between two recurrently hybridizing lynx species.

Recently, diverged species with overlapping distributional ranges have high chances of hybridizing and if hybrids are viable, genomic material can be transferred between species in a process called introgression. To characterize the patterns and consequences of introgression in species with historically low population sizes and recent steep declines resulting in genetic erosion, we analyze the Iberian and Eurasian lynx (EL) as an illustrative and relevant case study. While genome-wide introgression was already detected, here we apply a method using a deep convolutional neural network to detect specific regions of the genome with signals of introgression in three populations of these two species. Over 6% of the genome of both Iberian lynx and ELw shows introgression from the other species, compared with only 2% in the ELs. This observation, along with the results from demographic modeling, suggests that the ELw population is genetically closest to the source of EL introgression, a probably now extinct group that coexisted with the Iberian lynx in Southern Europe and Northern Iberia until recently. As predicted by theory, introgression was generally higher in populations with smaller effective sizes and in genomic regions of high recombination. However, the Iberian lynx did not show higher overall introgression than the more abundant ELw, and coding regions introgressed as frequently as intergenic regions. Local genetic diversity is boosted approximately 3-fold in genomic windows where introgression occurs, potentially including the adaptively relevant and highly diverse MHC region of the Iberian lynx.

Animals↗
PubMed2001

Histologic analysis of the implanted cartilage in an exact-fit osteochondral transplantation model.

PURPOSE: Osteochondral transplantation is one of the useful treatments for articular cartilage defect. However, the histologic change of the implanted cartilage has not been reported in detail. We investigated the histology of exact-fit osteochondral transplants used to repair articular cartilage defects in an animal model. TYPE OF STUDY: This was a nonrandomized control study using an animal model. METHODS: Sixteen skeletally mature female Japanese white rabbits were used in the study. The region of the femoral groove was selected as the site for the osteochondral defect. A full-thickness cylindrical defect (7 mm in diameter and 7 mm in depth) through the articular cartilage and into the subchondral bone was made using the Osteochondral Autograft Transfer System (Arthrex, Naples, FL). The entire osteochondral fragment was removed and then returned to its original site in the femoral condyle precisely. Thus, the defect was repaired with an autogenous osteochondral transplantation of exactly the same size and configuration as the defect. Specimens were obtained 2, 4, 12, and 24 weeks postoperatively and were analyzed both macroscopically and histologically. RESULTS: Macroscopically, there was smooth continuity of the articular surface and the integration of the graft to the normal host cartilage. However, histologic examination showed that the layer of the grafted cartilage was thicker than that of the normal host cartilage and the extracellular matrix of the implanted cartilage exhibited a stronger staining pattern with safranin-O fast green than the normal cartilage. Cell density was higher in the grafted cartilage, particularly in the middle and the deep zones. Round and polygonal hypertrophic clusters of chondrocytes were observed in the middle and deep zones of the grafted cartilage. CONCLUSIONS: The histologic properties of the exact-fit implanted cartilage were different from that of normal articular cartilage. Further investigation of mechanical and structural properties of grafted cartilage is necessary to verify the long-term effects of osteochondral transplantation.

Animals↗
PubMed1992

Subunit assembly and active site location in the structure of glutamate dehydrogenase.

The three-dimensional crystal structure of the NAD(+)-linked glutamate dehydrogenase from Clostridium symbiosum has been solved to 1.96 A resolution by a combination of isomorphous replacement and molecular averaging and refined to a conventional crystallographic R factor of 0.227. Each subunit in this multimeric enzyme is organised into two domains separated by a deep cleft. One domain directs the self-assembly of the molecule into a hexameric oligomer with 32 symmetry. The other domain is structurally similar to the classical dinucleotide binding fold but with the direction of one of the strands reversed. Difference Fourier analysis on the binary complex of the enzyme with NAD+ shows that the dinucleotide is bound in an extended conformation with the nicotinamide moiety deep in the cleft between the two domains. Hydrogen bonds between the carboxyamide group of the nicotinamide ring and the side chains of T209 and N240, residues conserved in all hexameric GDH sequences, provide a positive selection for the syn conformer of this ring. This results in a molecular arrangement in which the A face of the nicotinamide ring is buried against the enzyme surface and the B face is exposed, adjacent to a striking cluster of conserved residues including K89, K113, and K125. Modeling studies, correlated with chemical modification data, have implicated this region as the glutamate/2-oxoglutarate binding site and provide an explanation at the molecular level for the B type stereospecificity of the hydride transfer of GDH during the catalytic cycle.

Amino Acid Sequence↗
PubMed1994

Dermal and underlying tissue pharmacokinetics of lidocaine after topical application.

The deep-tissue penetration of lidocaine below a dermally applied site was quantified in a rat model. The concentrations of lidocaine in tissues below the applied site were measured and compared with plasma concentrations and concentrations in similar tissues on the contralateral side. The direct penetration of lidocaine was predominant for the first 2 h up to a depth of about 1 cm below the applied site. A physiologically based pharmacokinetic model based on apparent tissue-tissue clearances and local blood flow to tissues is presented which adequately describes the concentration-time profiles of lidocaine in underlying tissues after dermal application. The apparent tissue-tissue clearances were estimated by nonlinear regression assuming first-order diffusional mass transfer of lidocaine between the various tissue compartments below the applied site in anesthetized rats. Tissue levels of lidocaine were estimated using simulations from the model with and without direct penetration and tissue blood supply. Dermal microcirculation is not a perfect sink for lidocaine.

Administration, Topical↗
PubMed2006

The origin and diversification of eukaryotes: problems with molecular phylogenetics and molecular clock estimation.

Determining the relationships among and divergence times for the major eukaryotic lineages remains one of the most important and controversial outstanding problems in evolutionary biology. The sequencing and phylogenetic analyses of ribosomal RNA (rRNA) genes led to the first nearly comprehensive phylogenies of eukaryotes in the late 1980s, and supported a view where cellular complexity was acquired during the divergence of extant unicellular eukaryote lineages. More recently, however, refinements in analytical methods coupled with the availability of many additional genes for phylogenetic analysis showed that much of the deep structure of early rRNA trees was artefactual. Recent phylogenetic analyses of a multiple genes and the discovery of important molecular and ultrastructural phylogenetic characters have resolved eukaryotic diversity into six major hypothetical groups. Yet relationships among these groups remain poorly understood because of saturation of sequence changes on the billion-year time-scale, possible rapid radiations of major lineages, phylogenetic artefacts and endosymbiotic or lateral gene transfer among eukaryotes. Estimating the divergence dates between the major eukaryote lineages using molecular analyses is even more difficult than phylogenetic estimation. Error in such analyses comes from a myriad of sources including: (i) calibration fossil dates, (ii) the assumed phylogenetic tree, (iii) the nucleotide or amino acid substitution model, (iv) substitution number (branch length) estimates, (v) the model of how rates of evolution change over the tree, (vi) error inherent in the time estimates for a given model and (vii) how multiple gene data are treated. By reanalysing datasets from recently published molecular clock studies, we show that when errors from these various sources are properly accounted for, the confidence intervals on inferred dates can be very large. Furthermore, estimated dates of divergence vary hugely depending on the methods used and their assumptions. Accurate dating of divergence times among the major eukaryote lineages will require a robust tree of eukaryotes, a much richer Proterozoic fossil record of microbial eukaryotes assignable to extant groups for calibration, more sophisticated relaxed molecular clock methods and many more genes sampled from the full diversity of microbial eukaryotes.

Eukaryotic Cells↗
PubMed2000

Paranasal sinuses and nasopharynx CT and MRI.

Neoplastic disease of the nose, paranasal sinuses, the nasopharynx and the parapharyngeal space requires thorough assessment of location and extent in order to plan appropriate treatment. CT allows the deep soft tissue planes to be evaluated and provides a complement to the physical examination. It is especially helpful in regions involving thin bony structures (paranasal sinuses, orbita); here CT performs better than MRI. MRI possesses many advantages over other imaging modalities caused by its excellent tissue contrast. In evaluating regions involving predominantly soft tissue structures (ec nasopharynx and parapharyngeal space) MRI is superior to CT. The possibility to obtain strictly consecutive volume data sets with spiral CT or 3D MRI offer excellent perspectives to visualize the data via 2D or 3D postprocessing. Because head and neck tumors reside in a complex area, having a 3D model of the anatomical features may assist in the delineation of pathology. Data sets may be transferred directly into computer systems and thus be used in computer assisted surgery.

Angiofibroma↗
PubMed1993

Pathogenesis of immune-mediated neuropathies.

A variety of peripheral neuropathies are believed to be immune-mediated. Acute inflammatory demyelinating polyneuropathy or Guillain-Barré syndrome (GBS) is the prototype of these neuropathies. GBS is characterized by acute progressive motor weakness of the extremities and of bulbar and facial musculature. Deep tendon reflexes are reduced or absent, and sensory symptoms are mild. Respiratory failure and autonomic dysfunction may be seen. The cerebrospinal fluid shows increased protein and no or very few cells. The nerve conduction velocity is slowed, and the pathology shows segmental demyelination with mononuclear cell infiltration. Studies from man and experimental animals suggest an immunologic basis for demyelination of the peripheral nerves in GBS, but the mechanism is not well understood. Experimental allergic neuritis, an animal model of GBS, is induced in laboratory animals by immunization with myelin P2 protein, some peptides of P2 protein, and galactocerebroside. The animals develop weakness and show electrophysiologic and pathologic features similar to GBS. P2-reactive T cells and antigalactocerebroside antisera can adoptively transfer experimental allergic neuritis. Various antibodies to peripheral nerve myelin and circulating immune complexes have been found in patients with GBS. The target antigen(s) for these antibodies are not well understood, but neutral glycolipids cross-reactive with Forssman antigen and gangliosides are possible candidates. The mainstay of therapy is the management of the paralyzed patient. Steroids are ineffective. Plasmapheresis, especially early in the course of the disease, can shorten the duration of paralysis and intubation. Results from a multicenter study in the Netherlands demonstrate the efficacy of high-dose immune globulin therapy in GBS.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2000

Adrenodoxin reductase-adrenodoxin complex structure suggests electron transfer path in steroid biosynthesis.

The steroid hydroxylating system of adrenal cortex mitochondria consists of the membrane-attached NADPH-dependent adrenodoxin reductase (AR), the soluble one-electron transport protein adrenodoxin (Adx), and a membrane-integrated cytochrome P450 of the CYP11 family. In the 2.3-A resolution crystal structure of the Adx.AR complex, 580 A(2) of partly polar surface are buried. Main interaction sites are centered around Asp(79), Asp(76), Asp(72), and Asp(39) of Adx and around Arg(211), Arg(240), Arg(244), and Lys(27) of AR, respectively. In particular, the region around Asp(39) defines a new protein interaction site for Adx, similar to those found in plant and bacterial ferredoxins. Additional contacts involve the electron transfer region between the redox centers of AR and Adx and C-terminal residues of Adx. The Adx residues Asp(113) to Arg(115) adopt 3(10)-helical conformation and engage in loose intermolecular contacts within a deep cleft of AR. Complex formation is accompanied by a slight domain rearrangement in AR. The [2Fe-2S] cluster of Adx and the isoalloxazine rings of FAD of AR are 10 A apart suggesting a possible electron transfer route between these redox centers. The AR.Adx complex represents the first structure of a biologically relevant complex between a ferredoxin and its reductase.

Adrenodoxin↗
PubMed1984

High resolution localization of the tRNA anticodon interaction site on the Escherichia coli 30 S ribosomal subunit.

A body of previous work has shown that when Escherichia coli tRNAVal1 is placed in the P site of E. coli ribosomes and irradiated, the 5'-anticodon base of this tRNA, 5-carboxymethoxyuridine, is cross-linked to C-1400 of the 16 S rRNA. By tagging the carboxyl group of the cross-linked tRNA residue with a 2,4-dinitrophenyl (DNP) group attached via a 9 A spacer, it has been possible to directly visualize this cross-linking site by immunoelectron microscopy. The DNP group was attached by addition of ethylenediamine to the carboxyl group, followed by condensation of the newly formed free amino group with the N-hydroxysuccinimide ester of N-2,4-dinitrophenyl-gamma-aminobutyric acid. When reacted with anti-DNP antibody, this modification brings the surface of the antibody to within 9 A of the pyrimidine ring which was cross-linked. Neither codon-dependent binding nor cross-linking were materially affected by the tRNA modification. The tRNA-ribosome adduct formed a stable complex with anti-DNP antibody only when 50-30 S subunit association was prevented. Electron microscopic examination of the immune complexes showed that greater than 95% of those detected had the antibody localized deep in the cleft which separates the head and neck of the 30 S from the large protrusion. Since this is the site of cross-linking of the anticodon of tRNA, we conclude that this region on the 30 S subunit corresponds to the decoding site.

Antibodies↗
PubMed1990

A dosimetric approach for relating the biological response of the lung to the accumulation of inhaled mineral dust.

Results from studies of the retention of contrasting mineral dusts inhaled by rats (for periods of up to three months) and the resultant changes in the phagocyte defence system of the deep lung were examined. The dusts used were titanium dioxide (relatively innocuous) and quartz (relatively toxic). The parameters assessed included the accumulation of material in the lung and lymph nodes during chronic exposure and the associated leukocyte response as assessed by broncho-alveolar lavage. The principal findings were that: (a) low level exposure to titanium dioxide produced no measurable inflammation (as indicated by neutrophil recruitment) but higher concentrations (30, 50, and 90 mg/m3) caused the transfer of dust to lymph nodes and first evidence of inflammation; and (b) for quartz, there was a more prominent response and earlier transfer of material to the lymph nodes. The suggested relation between changes in the neutrophil population and dust accumulation is discussed in terms of a quantitative dosimetric model, from which implications for assessing and managing human exposures emerge.

Animals↗
PubMed2003

Structural and functional analysis of a truncated form of Saccharomyces cerevisiae ATP sulfurylase: C-terminal domain essential for oligomer formation but not for activity.

ATP sulfurylase catalyzes the first step in the activation of sulfate by transferring the adenylyl-moiety (AMP approximately ) of ATP to sulfate to form adenosine 5'-phosphosulfate (APS) and pyrophosphate (PP(i)). Subsequently, APS kinase mediates transfer of the gamma-phosphoryl group of ATP to APS to form 3'-phosphoadenosine 5'-phosphosulfate (PAPS) and ADP. The recently determined crystal structure of yeast ATP sulfurylase suggests that its C-terminal domain is structurally quite independent from the other domains, and not essential for catalytic activity. It seems, however, to dictate the oligomerization state of the protein. Here we show that truncation of this domain results in a monomeric enzyme with slightly enhanced catalytic efficiency. Structural alignment of the C-terminal domain indicated that it is extremely similar in its fold to APS kinase although not catalytically competent. While carrying out these structural and functional studies a surface groove was noted. Careful inspection and modeling revealed that the groove is sufficiently deep and wide, as well as properly positioned, to act as a substrate channel between the ATP sulfurylase and APS kinase-like domains of the enzyme.

Amino Acid Sequence↗
PubMed2000

Quantification of, visualization of, and compensation for brain shift using intraoperative magnetic resonance imaging.

OBJECTIVE: Modern neuronavigation systems lack spatial accuracy during ongoing surgical procedures because of increasing brain deformation, known as brain shift. Intraoperative magnetic resonance imaging was used for quantitative analysis and visualization of this phenomenon. METHODS: For a total of 64 patients, we used a 0.2-T, open-configuration, magnetic resonance imaging scanner, located in an operating theater, for pre- and intraoperative imaging. The three-dimensional imaging data were aligned using rigid registration methods. The maximal displacements of the brain surface, deep tumor margin, and midline structures were measured. Brain shift was observed in two-dimensional image planes using split-screen or overlay techniques, and three-dimensional, color-coded, deformable surface-based data were computed. In selected cases, intraoperative images were transferred to the neuronavigation system to compensate for the effects of brain shift. RESULTS: The results demonstrated that there was great variability in brain shift, ranging up to 24 mm for cortical displacement and exceeding 3 mm for the deep tumor margin in 66% of all cases. Brain shift was influenced by tissue characteristics, intraoperative patient positioning, opening of the ventricular system, craniotomy size, and resected volume. Intraoperative neuronavigation updating (n = 14) compensated for brain shift, resulting in reliable navigation with high accuracy. CONCLUSION: Without brain shift compensation, neuronavigation systems cannot be trusted at critical steps of the surgical procedure, e.g., identification of the deep tumor margin. Intraoperative imaging allows not only evaluation of and compensation for brain shift but also assessment of the quality of mathematical models that attempt to describe and compensate for brain shift.

Adolescent↗
PubMed2004

Thermal-electrical modeling for epicardial atrial radiofrequency ablation.

Epicardial radiofrequency ablation is increasingly being used for intraoperative treatment of atrial fibrillation. However, the effect of different parameters on the lesion characteristics has not been sufficiently characterized. We used a finite element model to calculate the temperature distribution in the atrial tissue under different conditions during a constant voltage radiofrequency ablation. Our simulation results show that although in the case of a thin atrium the lesion was less deep for a thin atrium, it was easier to achieve transmurality. While considering a thinner atrium, the location of the hottest point of the lesion shifted from the electrode tip to epicardial surface. This effect was due to the convective cooling of the circulating blood inside the atrium. This convective cooling phenomenon has almost negligible effects for atria thicker than 3 mm. The variability of the cooling values has no significant effect on the lesion, even for thin atria (1-2 mm). Increasing the electrode insertion depth (ID) in the tissue produced larger lesions. However, for thinner atria (thickness <2 mm), this increase in the ID reduced the lesion width. It was also proved that the presence of a fat layer between the electrode and the atrial tissue decreased significantly the lesion dimensions.

Adipose Tissue↗
PubMed1997

Energy, volatile production, and climatic effects of the Chicxulub Cretaceous/Tertiary impact.

A comprehensive analysis of volatiles in the Chicxulub impact strongly supports the hypothesis that impact-generated sulfate aerosols caused over a decade of global cooling, acid rain, and disruption of ocean circulation, which contributed to the mass extinction at the Cretaceous/Tertiary (K/T) boundary. The crater size, meteoritic content of the K/T boundary clay, and impact models indicate that the Chicxulub crater was formed by a short period comet or an asteroid impact that released 0.7-3.4 x 10(31) ergs of energy. Impact models and experiments combined with estimates of volatiles in the projectile and target rocks predict that over 200 gigatons (Gt) each of SO2 and water vapor, and over 500 Gt of CO2, were globally distributed in the stratosphere by the impact. Additional volatiles may have been produced on a global or regional scale that formed sulfate aerosols rapidly in cooler parts of the vapor plume, causing an early, intense pulse of sulfuric acid rain. Estimates of the conversion rate of stratospheric SO2 and water vapor to sulfate aerosol, based on volcanic production of sulfate aerosols, coupled with calculations of diffusion, coagulation, and sedimentation, demonstrate that the 200 Gt stratospheric SO2 and water vapor reservoir would produce sulfate aerosols for 12 years. These sulfate aerosols caused a second pulse of acid rain that was global. Radiative transfer modeling of the aerosol clouds demonstrates (1) that if the initial rapid pulse of sulfate aerosols was global, photosynthesis may have been shut down for 6 months and (2) that for the second prolonged aerosol cloud, solar transmission dropped 80% by the end of first year and remained 50% below normal for 9 years. As a result, global average surface temperatures probably dropped between 5 degrees and 31 degrees K, suggesting that global near-freezing conditions may have been reached. Impact-generated CO2 caused less than 1 degree K greenhouse warming and therefore was insignificant compare to the sulfate cooling. The magnitude of sulfate cooling depends largely upon the rate of ocean mixing as surface waters cool, sink, and are replaced by upwelling of deep ocean water. This upwelling apparently drastically altered ocean stratification and circulation, which may explain the global collapse of the delta 13C gradient between surface and deep ocean waters at the K/T boundary.

Acid Rain↗