Suitability of poroelastic and viscoelastic mechanical models for high and low frequency MR elastography.

PURPOSE: Descriptions of the structure of brain tissue as a porous cellular matrix support application of a poroelastic (PE) mechanical model which includes both solid and fluid phases. However, the majority of brain magnetic resonance elastography (MRE) studies use a single phase viscoelastic (VE) model to describe brain tissue behavior, in part due to availability of relatively simple direct inversion strategies for mechanical property estimation. A notable exception is low frequency intrinsic actuation MRE, where PE mechanical properties are imaged with a nonlinear inversion algorithm. METHODS: This paper investigates the effect of model choice at each end of the spectrum of in vivo human brain actuation frequencies. Repeat MRE examinations of the brains of healthy volunteers were used to compare image quality and repeatability for each inversion model for both 50 Hz externally produced motion and ≈1 Hz intrinsic motions. Additionally, realistic simulated MRE data were generated with both VE and PE finite element solvers to investigate the effect of inappropriate model choice for ideal VE and PE materials. RESULTS: In vivo, MRE data revealed that VE inversions appear more representative of anatomical structure and quantitatively repeatable for 50 Hz induced motions, whereas PE inversion produces better results at 1 Hz. Reasonable VE approximations of PE materials can be derived by equating the equivalent wave velocities for the two models, provided that the timescale of fluid equilibration is not similar to the period of actuation. An approximation of the equilibration time for human brain reveals that this condition is violated at 1 Hz but not at 50 Hz. Additionally, simulation experiments when using the "wrong" model for the inversion demonstrated reasonable shear modulus reconstructions at 50 Hz, whereas cross-model inversions at 1 Hz were poor quality. Attenuation parameters were sensitive to changes in the forward model at both frequencies, however, no spatial information was recovered because the mechanisms of VE and PE attenuation are different. CONCLUSIONS: VE inversions are simpler with fewer unknown properties and may be sufficient to capture the mechanical behavior of PE brain tissue at higher actuation frequencies. However, accurate modeling of the fluid phase is required to produce useful mechanical property images at the lower frequencies of intrinsic brain motions.

Coagulometer international sensitivity index (ISI) derivation, a rapid method using the prothrombin time/international normalized ratio (PT/INR) Line: a multicenter study.

BACKGROUND: The original WHO procedure for prothrombin time (PT) standardization has been almost entirely abandoned because of the universal use of PT coagulometers. These often give different international normalized ratio (INR) results from the manual method, between individual makes of instruments and with instruments from the same manufacture. METHOD: A simple procedure is required to derive local INR with coagulometers. The PT/INR Line method has recently been developed using five European Concerted Action on Anticoagulation (ECAA) certified plasmas to derive local INR. This procedure has been modified to derive a coagulometer PT/INR Line providing International Sensitivity Index (ISI) and mean normal PT (MNPT) for coagulometers and give local INR. Results have been compared with conventional ISI calibrations at the same laboratories. RESULTS: With human thromboplastins, mean ISI by local calibration was 0.93 (range: 0.77-1.16). With the PT/INR Line, mean coagulometer ISI was higher, for example 0.99 (0.84-1.23) but using the PT/INR Line derived MNPT there was no difference in local INR. Between-centre INR variation of a certified validation plasma was reduced with human and bovine reagents after correction with local ISI calibrations and the PT/INR Line. CONCLUSION: The PT/INR Line-ISI with its derived MNPT is shown to provide reliable local INR with the 13 different reagent/coagulometer combinations at the 28 centres in this international study.

An octahedral shear strain-based measure of SNR for 3D MR elastography.

A signal-to-noise ratio (SNR) measure based on the octahedral shear strain (the maximum shear strain in any plane for a 3D state of strain) is presented for magnetic resonance elastography (MRE), where motion-based SNR measures are commonly used. The shear strain, γ, is directly related to the shear modulus, µ, through the definition of shear stress, τ = µÎ³. Therefore, noise in the strain is the important factor in determining the quality of motion data, rather than the noise in the motion. Motion and strain SNR measures were found to be correlated for MRE of gelatin phantoms and the human breast. Analysis of the stiffness distributions of phantoms reconstructed from the measured motion data revealed a threshold for both strain and motion SNR where MRE stiffness estimates match independent mechanical testing. MRE of the feline brain showed significantly less correlation between the two SNR measures. The strain SNR measure had a threshold above which the reconstructed stiffness values were consistent between cases, whereas the motion SNR measure did not provide a useful threshold, primarily due to rigid body motion effects.

The prothrombin time/international normalized ratio (PT/INR) Line: derivation of local INR with commercial thromboplastins and coagulometers--two independent studies.

BACKGROUND: The WHO scheme for prothrombin time (PT) standardization has been limited in application, because of its difficulties in implementation, particularly the need for mandatory manual PT testing and for local provision of thromboplastin international reference preparations (IRP). METHODS: The value of a new simpler procedure to derive international normalized ratio (INR), the PT/INR Line, based on only five European Concerted Action on Anticoagulation (ECAA) calibrant plasmas certified by experienced centres has been assessed in two independent exercises using a range of commercial thromboplastins and coagulometers. INRs were compared with manual certified values with thromboplastin IRP from expert centres and in the second study also with INRs from local ISI calibrations. RESULTS: In the first study with the PT/INR Line, 8.7% deviation from certified INRs was reduced to 1.1% with human reagents, and from 7.0% to 2.6% with rabbit reagents. In the second study, deviation was reduced from 11.2% to 0.4% with human reagents by both local ISI calibration and the PT/INR Line. With rabbit reagents, 10.4% deviation was reduced to 1.1% with both procedures; 4.9% deviation was reduced to 0.5% with bovine/combined reagents with local ISI calibrations and to 2.9% with the PT/INR Line. Mean INR dispersion was reduced with all thromboplastins and automated systems using the PT/INR Line. CONCLUSIONS: The procedure using the PT/INR Line provides reliable INR derivation without the need for WHO ISI calibration across the range of locally used commercial thromboplastins and automated PT systems included in two independent international studies.

Effects of frequency- and direction-dependent elastic materials on linearly elastic MRE image reconstructions.

The mechanical model commonly used in magnetic resonance elastography (MRE) is linear elasticity. However, soft tissue may exhibit frequency- and direction-dependent (FDD) shear moduli in response to an induced excitation causing a purely linear elastic model to provide an inaccurate image reconstruction of its mechanical properties. The goal of this study was to characterize the effects of reconstructing FDD data using a linear elastic inversion (LEI) algorithm. Linear and FDD phantoms were manufactured and LEI images were obtained from time-harmonic MRE acquisitions with variations in frequency and driving signal amplitude. LEI responses to artificially imposed uniform phase shifts in the displacement data from both purely linear elastic and FDD phantoms were also evaluated. Of the variety of FDD phantoms considered, LEI appeared to tolerate viscoelastic data-model mismatch better than deviations caused by poroelastic and anisotropic mechanical properties in terms of visual image contrast. However, the estimated shear modulus values were substantially incorrect relative to independent mechanical measurements even in the successful viscoelastic cases and the variations in mean values with changes in experimental conditions associated with uniform phase shifts, driving signal frequency and amplitude were unpredictable. Overall, use of LEI to reconstruct data acquired in phantoms with FDD material properties provided biased results under the best conditions and significant artifacts in the worst cases. These findings suggest that the success with which LEI is applied to MRE data in tissue will depend on the underlying mechanical characteristics of the tissues and/or organs systems of clinical interest.

Time-harmonic magnetic resonance elastography of the normal feline brain.

Imaging of the mechanical properties of in vivo brain tissue could eventually lead to non-invasive diagnosis of hydrocephalus, Alzheimer's disease and other pathologies known to alter the intracranial environment. The purpose of this work is to (1) use time-harmonic magnetic resonance elastography (MRE) to estimate the mechanical property distribution of cerebral tissue in the normal feline brain and (2) compare the recovered properties of grey and white matter. Various in vivo and ex vivo brain tissue property measurement strategies have led to the highly variable results that have been reported in the literature. MR elastography is an imaging technique that can estimate mechanical properties of tissue non-invasively and in vivo. Data was acquired in 14 felines and elastic parameters were estimated using a globo-regional nonlinear image reconstruction algorithm. Results fell within the range of values reported in the literature and showed a mean shear modulus across the subject group of 7-8 kPa with all but one animal falling within 5-15 kPa. White matter was statistically stiffer (p<0.01) than grey matter by about 1 kPa on a per subject basis. To the best of our knowledge, the results reported represent the most extensive set of estimates in the in vivo brain which have been based on MRE acquisition of the three-dimensional displacement field coupled to volumetric shear modulus image reconstruction achieved through nonlinear parameter estimation. However, the inter-subject variation in mean shear modulus indicates the need for further study, including the possibility of applying more advanced models to estimate the relevant tissue mechanical properties from the data.

Comparison of local International Sensitivity Index calibration and 'Direct INR' methods in correction of locally reported International Normalized Ratios: an international study.

BACKGROUND: It is no longer feasible to check local International Normalized Ratios (INR) by the World Health Organization International Sensitivity Index (ISI) calibrations because the necessary manual prothrombin time technique required has generally been discarded. OBJECTIVES: An international collaborative study at 77 centers has compared local INR correction using the two alternative methods recommended in the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis guidelines: local ISI calibration and 'Direct INR'. METHODS: Success of INR correction by local ISI calibration and with Direct INR was assessed with a set of 27 certified lyophilized plasmas (20 from patients on warfarin and seven from normals). RESULTS: At 49 centers using human thromboplastins, 3.0% initial average local INR deviation from certified INR was reduced by local ISI calibration to 0.7%, and at 25 centers using rabbit reagents, from 15.9% to 7.5%. With a minority of commercial thromboplastins, mainly 'combined' rabbit reagents, INR correction was not achieved by local ISI calibration. However, when rabbit combined reagents were excluded the overall mean INR deviation after correction was reduced further to 3.9%. In contrast, with Direct INR, mean deviation using human thromboplastins increased from 3.0% to 6.6%, but there was some reduction with rabbit reagents from 15.9% to 10% (12.3% with combined reagents excluded). CONCLUSIONS: Local ISI calibration gave INR correction for the majority of PT systems but failed at the small number using combined rabbit reagents suggesting a need for a combined reference thromboplastin. Direct INR correction was disappointing but better than local ISI calibration with combined rabbit reagents. Interlaboratory variability was improved by both procedures with human reagents only.

[Genetic and microbiologic tests in periodontal disease]. / Test genetico e microbiologico nella malattia parodontale.

AIM: The presence of genetic polymorphisms IL-1A and IL-1B was demonstrated to be associated to an increased clinical severity of Periodontitis. The aim of our study was to verify the existence of a relationship between such genetic polymorphisms and pathogenic variations of Actinobacillus actinomycetemcomitans (Aa), Prevotella intermedia (Pi) and Porphyromonans gingivalis (Pg), in patients with periodontitis before and after active therapy. METHODS: Twenty-five patients were randomly selected among those attending the Department of Periodontology, University of Bologna, on the basis of radiographic and clinical data. At the end of active therapy, subjects had to undergo "PST" test. RESULTS: The "PST" was positive in 32% (8 out of 25) of patients; the majority of them (4 out of 8) were classified ADA IV, 3 were ADA III and 1 was ADA I (p > 0.05). All subjects with good hygiene therapy (13 out of 24 patients) have shown a reduced bacterial count after active clinical therapy (Fisher test p = 0.03). CONCLUSION: No statistically significant association was observed between positivity to "PST" and severity of periodontal disease.

Povidone-iodine as a periodontal pocket disinfectant.

OBJECTIVES AND BACKGROUND: Povidone-iodine [polyvinylpyrrolidone-iodine complex (PVP-iodine)] might constitute a valuable adjunct to current periodontal therapy because of its broad-spectrum antimicrobial activity, low potential for developing resistance and adverse reactions, wide availability, ease of use, and low financial cost. This investigation employed a randomized, split-mouth study design to determine the microbiological and clinical effects of 10% PVP-iodine subgingival irrigation in periodontitis lesions showing radiographic evidence of subgingival calculus. METHODS: Sixteen adults having at least one periodontal pocket of 6 mm or more in each quadrant of the dentition and harboring one or more periodontopathic bacteria participated in the study. In each subject, a study site in each quadrant was randomly chosen to receive either subgingival irrigation with 10% PVP-iodine together with scaling and root planing, scaling and root planing alone, subgingival irrigation with 10% PVP-iodine, or subgingival irrigation with sterile saline. Prior to therapy and at 5 weeks post-treatment, microbiological culture was carried out without knowledge of the clinical status or the type of treatment rendered. A blinded clinical examiner determined presence of dental plaque, probing pocket depth, and gingival bleeding on probing. Microbiological and clinical data were analyzed using a repeated measures analysis of variance and Kruskal-Wallis rank test with the Tukey and Mann-Whitney post hoc tests. RESULTS: At 5 weeks post-treatment, subgingival irrigation with PVP-iodine together with scaling and root planing caused a 95% or greater reduction in total pathogen counts in 44% of pockets having >/= 6 mm depth whereas scaling and root planing alone, povidone-iodine irrigation alone and water irrigation alone caused 95% reduction of total pathogens only in 6-13% of similar study sites (P = 0.02). Reduction in mean pocket depth was 1.8 mm for the PVP-iodine/scaling and root planing group, 1.6 mm for the scaling and root planing group, and 0.9 mm for the PVP-iodine and the saline monotherapy groups, with statistical significance reached for the scaling and root planing group vs. the PVP-iodine group (P = 0.04) and for the scaling and root planing group vs. the saline group (P = 0.02). Reduction in visible dental plaque, which ranged from 38% to 62%, showed no significant differences among treatment groups. CONCLUSIONS: The addition of subgingival PVP-iodine irrigation to conventional mechanical therapy may be a cost-effective means of reducing total counts of periodontal pathogens and helping control periodontal disease. However, subgingival irrigation with PVP-iodine without concomitant mechanical debridement might not improve microbiological and clinical variables in comparison with saline irrigation, at least not in sites with radiographic evidence of subgingival calculus.

Basic fibroblast growth factor within endothelial cells during vascularization of the anterior pituitary.

BACKGROUND: Basic fibroblast growth factor (FGF-2), a potent angiogenic peptide, is known to be present in gonadotropes of the anterior pituitary parenchyma of rats and mice, and has been isolated from endothelial cells of many organs. Its localization within endothelial cells has not been determined, nor the mechanisms by which it might be released from endothelial cells during normal organogenesis. METHODS: Localization of FGF within endothelial cells of the anterior pituitary was accomplished by immunocytochemistry and studied by light- and electron microscopy. Capillaries within the anterior pituitary were studied in fetal rats from day 15 to term, and in adult rats. RESULTS: At the onset stages of vascularization (15-18 days fetal), the cytoplasm of the endothelial cells of many of the invading, immature capillaries (thick-walled with few or no fenestrations) was intensely immunopositive for FGF. Immunoprecipitate-filled blebs and slender cytoplasmic processes projected from the endothelial cells into the presumptive pericapillary space and toward the parenchymal cells. As gestation progressed (19-20 day fetal), and an increasing number of capillaries acquired the features characteristic of capillaries in the anterior pituitary of adult animals, i.e., thin-walled and fenestrated, there were fewer capillaries demonstrating immunopositivity for FGF. Foci of released FGF, i.e., extracellular, were occasionally evident within the presumptive pericapillary spaces throughout gestation. By comparison, capillaries of the anterior pituitary of adult rats did not contain immunostainable FGF in their cytoplasm, nor were any blebs and/or processes filled with immunoprecipitate evident. However capillaries did reveal an immunopositive enhancement of their lumenal and ablumenal surfaces. CONCLUSIONS: During vascularization of the anterior pituitary, FGF within the cytoplasm of endothelial cells is released from blebs and/or processes of endothelial cells, and after the capillary bed is stabilized postnatally, these characteristics of vascularization are absent.

Breast cancer angiogenesis--new approaches to therapy via antiangiogenesis, hypoxic activated drugs, and vascular targeting.

Several groups have shown that quantitation of tumor angiogenesis by counting blood vessels in primary breast cancer gives an independent assessment of prognosis. Poor prognosis is associated with high blood vessel counts. We have shown that the rate of cell division in endothelial cells is much higher in breast tumours than in normal breast. Breast cancer cell lines and primary human breast tumours express a wide range of vascular growth factors, including VEGF, placenta growth factor, pleiotrophin, TGF beta 1, acidic and basic FGF, and platelet-derived endothelial cell growth factor. Inhibiting angiogenesis by blocking vascular growth factors would be difficult with highly specific agents, but drugs with a broader spectrum of antagonism may be effective. We have developed several suramin analogues which are less toxic than suramin in vivo but more potent in inhibiting angiogenesis, and these have been developed for Phase I. A combination of anti-angiogenesis agents with drugs activated by hypoxia may also be useful, because anti-angiogenesis alone may not kill cells, whereas activation of hypoxic drugs could synergize. New endpoints may be necessary because inhibition of new blood vessel formation may not cause tumour regression. Thus, the endpoint of stable disease and biochemical assessment of inhibition of angiogenesis may be much more important in therapeutic studies and for drug development in the future. The prognostic importance of angiogenesis suggests that this should be a major new therapeutic target.

Development of the vasculature of the anterior pituitary: ontogeny of basic fibroblast growth factor.

This study correlates the ontogeny of basic fibroblast growth factor (FGF) with the development of the vasculature of the anterior pituitary (AP) in two strains of rat, Sprague-Dawley (SD) and Fischer 344 (F344). Immunolocalization of FGF was followed from the first appearance of Rathke's pouch (RP) in 12-day (12d) fetuses, through each day of fetal development, and in 5, 20, and 50d postnatal female rats. In addition, the ontogeny of folliculo-stellate cells (FSC) is described, since previous studies suggested that these unique cells might function as phagocytes in the regulation of FGF. In both rat strains, vascularization of the AP commenced in 16d fetuses. In 15-20d fetuses, dense foci of immunopositivity for extracellular FGF were apparent at sites of capillary penetration adjacent to partially disrupted, immature gonadotropes. Localization of FGF was first detected in immature gonadotropes in 18d fetuses and persisted in the cytosol of a subpopulation of gonadotropes thereafter. In 15d fetuses, FGF was localized within the cytosol intimately associated with the peripheral-facing plasma membranes of all cells of the adenohypophysis, and persisted to variable degrees in later fetal stages. Localization of FGF within nuclei of AP parenchymal cells was evident only in 16-17d fetuses. Although the ontogeny of FGF and vascularization of the AP was very similar in both rat strains, the ontogeny of FSC differed markedly. In both strains, follicular lumens contained FGF during late fetal and early postnatal development. However, both electron microscopy and immunostaining for S-100 marker protein revealed that the postero-lateral edges of the AP of F344 rats often lacked FSC when compared to SD rats, a situation which could compromise regulation of FGF by FSC at the AP periphery in that strain, and thereby contribute to the neovascularization from systemic blood vessels known to occur in that strain during prolactinoma formation.

Andrew Pattison meeting the challenge of medicine today.

The common thread of medical education tends to tie up the many diverse interests that constitute Andrew Pattison's working week. Although he has diversified into health education for the masses through his Doctor Toby books and his talkback radio segments, he maintains contact with his grassroots through his general practice patients.

Pars distalis vasculature: Discovery Shuttle STS-29 rats compared to ground-based antiorthostatic rats.

The anterior pituitary glands of male, adult Long Evans rats carried 5 days in the Space Shuttle Discovery (STS-29) have been compared with two groups of ground-based controls. All of the animals were part of a study (SE82-08) into the effects of gravity versus a microgravity environment on fracture healing. All had sustained a right, mid-shaft fibular osteotomy. The duration of the study was 10 days, and animals in all groups were weight bearing for the 5 days prior to shuttle lift off. The three experimental groups consisted of four rats each: flight (F) and two ground-based control groups, weight bearing (WB) and suspended (S). The suspension group was in a Holton/Sweeney head-down suspension apparatus (antiorthostatic) for the final 5 days of the study. The anterior pituitary glands of F and WB rats were essentially identical. The vasculature and parenchymal cells appeared unaffected in both instances. However, the anterior pituitary glands of S rats were dramatically altered. The vasculature was widely expanded with proteinaceous deposition covering the lumenal endothelial surfaces, and entrapping numerous platelets and aggregates of red blood cells. Parenchymal cells were highly vacuolated, occasionally with membranous vacuoles, but most often revealing large, clear cytoplasmic zones unlined by any membranes. Whereas profiles of exocytosis were numerous in F rats, and present in WB rats, they were essentially absent in S rats. These results indicate that weightlessness over a 5-day flight period does not influence the structural integrity of the anterior pituitary gland and may in fact promote secretory granule release. However, the head-down tilt model, frequently used to study fracture repair under conditions that mimic weightlessness, has a profound impact on the vasculature of the anterior pituitary gland which then affects the structural and functional characteristics of the parenchymal cells.

A comparison of the effects of three positive inotropic agents (amrinone, milrinone and medorinone) on platelet aggregation in human whole blood.

Amrinone, milrinone and medorinone inhibit platelet aggregation in human whole blood. They are particularly potent inhibitors of arachidonic acid induced aggregation, inhibiting by 50% (IC50) at concentrations of 1.5 microM (milrinone), 7.5 microM (medorinone) and 48 microM (amrinone). Each drug was less potent at inhibiting ADP and collagen-induced aggregation. The rank order for inhibition of arachidonic acid - induced aggregation correlated well with the rank order of cyclic AMP phosphodiesterase inhibition for these drugs when compared to the response of a reference cAMP phosphodiesterase inhibitor (CI-930) and a reference cGMP phosphodiesterase inhibitor (M & B 22948). Since inhibition of platelet aggregation in vitro occurred at clinically relevant concentrations, it is evident that these agents have potentially beneficial antithrombotic properties.

The comparative pharmacokinetics and gastric toxicity of bezafibrate and ciprofibrate in the rat.

1. The comparative gastric toxicology and pharmacokinetics of two phenoxyisobutyrate derivatives have been evaluated in the Fischer rat. 2. After oral administration of single daily doses for 7 days, the plasma elimination half-life for bezafibrate was rapid (t1/2 of 4-5 h) in comparison to ciprofibrate (t1/2 of 76 h). 3. The area under the plasma drug concentration versus time curve (AUC) 0-24 (micrograms.h/ml +/- SD) for bezafibrate (dose 125 mg/kg per day) was 1553 +/- 334, which was less than half the value of 3748 +/- 358 achieved by ciprofibrate (10 mg/kg per day) after 7 days. 4. Oral administration of ciprofibrate at 10 mg/kg every 48 h produced similar sustained plasma concentrations to those achieved by bezafibrate 125 mg/kg dosed every 12 h. The AUC 0-48 values (micrograms.h/ml +/- SD) achieved were 5124 +/- 450 for bezafibrate compared to 4207 +/- 240 for ciprofibrate. 5. In chronic oral multidose studies with ciprofibrate and bezafibrate, similar gastric toxicity (neuroendocrine cell hyperplasia) occurred in the rat when dose regimens were adjusted to compensate for the pharmacokinetic differences between these two drugs.

The trophic effects of gastrin on fundic neuroendocrine cells of the rat stomach.

The histomorphological effect of multidose administration of 6 mg/kg pentagastrin b.d. for 5 weeks, and 1000 mg/kg sodium bicarbonate b.d. for 13 weeks, on the rat fundic mucosa has been examined. Sodium bicarbonate induced a significant hypergastrinaemia (plasma gastrin concentrations were 370.5 pg/ml in the control versus 642.6 pg/ml in sodium bicarbonate-treated rats after 13 weeks, P less than 0.01). Both treatment regimens induced fundic neuroendocrine cell hyperplasia. The cellular proliferation that occurred following hypergastrinaemia of endogenous or exogenous origin suggests that systemic gastrin concentrations play a major role in the control of fundic neuroendocrine cell populations.