Cardiac Mechanoenergetics Replicated by Cross-Bridge Model

The aim of this work is to reproduce the experimentally measured linear dependence of cardiac muscle oxygen consumption on stress–strain area using a model, composed of a three-state Huxley-type model for cross-bridge interaction and a phenomenological model of Ca²⁺-induced activation. By selecting particular cross-bridge cycling rate constants and modifying the cross-bridge activation model, we replicated the linear dependence between oxygen consumption and stress–strain area together with other important mechanical properties of cardiac muscle such as developed stress dependence on the sarcomere length and force-velocity relationship. The model predicts that (1) the amount of the passenger cross bridges, i.e., cross bridges that detach without hydrolyzing ATP molecule, is relatively small and (2) ATP consumption rate profile within a beat and the amount of the passenger cross bridges depend on the contraction protocol. © 2000 Biomedical Engineering Society. PAC00: 8719Rr, 8719Ff, 8710+e, 8719Hh     

Is hydroxyapatite cement an alternative for allograft bone chips in bone grafting procedures? A mechanical and histological study in a rabbit cancellous bone defect model

To evaluate in vivo performance of hydroxyapatite cement (HAC) as a porous bone graft substitute, HAC was mixed (1:1 ratio) with either porous calcium-phosphate granules (80% tricalcium phosphate, 20% hydroxyapatite) or defatted morsellized cancellous bone (MCB) allograft and implanted bilaterally in cylindrical drill holes in distal femurs of rabbits. Groups with empty defects and impacted MCB were used for reference. After 8 weeks, one femur from each pair was examined histologically. All contralateral specimens and Time-0 specimens were used for mechanical indentation tests. Histology showed that some empty defects were filled with newly formed osteopenic bone after 8 weeks. The impacted MCB showed remodeling into new vital bone. Incorporation of the HAC/MCB composite was incomplete, whereas minimal new bone ingrowth was found in the HAC/granule composites. Though not different from each other, both composites were significantly stronger than empty defects, incorporated impacted MCB, and intact cancellous bone. At Time 0, the mechanical behavior of impacted MCB was similar to both HAC composites. In conclusion, composites of HAC and porous biomaterials can maintain relatively high strength over 8 weeks in vivo, but their incorporation into a new bony structure is slower than impacted MCB. The HAC/MCB composite showed favorable incorporation behavior.     

Prediction of life expectancy in patients with spinal epidural metastasis

Background

The treatment of spinal epidural metastasis is multidisciplinary and usually involves a team of medical oncologists, radiologists, radiotherapists, and spinal surgeons. Life expectancy is one of the factors considered when deciding whether surgery is warranted. Because expert estimates of life expectancy are generally not reliable, a prediction model is needed. Here, we temporally validated a model that was previously validated geographically.

Methods

The records of 110 consecutive patients who were referred with a spinal epidural metastasis were collected prospectively from 2009 to 2013 in order to validate the model, which was published in 2011. The actual and estimated life expectancies were represented graphically, and calibration and discrimination were determined. The calibration slope, Harrell''s c-index, D, and RD2 were calculated. Hazard ratios in the derivation set of 2011 were compared with the validation set. Misspecification was determined using the joint test for β*.

Results

The calibration slope was 0.64 ± 0.15 (95% CI: 0.34–0.94), Harrell''s c-index was 0.72, D was 1.08, and RD2 was 0.22, indicating slightly worse discrimination in the derivation set. The joint test for β* = 0 was statistically significant and indicated misspecification; however, this misspecification was attributed entirely to the surgical group.

Conclusions

We validated a prediction model for surgical decision making, showing that the model''s overall performance is good. Based on these results, this model will help clinicians to decide whether to offer surgery to patients with spinal epidural metastasis.     

Kinematic analysis of left ventricular deformation in myocardial infarction using magnetic resonance cardiac tagging

The Magnetic Resonance (MR) tagging technique provides detailed information about 2D motion in the plane of observation. Interpretation of this information as a reflection of the 3D motion of the entire cardiac wall is a major problem. In finite element models of the mechanics of the infarcted heart, an infarcted region causes motional asymmetry, extending far beyond the infarct boundary. Here we present a method to quantify such asymmetry inamplitude and orientation. For this purpose images of a short-axis cross-section of the ejecting left ventricle were acquired from 9 healthy volunteers and 5 patients with myocardial infarction. MR-tags were applied in a 5 mm grid at end-diastole. The tags were tracked by video-image analysis. Tag motion was fitted to a kinematic model of cardiac motion. For the volunteers and the patients the center of the cavity displaced by about the same amount(p=0.11) during the ejection phase: 3.8 ± 1.4 and 3.0 ± 0.9 mm (mean ± sd), respectively. Cross-sectional rotation and the decrease in cross-sectional area of the cavity were both greater in the volunteers than in the patients: 6.4 ± 1.5 vs. 3.0 ± 0.8 degrees (p<0.001), and 945 ± 71 vs. 700 ± 176 mm 2 (p=0.02), respectively. In the patients, asymmetry of wall motion, as expressed by a sine wave dependency of contraction around the circumference, was significantly enlarged (p=0.02). The proposed method of kinematic analysis can be used to assess cardiac deformation in humans. We expect that by analyzing images of more cross-sections simultaneously, the 3D location and the degree of infarction can be assessed efficiently.     

6-hydroxydopamine lesion in the A8 cell group of cats produces a short-lasting decreased accuracy in goal-directed forepaw-movements.

Recently, feline studies have shown that a lesion in the retrorubral area, which includes the dopaminergic A8 cell group, produces motor programming deficits inherent to a hypofunction of the A9 system. A hypofunction in the striatal terminal area of A9 fibers, in turn, is known to produce a hypofunction of its first-order output station, namely the substantia nigra pars reticulata (SNR). The integrity of the SNR allows animals to execute (1) 'postural adjustments that rely on proprioceptive stimuli that originate in body parts at rest' and (2) 'non-externally guided' targeting movements. In view of these considerations, the (dys)function of the SNR of cats with a bilaterally 6-hydroxydopamine lesion of A8 cells in the retrorubral area was tested in an experimental set-up that allows the assessment of changes in these functions. The A8 lesion produced: (a) a short-lasting increase in the number of accurate targeting movements as well as an increase in the time required for the collection of six pellets: these deficits disappeared 4-7 days after the lesion; (b) a long-lasting disappearance of (1) 'postural adjustments that rely on proprioceptive stimuli that originate in body parts at rest' and (2) 'non-externally guided targeting movements'; and (c) a long-lasting display of a new strategy that allowed the lesioned cat to collect its pellets despite of its other deficits. These data led to the conclusion that a lesion of A8 cells even disrupts the function of the SNR, being one of the outputstations of the A8 cell group.     

Defects in mismatch repair occur after APC mutations in the pathogenesis of sporadic colorectal tumours

The roles of the intrinsic mutation rate and genomic instability in tumorigenesis are currently controversial. In most colorectal tumours, it is generally supposed that the first mutations occur at the adenomatous polyposis coli (APC) locus; APC mutations are thought to provide cells with a selective advantage but have no known effect on the mutation rate. It has also been suggested that genomic instability is the initiating event in colorectal tumorigenesis and, if this is true, mutations of DNA mismatch repair (MMR) genes (or at similar loci) are the most likely candidates. If defective MMR precedes APC mutations, the APC mutations of colon tumours with defective MMR and hence replication errors (RER+) should differ from those of RER- tumours, in at least three specific ways: (1) a higher frequency of allele loss at APC in RER- tumours; (2) more frameshift than nonsense mutations in RER+ tumours; and (3) APC mutations in simple repeat sequences [(N)_n, (N₁N₂)_n, or (N₁N₂N₃)_n] in RER+ tumours. We found no evidence that sporadic RER+ and RER- colon cancers (including cell lines) differ in any of these three ways. Although it remains possible that MMR is abnormal in tumours from HNPCC families before APC mutations occur, it is likely that in sporadic colon tumours, APC mutations, rather than genomic instability, are the initiating events in tumorigenesis. Hum Mutat 11:114–120, 1998. © 1998 Wiley-Liss, Inc.     

Tracking a century of global expansion and evolution of HIV to drive understanding and to combat disease

Since the isolation of HIV, multiple transmissions are thought to have occurred between man and other old-world primates. Assessment of samples from apes and human beings with African equatorial forest ancestry has traced the origin of HIV-1 to chimpanzees, and dated its most recent common ancestor to 1908. The evolution of HIV-1 has been rapid, which has resulted in a complex classification, worldwide spread, and intermixing of strains; at least 48 circulating recombinant forms are currently identified. In addition to posing a nearly insurmountable challenge for diagnosis, treatment, vaccine development, and prevention, this extreme and divergent evolution has led to differences in virulence between HIV-1 groups, subtypes, or both. Coincidental changes in human migration in the Congo river basin also affected spread of disease. Research over the past 25 years and advances in genomic sequencing methods, such as deep DNA sequencing, have greatly improved understanding and analysis of the thousands to millions of full infectious HIV-1 genomes.     

Rumination or belching–regurgitation? Differential diagnosis using oesophageal impedance–manometry

Background Rumination is an eating disorder clinically suspected in the presence of chronic regurgitation of recently ingested food with subsequent re‐mastication and swallowing. Oesophageal manometry is currently used to confirm the diagnosis, however, it is difficult to distinguish rumination from postprandial belching‐regurgitation, being the manometric pattern identical in both situations. Oesophageal impedance allows recognition between liquid and gas gastro‐oesophageal reflux. Our aims were (i) to improve diagnosis of rumination using combined impedance–manometry (ii) to assess the gastro‐oesophageal pressure‐flow pattern in rumination events. Methods Sixteen patients with clinically suspected rumination underwent impedance–manometry monitoring for 1 h after a solid liquid meal. Manometry was first analysed blindly to the impedance pattern. All events marked by the patients and straining episodes were identified. After the manometric analysis, impedance tracings were unblinded and each straining episode was analysed for presence of liquid and/or gas oesophageal retrograde flow. Only rumination events were included for additional evaluation. Key results Postprandial manometry showed a pattern compatible with rumination in 12/16 patients. In total, impedance–manometry confirmed the clinical diagnosis of rumination in eight of the 16 patients with clinical suspicion of rumination. In 102 clearly identified rumination events, the onset of gastric strain (manometry) occurred before the onset of oesophageal liquid retroflow (impedance) in 58% of cases or simultaneously in 37% of cases. In most cases (86%), oesophageal retrograde flow started after an initial increase in abdominal pressure but before the peak gastric strain pressure. Conclusions & Inferences Postprandial impedance–manometry monitoring improves diagnosis of rumination because it allows distinction between rumination and postprandial belching and regurgitation. During rumination, oesophageal liquid retrograde flow is first driven by an early small rise in intragastric pressure preceding the peak pressure observed during straining.