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Pantalar and tibiotalocalcaneal arthrodesis for post-traumatic osteoarthrosis of the ankle and hindfoot.

Twenty-one patients had a unilateral extended arthrodesis of the ankle and hindfoot (a tibiotalocalcaneal procedure in thirteen patients and a pantalar procedure in eight) for post-traumatic osteoarthrosis or deformity, or both. The operation was performed through a transfibular extended lateral approach, and autogenous bone graft and rigid internal fixation was used. A final alignment of 0 to 5 degrees of valgus, 0 to 5 degrees of calcaneus, and external rotation equal to that of the contralateral side was sought. Subjective and objective evaluation, including a personal interview, physical examination, and radiographic and dynamic pedobarographic analysis, was performed at a mean interval of thirty-two months (range, twenty-four to fifty-four months) after the operation. A solid fusion was achieved in eighteen (86 per cent) of the twenty-one patients. There were five malunions (24 per cent) and two superficial wound problems (10 per cent). Of the seventeen patients who were not retired from work, eleven returned to work: nine to an occupation that involved standing and two to a sedentary occupation. Although seventeen (81 per cent) of the twenty-one patients reported that they were much improved, twenty (95 per cent) had some pain, and most benefited from modifications in shoe-wear. Patients who had had a tibiotalocalcaneal arthrodesis were more mobile and functioned at a higher level than those who had had a pantalar arthrodesis. Extended arthrodesis of the ankle and hindfoot is a complex, technically demanding procedure, and should be regarded as a salvage operation capable of producing a satisfactory result and usually providing a reasonable alternative to amputation.

Adult

Nuclear magnetic resonance investigations of calcium antagonist drugs. II: Conformational and dynamic features of verapamil in [2H6]DMSO.

Conformational features of verapamil in [2H6]DMSO have been delineated by measuring 13C and 1H NMR parameters. Spin-lattice relaxation rates were interpreted within the frame of an extended alkane chain with segmental motions hampered by the aromatic substituents at both ends. The effective correlation times were all evaluated in the range 0.16-0.22 ns at 293 K. The aromatic rings were found to lie somewhat out-of-plane with the alkane chain. The NMR data were used to construct a Dreiding model of the most probable spatial arrangement and a molecular modeling system was utilized to represent the "preferred" conformation of verapamil in solution.

Calcium Channel Blockers

Engineering the Vero Cell Lineage: Toward a Programmable Vaccine Manufacturing Platform.

Vero cells remain an indispensable continuous substrate for human viral vaccine manufacturing. Despite decades of empirical process optimization, intrinsic genomic instability, including segmental aneuploidy and dynamic chromatin rearrangements, continues to limit the durability of engineered phenotypes under sustained viral burden and bioreactor stress. Here, we review the expanding engineering toolkit for the Vero lineage across a three-layered functional framework: the membrane interface, cytoplasmic foundry, and nuclear blueprint, evaluating translational prospects at each level. Receptor transplantation and morphological reprogramming have broadened viral entry range and enabled suspension-adapted culture formats, while metabolic flux management and temporally controlled apoptosis modulation have addressed intracellular production bottlenecks, albeit often with trade-offs between productivity, biosafety, and long-term population stability. At the genomic level, targeted perturbations of transcriptional regulators and emerging epigenetic interventions offer more durable gains, yet expression drift, clonal heterogeneity, and karyotypic instability during extended passaging highlight the need for locus-level precision rather than constitutive trait installation. Looking forward, infection-responsive dynamic logic circuits and the systematic identification of Vero-specific genomic safe harbors could shift the paradigm toward a conditionally responsive manufacturing architecture. Collectively, these advances suggest a pathway for transitioning the Vero lineage from a passive, empirically optimized biological substrate into a conditionally responsive, genomically stable, and programmable platform for modern vaccine preparedness.

Vero cells

A 1H NMR study of human calcitonin in solution.

Human calcitonin (hCT) has been investigated by NMR at 400 MHz in DMSOd6 and in an 85% DMSOd6-15% 1H2O (v/v) cryoprotective mixture. All backbone and side-chain resonances have been assigned, and the secondary structure has been determined in both solvents. In DMSOd6, the simultaneous presence of d alpha N, dNN, and some specific weak medium-range nuclear Overhauser effects, together with the amide temperature coefficients and the analysis of the NH-alpha CH spin-spin coupling constants, indicates that hCT is highly flexible but with three domains (comprising segments Asn3-Gly10, Gln14-Thr21, and Thr25-Ala31) in extended conformations which dynamically transform into isolated beta turns in the N- and C-terminal regions and into adjacent tight turns, resembling a 3(10) helix structure, in the central part. The DMSO-water mixture rigidifies the polypeptide chain, favoring an ordered, extended conformation. NOESY data indicate the presence of a short double-stranded antiparallel beta sheet in the central region made by residues 16-21 and connected by a two-residue hairpin loop formed by residues 18 and 19. Two tight turns, formed by residues 3-6 and 28-31, were also identified. The central beta sheet does not favor an amphipathic distribution of the residues as found for salmon calcitonin [Motta, A., Castiglione Morelli, M. A., Goud, N., & Temussi, P. A. (1989) Biochemistry 28, 7998-8002]. This is in agreement with the smaller tendency of hCT to form the amphipathic alpha helix, postulated to be responsible for the interaction of hCT with lipids. The possible role of the cis-trans isomerism of Pro is discussed.

Amino Acid Sequence

Intracellular HRP study of nociceptive neurons within the ventrobasal complex of the cat thalamus.

Locations and morphological characteristics of nociceptive specific (NS) and wide dynamic range (WDR) neurons of the ventrobasal (VB) thalamic complex were studied using an intracellular HRP injection technique in cats anesthetized with urethane and chloralose. Both NS and WDR neurons were found within the marginal zone of the VB complex. Their somata were confined to the VB complex, but dendrites were extended into the structures of the thalamus surrounding the VB complex. NS neurons were found in the caudal part of the VB complex, whereas WDR neurons were found more rostrally. Examinations of their locations within the marginal zone of the VB complex confirmed the somatotopic organization, as found previously. We also confirmed the previous reports that there are 3 different types of low-threshold mechanoreceptive (LTM) neurons within the VB complex. They are type I, type II and type III neurons. Both NS and WDR neurons were either type I or type II neurons. Obvious morphological differences were not found between LTM neurons and two classes of nociceptive VB neurons investigated.

Animals

Controlled deposition of tantalum powder in a cast of the human airways: applications for aerosol bronchography.

A hollow latex cast of the human larynx and tracheobronchial tree extending to 2 mm diameter airways "inhaled" tantalum powder (mass median aero-dynamic diameter equals 9.2 mum, omicron-g equals 1.41) at 8 liters/min. Tantalum deposited within the cast as predicted by preliminary deposition calculations. These calculations predicted deposition surface densities among greater than 2 mm diam. airways to have a range of similar to 2:1, and also predicted less than 5% alveolar deposition. A deposition surface density of 8 mg/cm-2 provided good bronchographic visualization. Single rice grains located within some airways were distinctly outlined. The small amount of tantalum needed to outline the airways be a simulated voluntary inhalation indicates that tantalum may be suitable for use as a bronchographic contrast medium when administered under strictly controlled exposure conditions.

Aerosols

Mean field stochastic boundary molecular dynamics simulation of a phospholipid in a membrane.

Computer simulations of phospholipid membranes have been carried out by using a combined approach of molecular and stochastic dynamics and a mean field based on the Marcelja model. First, the single-chain mean field simulations of Pastor et al. [(1988) J. Chem. Phys. 89, 1112-1127] were extended to a complete dipalmitoylphosphatidylcholine molecule; a 102-ns Langevin dynamics simulation is presented and compared with experiment. Subsequently, a hexagonally packed seven-lipid array was simulated with Langevin dynamics and a mean field at the boundary and with molecular dynamics (and no mean field) in the center. This hybrid method, mean field stochastic boundary molecular dynamics, reduces bias introduced by the mean field and eliminates the need for periodic boundary conditions. As a result, simulations extending to tens of nanoseconds may be carried out by using a relatively small number of molecules to model the membrane environment. Preliminary results of a 20-ns simulation are reported here. A wide range of motions, including overall reorientation with a nanosecond decay time, is observed in both simulations, and good agreement with NMR, IR, and neutron diffraction data is found.

Computer Simulation

Extension of a binaural cross-correlation model by contralateral inhibition. I. Simulation of lateralization for stationary signals.

Running interaural cross correlation is a basic assumption to model the performance of the binaural auditory system. Although this concept is particularly suited to simulate psychoacoustic localization phenomena, there exist some localization effects which cannot be explained by pure cross correlation. In this paper a model of interaural cross correlation is extended by a "contralateral-inhibition mechanism" and by "monaural detectors" in order to simulate a wide range of psychoacoustic lateralization data. The extended model explains lateralization of pure tones with interaural time differences as well as with interaural level differences. Multiple images are predicted for tones with characteristic combinations of interaural signal parameters and for noise signals with different degrees of interaural cross correlation. The model is also capable of simulating dynamic lateralization phenomena, such as the "law of the first wave front" which is dealt with in a companion paper [Lindemann, J. Acoust. Soc. Am. 80, 1623-1630 (1986)]. The present paper is restricted to a comparison of the model predictions for stationary signals with the results of dichotic listening experiments.

Auditory Perception

Variability of evolutionary rates of DNA.

A statistical analysis of DNA sequences from four nuclear loci and five mitochondrial loci from different orders of mammals is described. A major aim of the study is to describe the variation in the rate of molecular evolution of proteins and DNA. A measure of rate variability is the statistic R, the ratio of the variance in the number of substitutions to the mean number. For proteins, R is found to be in the range 0.16 less than R less than 35.55, thus extending in both directions the values seen in previous studies. An analysis of codons shows that there is a highly significant excess of double substitutions in the first and second positions, but not in the second and third or first and third positions. The analysis of the dynamics of nucleotide evolution showed that the ergodic Markov chain models that are the basis of most published formulas for correcting for multiple substitutions are incompatible with the data. A bootstrap procedure was used to show that the evolution of the individual nucleotides, even the third positions, show the same variation in rates as seen in the proteins. It is argued that protein and silent DNA evolution are uncoupled, with the evolution at both levels showing patterns that are better explained by the action of natural selection than by neutrality. This conclusion is based primarily on a comparison of the nuclear and mitochondrial results.

Animals

Glutamate-immunoreactive terminals synapse on primate spinothalamic tract cells.

Glutamate has been shown to excite spinothalamic tract (STT) neurons and has been localized to primary afferent neurons, spinal cord projection neurons, and interneurons in the spinal cord dorsal horn. The likelihood that glutamate-immunoreactive (GLU-IR) terminals directly innervate STT neurons was investigated. For these studies three lamina IV or V STT cells in the lumbar spinal cords of three monkeys (Macaca fascicularis) were identified electrophysiologically and characterized. Two were identified as high threshold neurons and one as a wide dynamic range neuron. Following intracellular injection of the cells with HRP and reaction to give the cells a Golgi-like appearance, the tissues were processed for electron microscopy. Postembedding immunogold methods with antibodies specific for glutamate were used to identify GLU-IR terminals apposing the somata and dendrites of the STT neurons, including dendrites that extended into laminae IV and III. The GLU-IR terminals were numerous and constituted a mean of 46% of the population counted that appose the STT soma and 50% of the profiles apposing the dendrites. Fifty-four percent of the somatic and 50% of the dendritic surface length was contacted by GLU-IR terminals. Most terminals contained round clear vesicles and some contained a variable number of large dense core vesicles. For one of the three cells examined it was determined that 45% of the terminals apposing the soma were GLU-IR and 30% of the terminals were gamma aminobutyric acid-immunoreactive (GABA-IR). In an additional monkey, a lamina I cell retrogradely labeled from the ventral posterolateral nucleus of the thalamus was found to be ensheathed in glial processes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals

Characterization of synthetic carrier ampholytes by repetitive scanning of the electric field during focusing.

This paper reports the utilization of a potential gradient array detector for monitoring the dynamics of the electric field during isoelectric focusing. Transient and steady state electric field profiles are presented for synthetic carrier ampholyte mixtures with a wide (approximately 3-10) pH range. Two available commercial products (Ampholine and Pharmalyte) and a laboratory synthesized mixture (PEHA ampholytes) are compared. The formation of conductivity gaps and their migration toward the cathode in extended experiments (cathodic drift) can be visualized with this system.

Ampholyte Mixtures

Temperature dependence of the low frequency dynamics of myoglobin. Measurement of the vibrational frequency distribution by inelastic neutron scattering.

Inelastic neutron scattering spectra of myoglobin hydrated to 0.33 g water (D2O)/g protein have been measured in the low frequency range (1-150 cm-1) at various temperatures between 100 and 350 K. The spectra at low temperatures show a well-resolved maximum in the incoherent dynamic structure factor Sinc(q, omega) at approximately 25 cm-1 and no elastic broadening. This maximum becomes gradually less distinct above 180 K due to the increasing amplitude of quasielastic scattering which extends out to 30 cm-1. The vibrational frequency distribution derived independently at 100 and 180 K are very similar, suggesting harmonic behavior at these temperatures. This result has been used to separate the vibrational motion from the quasielastic motion at temperatures above 180 K. The form of the density of states of myoglobin is discussed in relation to that of other amorphous systems, to theoretical calculations of low frequency modes in proteins, and to previous observations by electron-spin relaxation of fractal-like spectral properties of proteins. The onset of quasielastic scattering above 180 K is indicative of a dynamic transition of the system and correlates with an anomalous increase in the atomic mean-squared displacements observed by Mössbauer spectroscopy (Parak, F., E. W. Knapp, and D. Kucheida. 1982. J. Mol. Biol. 161: 177-194.) and inelastic neutron scattering (Doster, W., S. Cusack, and W. Petry, 1989. Nature [Lond.]. 337: 754-756.) Similar behavior is observed for a hydrated powder of lysozyme suggesting that the low frequency dynamics of globular proteins have common features.

Deuterium

Integrative multi-omics and single-cell analysis identifies EGFR pathway activation and metabolic reprogramming as potential synthetic lethal vulnerabilities in resistance to the FGFR inhibitor AZD4547.

BACKGROUND: Although fibroblast growth factor receptor (FGFR) inhibitors (FGFRi) have demonstrated clinical promise, the inevitable emergence of acquired resistance remains a critical bottleneck, severely compromising their long-term clinical efficacy. The pan-cancer molecular landscape and heterogeneous mechanisms driving this resistance, ranging from genetic alterations to dynamic network rewiring, remain poorly understood. METHODS: We integrated large-scale pharmacogenomic profiling of the FGFR inhibitor AZD4547 from the GDSC2 and PRISM databases with single-cell RNA sequencing to dissect the multi-omics landscape of FGFRi resistance across 312 cell lines from 8 cancer types. This multi-omics framework was further extended by machine learning modeling and systematic synthetic lethality screening to uncover actionable therapeutic targets. In vitro viability assays and western blot analysis were subsequently conducted to experimentally evaluate the predicted FGFR-EGFR synthetic lethality. RESULTS: Our dual-database analysis unveiled a multi-dimensional atlas of FGFRi resistance. We identified cancer-specific genomic drivers, such as ELF4 amplification in glioblastoma, alongside key transcriptomic markers including UCP2 and FSCN1, highlighting a shift towards metabolic reprogramming and epithelial-mesenchymal transition (EMT). Single-cell analysis unveiled that resistance is linked to the heterogeneous enrichment of baseline subpopulations characterized by distinct metaprograms, including cell-cycle dysregulation. Furthermore, a random forest model built on a LASSO-derived transcriptomic signature was constructed, demonstrating promising predictive capability for AZD4547 sensitivity (mean test-set AUC = 0.73, 95% CI [0.63, 0.80]); the signature generalized well to erdafitinib but showed limited transferability to some other FGFR inhibitors (e.g. pemigatinib, BGJ398). Most notably, our synthetic lethal screening revealed a convergent reliance on compensatory RTK signaling (specifically EGFR pathway enrichment) and downstream MAPK/PI3K cascades in resistant phenotypes, providing converging computational evidence for EGFR pathway activation as an adaptive bypass mechanism. This predicted synthetic lethality was experimentally supported in two FGFR-dependent cell line models (RT112 and CCLP1), in which combined FGFR-EGFR inhibition produced marked synergistic antiproliferative effects. CONCLUSIONS: This study establishes a comprehensive multi-omics atlas of resistance to the FGFR inhibitor AZD4547, delineating convergent mechanisms of metabolic reprogramming and EGFR-mediated bypass signaling. Our findings characterize the resistance as a dynamic network rewiring and nominate rational combination strategies to overcome this therapeutic bottleneck. While FGFR-EGFR co-inhibition is experimentally supported, metabolic co-targeting remains a computationally derived, hypothesis-generating strategy.

Benzamides

Long-term results of conservative and operative management in complete paraplegics with spinal cord injuries between T10 and L2 with respect to function.

This study analyzed 87 athletes attending the Para Olympic Games at Stoke Mandeville in 1984. All athletes had had complete neurologic lesions between the levels of T10 adn L2. Clinical details were obtained from each athlete. Assessment then consisted of measurement of spinal movement in the sagittal plane using spondylometers and movement in the rotation plane using a rotameter. Body trunk strength was measured with the athletes in their own wheelchairs using a myometer. This gave a recording of kilograms of force. Trunk balance was assessed on both a static and a dynamic basis. The age, sex, follow-up period, and body weight for both spinal fusion and conservatively treated groups were similar. There was little difference in the incidence of pain between those treated by conservative and operative methods. There was statistically significant difference in the range of sagittal plane and rotation movement. There was no difference in flexor trunk power measured with the myometer between the two groups, but when extensor power was measured it was found to be 25% less in the spinal fusion group. There was no difference between the two groups when tested for static and dynamic trunk balance. Two other athletes who had had spinal fusions extending from the upper thoracic region to the sacrum showed unusually poor trunk stability. Overall, this study demonstrates that spinal fusion, particularly over multiple segments in complete paraplegics, has a deleterious effect not only on spinal movement but also on body trunk strength.

Adolescent

Kinetics of charge transfer at the lipid bilayer-water interface on the nanosecond time scale.

Advances in instrumentation allow electrical measurements across the planar lipid bilayer to be made with nanosecond time resolution. The electron transfer reaction between photoexcited magnesium octaethylporphyrin in the lipid to a variety of ionically charged acceptors in the water is found to be purely dynamic over a wide range of concentrations of acceptors and up to the time constant of the apparatus, 4 ns. The saturation of the amplitude of the photovoltage with increasing concentration of acceptor is caused by the finite lifetime of the excited state, not by formation of a static pigment-acceptor complex. The reactions are an excellent probe of the lipid-water interface over an extended time scale. No appreciable barrier to reaction exists at this interface beyond the 5-ns time. That is, any water or choline group structure may be evanescent on this time scale. Electrostatic interactions indicate that the acceptor molecules penetrate to the level of the phosphocholine groups with differing orientations. It will be possible to extend the time scale into the picosecond range by decreasing the response time and by deconvolutions.

Electric Conductivity

Warming-up and stretching for improved physical performance and prevention of sports-related injuries.

Competitive and recreational athletes typically perform warm-up and stretching activities to prepare for more strenuous exercise. These preliminary activities are used to enhance physical performance and to prevent sports-related injuries. Warm-up techniques are primarily used to increase body temperature and are classified in 3 major categories: (a) passive warm-up - increases temperature by some external means; (b) general warm-up - increases temperature by nonspecific body movements; and (c) specific warm-up - increases temperature using similar body parts that will be used in the subsequent, more strenuous activity. The best of these appears to be specific warm-up because this method provides a rehearsal of the activity or event. The intensity and duration of warm-up must be individualised according to the athlete's physical capabilities and in consideration of environmental factors which may alter the temperature response. The majority of the benefits of warm-up are related to temperature-dependent physiological processes. An elevation in body temperature produces an increase in the dissociation of oxygen from haemoglobin and myoglobin, a lowering of the activation energy rates of metabolic chemical reactions, an increase in muscle blood flow, a reduction in muscle viscosity, an increase in the sensitivity of nerve receptors, and an increase in the speed of nervous impulses. Warm-up also appears to reduce the incidence and likelihood of sports-related musculoskeletal injuries. Improving flexibility through stretching is another important preparatory activity that has been advocated to improve physical performance. Maintaining good flexibility also aids in the prevention of injuries to the musculoskeletal system. Flexibility is defined as the range of motion possible around a specific joint or a series of articulations and is usually classified as either static or dynamic. Static flexibility refers to the degree to which a joint can be passively moved to the end-points in the range of motion. Dynamic flexibility refers to the degree which a joint can be moved as a result of a muscle contraction and may therefore not be a good indicator of stiffness or looseness of a joint. There are 3 basic categories of stretching techniques: (a) ballistic--which makes use of repetitive bouncing movements; (b) static--which stretches the muscle to the point of slight muscle discomfort and is held for an extended period; and (c) proprioceptive neuromuscular facilitation - which uses alternating contractions and stretching of the muscles. Each of these stretching methods is based on the neurophysiological phenomenon involving the stretch reflex.(ABSTRACT TRUNCATED AT 400 WORDS)

Athletic Injuries

Solution conformations of human growth hormone releasing factor: comparison of the restrained molecular dynamics and distance geometry methods for a system without long-range distance data.

A series of three-dimensional structures of the 1-29 fragment of human growth hormone releasing factor in trifluoroethanol have been determined by molecular dynamics and distance geometry methods. The resulting structures satisfy information from nuclear Overhauser effect (NOE) distance data and an empirical potential energy function. Although the polypeptide was found to have an ordered structure in all simulations, the NOE data were not sufficient for global convergence to a unique three-dimensional geometry. Several satisfactory structures have been determined, all of which are extended conformations consisting of a short beta-strand and two alpha-helices (residues 6-13 and residues 16-29) connected by short segments of less well defined secondary structure. Because of the lack of NOE data connecting the helix segments, their relative orientation is not uniquely determined.

Growth Hormone-Releasing Hormone

New thermionic detector utilizing orthogonal nebulization for capillary column liquid chromatography.

A new version of the previously studied phosphorus-sensitive, dual-flame thermionic detector has been developed for microcolumn liquid chromatography. The total column effluent is orthogonally nebulized and aspirated directly into a primary air-hydrogen diffusion flame. Phosphorus compounds with molecular weights extending beyond 500 a.m.u. are then selectively detected by measuring the conductivity of the secondary flame in the presence of a rubidium silicate bead. The sensitivity was found to be 1.36 X 10(-11) g phosphorus/sec at the maximum of a Gaussian peak, and the signal increased linearly with concentration over 2 orders of magnitude for dilute samples. Possible mechanisms accounting for the negative orientation of the signal and for the limited dynamic range are discussed.

Chemical Phenomena