Effects of the polyphenol resveratrol on contractility of human term pregnant myometrium.

The ideal agent for prevention and treatment of uterine abnormal contractility has not been found. The polyphenol resveratrol possesses a wide spectrum of pharmacologic properties, but its influence on the contractility of human myometrium is not defined. The present study evaluated the effect of resveratrol on the oxytocin-induced contractions of human term pregnant myometrium in vitro and the contribution of different K(+) channels to resveratrol action. Resveratrol induced a concentration-dependent relaxation of myometrium contractions (pD2 value and maximal responses were 4.52 and 82.25%, respectively). Glibenclamide, a selective blocker of ATP-sensitive (KATP), iberiotoxin, a selective blockers of big-calcium sensitive (BK(Ca)) and 4-aminopiridine, a non-selective blocker of voltage-sensitive (Kv) channels induced a significant shift to the right of the concentration-response curves of resveratrol. Inhibition achieved by 0.1 mM resveratrol was insensitive to all K(+) channel blockers. A K(+) channel opener, pinacidil, inhibited oxytocin-induced contractions of pregnant myometrium with comparable potency and efficacy to resveratrol (pD2 values and maximal relaxation were 4.52 and 83.67%, respectively). Based on K(+) channel opener/blocker affinities, it appears that the inhibitory response of resveratrol involves different myometrial K(+) channels. When applied in high concentrations, resveratrol has an additional K(+)-channel-independent mechanism(s) of action. Furthermore, immunohistochemistry staining and western blot analyses detected the presence and distribution of KATP, BK(Ca) and Kv channel proteins in pregnant myometrium.

Differential expression of KCNQ1 K+ channel in tubular cells of frog kidney.

The aim of this study was to evaluate KCNQ1 K+ channel expression in the frog kidney of Rana esculenta. KCNQ1 K+ channel, also known as KvLQT1, is the pore forming a-subunit of the IKs K+ channel, a delayed rectifier voltage-gated K+ channel, which has an important role in water and salt transport in the kidney and gastrointestinal tract. The expression of KCNQ1 K+ channel along tubular epithelium differs from species to species. In the present study the expression of KCNQ1 K+ channel in the frog kidney has been demonstrated by immunohistochemistry. The presence of KCNQ1 K+ channel was demonstrated in the epithelial cells of distal convoluted tubule and collecting duct. However, the pattern of expression of KCNQ1 K+ channel differs between distal convoluted tubules and collecting duct. All epithelial cells of distal convoluted tubules revealed basolateral expression of KCNQ1 K+ channel. On the contrary, only the single cells of collecting duct, probably intercalated cells, showed diffuse cell surface staining with antibodies against KCNQ1 K+ channel. These findings suggest that KCNQ1 K+ channel has cell-specific roles in renal potassium ion transport.

Initial stability of type-2 tibial defect treatments.

Treatment of proximal tibial defects is important to the survival of tibial prosthesis after total knee replacement. The objective of this finite element study was to determine a better understanding of the stresses produced by different treatment options for moderate uncontained type-2 defects. Methods analysed were the use of metal wedges, metal blocks, cement wedges, and cement blocks for the two defect angles 15 degrees and 30 degrees. The effect of a stem extension on the stress profiles was also analysed for each defect treatment and angle to establish the necessity of these extensions and consequent bone removal on the stability of the augments. Equivalent stresses in two regions of interest (ROIs) adjacent to the augments and shear stresses along the bone-cement interface of the defect were investigated. The lowest equivalent stresses were found in the metal block augment for both defect angles and ROIs. The highest equivalent stress in the ROIs and shear stress values along the bone-cement interface of the defect were found in the cement wedge augment model for both defect angles. Stem extensions were shown to increase equivalent stresses in the bone closer to the tibial stem but to decrease equivalent stresses closer to the cortical bone. The use of a stem extension significantly increased the shear stresses in the cement in all cases except in the metal block model. It is recommended that metal block augments are used without a stem extension in small-defect (i.e. peripheral defect angle of 15 degrees) total knee replacement procedures.

Computer modelling study of the mechanism of optic nerve injury in blunt trauma.

AIM: The potential causes of the optic nerve injury as a result of blunt object trauma, were investigated using a computer model. METHODS: A finite element model of the eye, the optic nerve, and the orbit with its content was constructed to simulate blunt object trauma. We used a model of the first phalanx of the index finger to represent the blunt body. The trauma was simulated by impacting the blunt body at the surface between the globe and the orbital wall at velocities between 2-5 m/s, and allowing it to penetrate 4-10 mm below the orbital rim. RESULTS: The impact caused rotations of the globe of up to 5000 degrees /s, lateral velocities of up to 1 m/s, and intraocular pressures (IOP) of over 300 mm Hg. The main stress concentration was observed at the insertion of the nerve into the sclera, at the side opposite to the impact. CONCLUSIONS: The results suggest that the most likely mechanisms of injury are rapid rotation and lateral translation of the globe, as well as a dramatic rise in the IOP. The strains calculated in the study should be sufficiently high to cause axonal damage and even the avulsion of the nerve. Finite element computer modelling has therefore provided important insights into a clinical scenario that cannot be replicated in human or animal experiments.

Mechanistic hypothesis for eye injury in infant shaking : An experimental and computational study.

The terms abusive head injury and shaken baby syndrome are used to describe a unique pattern of nonaccidental traumatic injuries occurring in children that many clinicians and researchers have good reason to believe is caused by violent shaking. Typical injuries include severe brain injury, with intracranial and retinal hemorrhages, but the pathogenesis of injuries is poorly understood. A major paradox in head trauma in infants is that the injuries induced by a shaking event are much more severe than those caused by even very violent single-impact head trauma, despite the relatively low accelerations in shaking.We have developed a finite element computer model of the eye, orbit, and orbital bone and used it to simulate the effects of single-impact and oscillatory motion inputs. The model was informed by data from semiquantitative in vitro anatomical traction experiments on in situ rabbit eyes. The new results reported here strongly suggest that suction between the eye and its surrounding fat dominates the dynamical stability of the system composed of the eye, its socket, and the components and material supporting the eye. Computer simulations incorporating this functional anatomical relationship show that deceleration of the head generates pressure gradients inside and outside the eye; these could cause damaging shear stresses in structures such as the retina and blood vessels. Simulations also show that oscillating the bone of the orbit causes the eye to move anteriorly and posteriorly with an increasing amplitude, building up the stresses within the eye over time. This is the first time that any biomechanical mechanism has been identified that might explain the disproportionally severe injuries caused by an oscillatory mechanism such as violent shaking of an abused infant. However, further study is required and this conclusion is therefore preliminary and provisional.

Mathematical study of the role of non-linear venous compliance in the cranial volume-pressure test.

The role of the cerebral venous bed in the cranial volume-pressure test was examined by means of a mathematical model. The cerebral vascular bed was represented by a single arterial compartment and two venous compartments in series. The lumped-parameter formulation for the vascular compartments was derived from a one-dimensional theory of flow in collapsible tubes. It was assumed in the model that the cranial volume is constant. The results show that most of the additional volume of cerebrospinal fluid (deltaV(CSF)) was accommodated by collapse of the cerebral venous bed. This profoundly altered the venous haemodynamics and was reflected in the cranial pressure P(CSF). The cranial volume-pressure curve obtained from the model was consistent with experimental data; the curve was flat for 0 < or = deltaV(CSF) < or = 20 ml and 35 < or = deltaV(CSF) < or = 40 ml, and steep for 20 < or = deltaV(CSF) < or = 35 ml and deltaV(CSF) > or = 40 ml. For deltaV(CSF) > 25 ml and P(CSF) > 5.3 kPa (40 mmHg), cerebral blood flow dropped. When P(CSF) was greater than the mean arterial pressure, all the veins collapsed. The conclusion of the study was that the shape of the cranial volume-pressure curve can be explained by changes in the venous bed caused by various degrees of collapse and/or distension.

A mechanical model of cerebral circulation during sustained acceleration.

BACKGROUND: High positive Gz may result in inadequate blood supply to the brain even if the central blood pressures are maintained at normal levels. We use a mechanical model to simulate the influence of sustained +Gz on cerebral circulation. METHODS: The model consists of ascending and descending tubes representing the extracranial arteries and veins, respectively, and a cranium in which the tubes are enclosed within water-filled rigid container to account for the skull and the cerebrospinal fluid. A thick-walled Tygon tube and a thin-walled surgical drain tube were used for the arteries and veins, respectively. The flow of water was driven by a pressure difference at the model ends, and the change in the gravitational vector was accomplished by tilting the model. RESULTS: The flow drops with an increasing tilt angle only if the descending arm collapses. However, when the pressures at the model ends are sufficiently elevated, the flow is restored to normal value. In the cranium model, the pressure in the water surrounding the tubes always stays close to the pressure in the surgical tubing. Consequently, the tubes in the container do not collapse. CONCLUSIONS: The principal effect of Gz on flow through the model occurs via changes in the resistance of the collapsed descending arm. As the pressures at the model ends are elevated, the descending arm opens and the flow increases. The pressure in the cranium model is dictated by the condition that the volume of the container has to remain constant.

Differential RNA cleavage and polyadenylation of the glutamate transporter EAAT2 in the human brain.

We cloned four novel transcripts of the excitatory amino acid transporter 2, named EAAT2/3UT1-4, resulting from differential cleavage and polyadenylation. Tandem poly (A) sites were found to be functional at 72, 654, 973 nucleotides and more than 2 kb downstream of the stop codon. A tissue-specific expression was identified for 3'-variants of the EAAT2 RNA, most prominently for EAAT2/3UT4 (hippocampus>cortex>>cerebellum>thalamus) as demonstrated by Northern blot analysis and quantitative PCR. We conclude, that alternative poly (A) selection may contribute to the reported differential EAAT2 protein expression under normal and diseased conditions.

A mathematical model of cerebral perfusion subjected to Gz acceleration.

BACKGROUND: When the human body is exposed to a high gravitational load, the blood supply to the brain is reduced and loss of consciousness may occur. Our goal is to identify the principal mechanical causes of reduced blood supply to the brain during high +Gz. METHODS: We have developed a mathematical model to investigate the influence of Gz on the cerebral circulation. Blood flow is modeled using a one-dimensional flow approximation, in which the cross-sectional area of elastic vessels is determined as a non-linear function of the transmural (blood minus external) pressure. The intracranial vessels are subjected to cerebrospinal fluid pressure (PCSF) which is determined from the condition that the cranial volume is conserved. RESULTS: For a constant pressure difference of 100 mm Hg applied to the arterial and venous ends of the model, blood flow is diminished for +Gz. At approximately +5 G, the blood flow predicted by the model is insufficient to maintain normal functioning of the brain. PCSF is approximately equal to the blood pressure in the large intracranial veins for all values of Gz. Extracranial arteries and the intracranial vessels do not collapse, even when Gz is substantially higher than normal. However, the extracranial veins are collapsed even for moderate +Gz. CONCLUSIONS: Even if cardiac output is maintained at normal levels, cerebral perfusion will fall because of the increasing resistance of the cerebral flow circuit. This increase is largely due to the collapse of the extracranial veins, which begins at moderate Gz and becomes dominant at a Gz of approximately 4.5.