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Perspectives on growth factors and orofacial development.

Despite the fact that orofacial clefts represent one of the most common birth defects, the molecular mechanisms by which the embryonic primordia of the midface grow and differentiate are not completely understood. A multiplicity of genes must be expressed and their protein products must interact in a highly orchestrated fashion to affect normal orofacial development. Several families of growth factors have emerged as key contributors to the choreography of cellular and tissue interactions contributing to morphogenesis of the orofacial region. This overview focuses on those growth factors that are generally accepted as playing a pivotal role in normal as well as abnormal development of first branchial arch-derived structures. Particular emphasis is given transforming growth factor-beta (TGF beta) and TGF alpha family members, as these have been the most extensively investigated with regard to their role in development of orofacial structures. Consideration is also given to evidence implicating developmental contributions from members of the bone morphogenetic protein and fibroblast growth factor families.

Animals↗

Consequences of elevated homocysteine during embryonic development and possible modes of action.

Elevated maternal homocysteine (Hcys) is a well-established risk factor for embryonic toxicity and the development of congenital defects, particularly neural tube closure defects and neurocristopathies. The mechanisms responsible are unclear but early work has focused on the role of folate metabolism because these defects are greatly reduced by folate supplementation. As a consequence, elevated Hcys is often looked upon as being an indirect consequence of faulty folate metabolism, although more recent studies show Hcys may act directly as a teratogen. Because Hcys is at the crossroads of protein and DNA metabolism, has a propensity to chemically modify proteins directly, can generate free radicals, and even perturb ligand binding to certain receptors, the developmental processes Hcys can potentially disturb are enumerable. But in recent years, investigators have begun identifying cellular and molecular targets for the direct action of Hcys. While elevating Hcys can alter a myriad of basic cellular activities needed for normal development, our current understanding as to the specific etiological mechanisms responsible for congenital defects is very speculative. Here we provide an overview of what is currently known regarding the toxicity and teratogenicity of elevated Hcys during embryonic development, paying particular attention to neural tube and neural crest cell morphogenesis.

Embryonic and Fetal Development↗

Finite element model of facial soft tissue. Effects of thickness and stiffness on changes following simulation of orthognathic surgery.

A study was conducted to investigate the influence of the thickness and stiffness of soft tissue on changes following orthognathic surgery. The finite element method was used to simulate surgery. Three finite element models with normal thickness and stiffness, twice the thickness and twice the stiffness were made in preparation for the simulation. The thickness of soft tissue had more effect than stiffness on posterior and vertical changes.

Cephalometry↗

Glucose concentration in subcutaneous extracellular space.

OBJECTIVE: To compare the subcutaneous glucose sensor measurements with two reference methods. Previous studies provide conflicting findings about the real glucose concentrations in subcutaneous tissue. Some suggest substantially lower concentration, whereas others measure proportionally higher glucose concentrations compared with the blood compartment. Before these results can be taken seriously as an expression of the real glucose concentration in the extracellular space, the measurements must be validated by an independent method. RESEARCH DESIGN AND METHODS: We applied a microdialysis-based enzyme sensor to measure glucose concentration in subcutaneous tissue. We also developed two reference methods: subcutaneous filtrate collection and an equilibration method using ultrafiltration membranes to support the earlier findings. We provided an anatomical model to explain the results. RESULTS: The mean overall intercellular filtrate glucose concentration, sampled with the filtrate collector and taken after a 6-h stabilization time, including the values during the glucose clamp period, was 46 +/- 9%. The mean subcutaneous glucose concentration measured with the glucose sensor, calibrated in vitro, was 44 +/- 8% of the mean venous blood glucose concentration. Mean overall intercellular equilibrate glucose concentration, i.e., the mean glucose concentration in the subcutaneous extracellular space, taken after a 4-h stabilization time, was 46 +/- 15% of the mean venous blood glucose concentration. CONCLUSIONS: The close agreement between the mean values of subcutaneous glucose concentrations, obtained with three independent methods--filtration, equilibration, and dialysis (sensor)--shows the real glucose concentration in subcutaneous interstitial fluid is approximately 50% the blood glucose value in normal humans. Our results clarify some of the conflicting evidence presented in previous studies.

Adult↗

Endometriosis: harmful survival of an ectopic tissue.

Endometriosis results from implantation of endometrial tissue outside the uterine cavity. Endometriosis might remain asymptomatic and discovered accidentally. However, it may cause symptoms, which include chronic pelvic pain, bleeding, infertility, and increases susceptibility to development of adenocarcinoma. The most prevailing hypothesis is that endometriosis results from implantation of endometrial tissue that gains access to peritoneal cavity by retrograde flow during menstruation. The factors contributing to the establishment and persistence of the endometriotic lesions (plaques) most probably include abnormalities of the genital tract, genetic predisposition, hormonal imbalance, altered immune surveillance, inflammatory response and abnormal regulation of the endometrial cells. The mediators that contribute to survival and progression of endometriosis are likely involved in the development of the symptoms of this process. Genomic studies have started to delineate the wide array of mediators involved and the complex genetic background required in the development of endometriosis. This review summarizes our current knowledge regarding the pathogenesis of endometriosis, including progress made with transgenic animals, and a clinical perspective on the diagnosis and management of this common process.

Animals↗

A study of the vibration of the basilar membrane in human temporal bone preparations by the use of the Mössbauer effect.

Using the Mössbauer technique, we have studied the vibration of the human basilar membrane and malleus head in the sound frequency range 0.2--9.0 kHz and at a sound pressure of 100 dB at the tympanic membrane. The displacement frequency response curves for the basilar membrane and the malleus head have similar shapes, with a maximum at about 1 kHz. Below and above 1 kHz the curves have a slope of about 10 dB/octave and--100 dB/octave, respectively. In addition, the basilar membrane has a maximum displacement at a frequency dependent distance from the stapes. A simple hydrodynamic model for the cochlea is used to interpret the experimental data. A possible mechanism for the frequency resolution of sound by the ear and noise-induced hearing loss is discussed.

Acoustic Stimulation↗

Patency tests of the maxillary ostium--model experiments.

The function of the maxillary ostia (phi 0.22-4.7 mm) has been evaluated in experiments on a nose-sinus model with variable sinusal volumes. A piston-pump producing to-and-fro volumes of 467 cm3 of air per revolution was used at a speed of 10 and 20 revolutions per minute (rpm). Three different techniques were used: simultaneous pressure recording in the sinus and the nose (Method I); simultaneous recording of the differential pressure between nose and sinus and the air-flow through the ostium (Method II); recording of the pressure rise inside the sinus upon the application of a constant artificial air-flow of 16,7 cm3 . s-1 or 2.0 cm3 . s-1 (Method III). All variables were recorded on an ink-jet recorder and onto tape when using methods I and II for later analysis on an x-y recorder. A pressure relationship of 1 : 1 was found between nose and sinus, independently of ostial diameters, sinusal volumes and piston-pump rates. The first method did not permit an isolated determination of the ostial function as the pressure values recorded are affected by ostial diameters, sinusal volumes and piston-pump rates. The pressure-flow relationship recorded with the second method was found to be dependent only on the ostial diameters. Hysteresis was observed at ostial diameters less than or equal to 1.63 mm. This is due to ostial diameter, sinusal volume and the rate of the nasal pressure changes. This method is suitable for an isolated determination of the ostial resistance, from which the equivalent ostial diameter can be calculated. With the third method using static air-flows and pressures the results are independent of the sinusal volume. This method is suitable for estimation of the ostial airway resistance and the equivalent ostial diameter. A striking similarity was observed between the results obtained with the last two methods in estimating equivalent ostial diameters.

Airway Resistance↗

Dispersion of aerosol particles in an airway cast of a dog.

Aerosol bolus dispersion was measured in the first branching generations of a replicate hollow cast. The cast was made from a solid cast of a beagle-dog tracheobronchial tree. The dispersion was measured after penetration of boluses into different volumetric depths, with different particle sizes and flow rates into the cast. An enhanced flow rate led to a decreasing dispersion in the cast. Particle size up to about 4 microns has no significant effect on dispersion.

Aerosols↗

Effect of flow rate on aerosol bolus penetration in a hollow canine lung airway cast.

A cast of dog tracheobronchial airways, which is complete to airways of 1 mm in diameter, was used for experimental studies of the effect of flow rate on aerosol bolus penetration during a tidal breath. Aerosol boli of 35 cm3 were injected during a 1-L inhalation of air. The recoveries of aerosol particles in expired air were measured after various breathholding times. The results show that the penetration depth of an aerosol bolus increases with decreasing flow rate, especially for flow in transition from a flat profile to a parabolic profile.

Aerosols↗

The influence of vasculature on temperature distributions in MECS interstitial hyperthermia: importance of longitudinal control.

The quality of temperature distributions that can be generated with the Multi Electrode Current Source (MECS) interstitial hyperthermia (IHT) system, which allows 3D control of the temperature distribution, has been investigated. For the investigations, computer models of idealised anatomies containing discrete vessels, were used. A 7-catheter hexagonal implant geometry with a nearest neighbour distance of 15 mm was used. In each interstitial catheter with a diameter of 2.1 mm a number of 1 up to 4 electrodes were placed along an 'active section' with a length of 50 mm. The electrode segments had lengths of 50, 20, 12 and 9 mm respectively. Both single vessel and vessel network situations were analysed. This study shows that even in situations with discrete vasculature and perfusion heterogeneity it remains possible to obtain satisfactory temperature distributions with the MECS IHT system. Due to its 3D spatial control the temperature homogeneity in the implant can be made quite satisfactory.

Blood Vessels↗

An accurate 3-D model for magnetic stimulation of the brain cortex.

We present a 3-D model for the simulation of a realistic clinical situation during magnetic stimulation. The electromagnetic problem is solved by reconstructing the inhomogeneous head tissues from magnetic resonance images and associating relative values of conductivity to each tissue. Application of Maxwell's equations in the integral form leads to an equivalent 3-D electrical network, whose solution gives the current density distribution in the brain. The high spatial resolution and rigorous electromagnetic approach make this model an accurate and useful tool for stimulator design and for estimating the efficiency and safety of this clinical methodology.

Algorithms↗