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Biomedical subjects

E Will

Publications and source records attributed to E Will.

At least 19 recordsLinked to original sources
PubMed2006

The effect of serial casting on gait in children with cerebral palsy: preliminary results from a crossover trial.

Serial casting aims to improve an equinus gait pattern in children with spastic cerebral palsy (SCP). We evaluated the effect of short-term stretch casting on gait in children with SCP, compared to the natural history. A crossover trial, consisting of a control phase and a casting phase, was conducted with children randomised into two groups. Both groups were assessed clinically, and using 3D gait analysis, at 0, 5 and 12 weeks. Subjects in one group had the 3 month casting phase first and in the other had the 3 month control period first. Casts were changed weekly and set at maximum available ankle dorsiflexion. The mean changes at 5 weeks and 12 weeks from baseline measurements in the casting phase were compared with the change within the same time interval in the control phase. Significant improvements in passive ankle dorsiflexion (knee flexed) were found at 5 and 12 weeks. Passive ankle dorsiflexion (knee extended), ankle dorsiflexion in single support, ankle dorsiflexion in swing and minimum hip flexion in stance improved significantly at 5 weeks but not at 12 weeks from baseline. Other kinematic parameters, the score on the Gillette Functional Assessment Questionnaire, and maximum reported walking distance were not changed by casting. Casting to improve range appears to improve passive and dynamic ankle dorsiflexion, but the changes are small, short lived and do not appear to affect function.

Biomechanical Phenomena↗
PubMed2003

Outcome after reconstruction of the anterior cruciate ligament in athletic patients. A comparison of early versus delayed surgery.

We randomised 31 patients with acute tears of the anterior cruciate ligament (ACL) to receive either early (within 2 weeks) or delayed (8 to 12 weeks) reconstruction using a quadruple hamstring graft in order to determine if there was any functional advantage to early reconstruction. Outcome measures included return of knee movement, muscle dynamometry, International Knee Documentation Committee (IKDC) scores and Tegner activity levels. Two cases of symptomatic deep-venous thrombosis occurred in the early group. The mean range of movement was significantly greater at two weeks in the delayed group. Quadriceps muscle power was significantly better in the delayed group at 12 weeks (p < 0.05). These trends were evident at later time points, but were not statistically significant. One patient in each group had clinically significant knee stiffness at 52 weeks. IKDC scores and Tegner activity levels were not significantly different at 52 weeks. We conclude that there is no functional advantage to be gained by early reconstruction of the ACL.

Adolescent↗
PubMed2001

Biochemical characterization of Gyp6p, a Ypt/Rab-specific GTPase-activating protein from yeast.

Gyp6p from yeast belongs to the GYP family of Ypt/Rab-specific GTPase-activating proteins, and Ypt6p is its preferred substrate (Strom, M., Vollmer, P., Tan, T. J., and Gallwitz, D. (1993) Nature 361, 736-739). We have investigated the kinetic parameters of Gyp6p/Ypt6p interactions and find that Gyp6p accelerates the intrinsic GTPase activity of Ypt6p (0.0002 min(-1)) by a factor of 5 x 10(6) and that they have a very low affinity for its preferred substrate (K(m) = 592 micrometer). Substitution with alanine of several arginines, which Gyp6p shares with other GYP family members, resulted in significant inhibition of GAP activity. Replacement of arginine-155 with either alanine or lysine abolished its GAP activity, indicating a direct involvement of this strictly conserved arginine in catalysis. Physical interaction of the catalytically inactive Gyp6(R155A) mutant GAP with Ypt6 wild-type and Ypt6 mutant proteins could be demonstrated with the two-hybrid system. Short N-terminal and C-terminal truncations of Gyp6p resulted in a complete loss of GAP activity and Ypt6p binding, showing that in contrast to two other Gyp proteins studied previously, most of the 458 amino acid-long Gyp6p sequence is required to form a three-dimensional structure that allows substrate binding and catalysis.

Base Sequence↗
PubMed2001

Targets and targeting.

Using the vocabulary of ballistics in medicine for emphasis can result in misleading exaggeration and semantic confusion. The dual meaning of target as either aiming point (aim at) or outcome (aim to achieve) creates a muddle in the efforts to comply with quality assurance initiatives. Disentangling the two meanings allows new approaches to the clinical technology required in a modern health care environment. An example can be shown in new strategies for the management of renal anemia with iron and erythropoietin. The potential to shape outcome distributions through validated, preemptive intervention thresholds offers the predictable results required by patients and payers. Using the management of patient cohorts as a platform for outcomes creates no necessary conflict with individualized clinical care. Future guideline statements should include the likely characteristics of compliant outcome populations, as a prompt to clinical goals and as an indication of the necessary cost and effort of compliance with treatment standards. Overemphasis in language is no substitute for considered clinical methodology.

Anemia↗
PubMed2000

Sequential action of two GTPases to promote vacuole docking and fusion.

Homotypic vacuole fusion occurs by sequential priming, docking and fusion reactions. Priming frees the HOPS complex (Vps 11, 16, 18, 33, 39 and 41) to activate Ypt7p for docking. Here we explore the roles of the GDP and GTP states of Ypt7p using Gdi1p (which extracts Ypt7:GDP), Gyp7p (a GTPase-activating protein for Ypt7p:GTP), GTPgammaS or GppNHp (non-hydrolyzable nucleotides), and mutant forms of Ypt7p that favor either GTP or GDP states. GDP-bound Ypt7p on isolated vacuoles can be extracted by Gdi1p, although only the GTP-bound state allows docking. Ypt7p is converted to the GTP-bound state after priming and stably associates with HOPS. Gyp7p can cause Ypt7p to hydrolyze bound GTP to GDP, driving HOPS release and accelerating Gdi1p-mediated release of Ypt7p. Ypt7p extraction does not inhibit the Ca(2+)-triggered cascade that leads to fusion. However, in the absence of Ypt7p, fusion is still sensitive to GTPgammaS and GppNHp, indicating that there is a second specific GTPase that regulates the calcium flux and hence fusion. Thus, two GTPases sequentially govern vacuole docking and fusion.

Calcium↗
PubMed2000

Analysis of muscle function in the lower limb after fracture of the diaphysis of the tibia in adults.

We examined the recovery of power in the muscles of the lower limb after fracture of the tibial diaphysis, using a Biodex dynamometer. Recovery in all muscle groups was rapid for 15 to 20 weeks following fracture after which it slowed. Two weeks after fracture the knee flexors and extensors have about 40% of normal power, which rises to 75% to 85% after one year. The dorsiflexors and plantar flexors of the ankle and the invertors and evertors of the subtalar joint are much weaker two weeks after injury, but at one year their mean power is more than that of the knee flexors and extensors. Our findings showed that age, the mode of injury, fracture morphology, the presence of an open wound and the Tscherne grade of closed fractures correlated with muscle power. It is age, however, which mainly determines muscle recovery after fracture of the tibial diaphysis.

Adolescent↗
PubMed2000

[Investigations of radiation exposure of the medical personnel during F-18-FDG PET studies].

AIM: The aim of the investigation was the identification of those working steps with the highest radiation exposure for the medical personnel during F-18-FDG-PET studies and to evaluate the effectiveness of radiation protection devices and instructions developed in our PET-center. METHODS: The personal dose and hand dose were measured for each working procedure during F-18-FDG-PET studies using electronic personal dosimeters and thermoluminescent dosimeters respectively. Additionally, measurements of the radiation level near the patient were taken. RESULTS: The mean personal dose resulting from syringe preparation was 1 microSv/syringe, from injection 3 microSv/patient, from blood sampling during quantitative studies 6 microSv/study, and from positioning and handling of the patient 6 microSv/study. The mean hand dose per syringe preparation was 710 microSv for each hand. The mean hand dose during injection was 13 microSv for the right hand and 27 microSv for the left hand. All above mentioned values were measured applying the routine radiation shielding in use in our PET center. CONCLUSION: With the developed radiation shielding and means to reduce radiation exposure applied the allowed annual dose for medical personnel are not exceeded. One exception is the hand dose resulting from syringe preparation. An automatic or remote filling device should be used at this working step.

Fluorodeoxyglucose F18↗
PubMed1999

Identification of the catalytic domains and their functionally critical arginine residues of two yeast GTPase-activating proteins specific for Ypt/Rab transport GTPases.

Ypt/Rab proteins constitute the largest subfamily of the Ras superfamily of monomeric GTPases and are regulators of vesicular protein transport. Their slow intrinsic GTPase activity (10(-4)-10(-3) min(-1) at 30 degrees C) has to be accelerated to switch the active to the inactive conformation. We have identified the catalytic domain within the C-terminal halves of two yeast GTPase-activating proteins (GAPs), Gyp1p and Gyp7p, with specificity for Ypt/Rab GTPases. The catalytically active fragments of Gyp1p and Gyp7p were more active than the full-length proteins and accelerated the intrinsic GTP hydrolysis rates of their preferred substrates by factors of 4.5 x 10(4) and 7.8 x 10(5), respectively. The K(m) values for the Gyp1p and Gyp7p active fragments (143 and 42 microM, respectively) indicate that the affinities of those GAPs for their substrates are very low. The catalytic domains of Gyp1p and Gyp7p contain five invariant arginine residues; substitutions of only one of them (R343 in Gyp1p and R458 in the analogous position of Gyp7p) rendered the GAPs almost completely inactive. We suggest that Ypt/Rab-GAPs, like Ras- and Rho-GAPs, follow the same mode of action and provide a catalytic arginine ('arginine finger') in trans to accelerate the GTP hydrolysis rate of the transport GTPases.

Amino Acid Sequence↗
PubMed1999

Primary structure and biochemical characterization of yeast GTPase-activating proteins with substrate preference for the transport GTPase Ypt7p.

Small GTPases of the Ypt/Rab family are regulators of vesicular protein trafficking in exo-and endocytosis. GTPase-activating proteins (GAP) play an important role as down regulators of GTPases. We here report the molecular cloning of a novel GAP-encoding gene (GYP7, for GAP for Ypt7) by high expression from a Saccharomyces cerevisiae genomic library. The GYP7 gene encodes a hydrophilic protein with a molecular mass of 87 kDa. Comparison of its primary sequence with that of the three other known GAPs for transport GTPases, the yeast Gyp6 and Gyp1 proteins and the Rab3A-GAP from rat brain, shows similarity between the yeast GAPs only. Like GYP6 and GYP1, GYP7 is not essential for yeast cell viability. Gyp7p was able to most effectively accelerate the intrinsic GTPase activity of Ypt7p. It was also active, but to a lesser extent, on Ypt31p, Ypt32p and Ypt1p. Ypt6p, Sec4p and the human H-Ras protein did not serve as substrates. We also report the identification and cloning of a gene from the dimorphic yeast Yarrowia lipolytica that encodes a protein whose primary structure and biochemical activity are significantly related to those of Gyp7p from baker's yeast.

Amino Acid Sequence↗
PubMed1999

Structural and functional analysis of a novel coiled-coil protein involved in Ypt6 GTPase-regulated protein transport in yeast.

The yeast transport GTPase Ypt6p is dispensable for cell growth and secretion, but its lack results in temperature sensitivity and missorting of vacuolar carboxypeptidase Y. We previously identified four yeast genes (SYS1, 2, 3, and 5) that on high expression suppressed these phenotypic alterations. SYS3 encodes a 105-kDa protein with a predicted high alpha-helical content. It is related to a variety of mammalian Golgi-associated proteins and to the yeast Uso1p, an essential protein involved in docking of endoplasmic reticulum-derived vesicles to the cis-Golgi. Like Uso1p, Sys3p is predominatly cytosolic. According to gel chromatographic, two-hybrid, and chemical cross-linking analyses, Sys3p forms dimers and larger protein complexes. Its loss of function results in partial missorting of carboxypeptidase Y. Double disruptions of SYS3 and YPT6 lead to a significant growth inhibition of the mutant cells, to a massive accumulation of 40- to 50-nm vesicles, to an aggravation of vacuolar protein missorting, and to a defect in alpha-pheromone processing apparently attributable to a perturbation of protease Kex2p cycling between the Golgi and a post-Golgi compartment. The results of this study suggest that Sys3p, like Ypt6p, acts in vesicular transport (presumably at a vesicle-docking stage) between an endosomal compartment and the most distal Golgi compartment.

Amino Acid Sequence↗
PubMed1999

Fractures of the tibia. Can their outcome be predicted?

We have carried out a prospective study to determine whether the basic descriptive criteria and classifications of diaphyseal fractures of the tibia determine prognosis, as is widely believed. A number of systems which are readily available were used, with outcome being determined by standard measurements including fracture union, the need for secondary surgery and the incidence of infection. Many validated functional outcomes were also used. The Tscherne classification of closed fractures proved to be slightly more predictive of outcome than the others, but our findings indicate that such systems have little predictive value.

Adult↗
PubMed1999

Dropped hallux after the intramedullary nailing of tibial fractures.

We made a prospective study of 208 patients with tibial fractures treated by reamed intramedullary nailing. Of these, 11 (5.3%) developed dysfunction of the peroneal nerve with no evidence of a compartment syndrome. The patients with this complication were significantly younger (mean age 25.6 years) and most had closed fractures of the forced-varus type with relatively minor soft-tissue damage. The fibula was intact in three, fractured in the distal or middle third in seven, with only one fracture in the proximal third. Eight of the 11 patients showed a 'dropped hallux' syndrome, with weakness of extensor hallucis longus and numbness in the first web space, but no clinical involvement of extensor digitorum longus or tibialis anterior. This was confirmed by nerve-conduction studies in three of the eight patients. There was good recovery of muscle function within three to four months in all cases, but after one year three patients still had some residual tightness of extensor hallucis longus, and two some numbness in the first web space. No patient required further treatment.

Adolescent↗
PubMed1996

Reamed or unreamed nailing for closed tibial fractures. A prospective study in Tscherne C1 fractures.

We performed a prospective, randomised study on 50 patients with Tscherne C1 tibial diaphyseal fractures comparing treatment with reamed and unreamed intramedullary nails. Our results show that reamed nailing is associated with a significantly lower time to union and a reduced requirement for a further operation. Unreamed nailing should not be used in the treatment of the common Tscherne C1 tibial fracture.

Adult↗
PubMed1994

Estimation of treatment dose in high-efficiency haemodialysis.

Blood urea concentration is artificially low immediately following high-efficiency dialysis of duration T and will rise ('rebound') due to the continued diffusion of urea from the intracellular to the extracellular space. This leads to an overestimate of the efficiency of the dialysis given by KT/V (where V is the total distribution volume of urea and K is the urea clearance of the dialyser) if the true equilibrium blood concentration of urea is not used in the calculation of KT/V by the single-pool urea kinetic model (UKM). The measurement of the equilibrium urea concentration entails an additional blood sample 60 min after dialysis, but an estimate may be calculated using a blood sample taken 80 min following the start of dialysis together with an approximate formula derived from the 2-pool model. In 14 patients, an average error in the calculation of KT/V of 35% (range 19-75%) by the single-pool UKM was reduced to 13% (range 1-55%, but 8 measurements to < 7%) using the approximate technique. It is concluded that the approximate technique significantly improves the accuracy of dose estimation in high-efficiency dialysis without inconveniencing the patient.

Algorithms↗
PubMed1994

Comparison of approximate and iterative methods to calculate the efficiency of haemodialysis as KT/V.

Dialysis dose is given by the index KT/V, where K is the dialyser urea clearance, T the duration of dialysis and V the notional urea distribution volume. KT/V may be calculated using the single pool model and an iterative calculation which requires a computer program. Three estimates of KT/V, each based on simple correction of the log ratio in (C0/C1), where C0, C1 denote the pre- and post-dialysis blood urea concentrations in mg/ml, were developed and compared with the values of KT/V given by iteration. The first estimate was given by adding two terms to the log ratio to account for the effect of ultrafiltration and urea generation while the second and third estimates were given by increasing the log ratio by 12.5% and 15% respectively. All estimates gave good agreement when compared with the iterative technique by Bland-Altman analysis for 27 patients on standard 4 hour dialysis treatment using 4 different dialysers (0.71 < KT/V < 1.62). The mean difference in all cases was less than 0.025 and the differences were not clinically significant. The use of these approximate formulae to estimate dialysis efficiency avoids the need for complex calculation or additional blood samples.

Adult↗
PubMed1993

An analysis of the single-pool urea kinetic model and estimation of errors.

The single-pool urea kinetic model assumes that urea is distributed within the body in a volume Vf at a uniform concentration. It may be used to describe the clearance of urea during and following haemodialysis, and to determine the value of the urea concentration at the end of dialysis Cf or the urea generation rate G, and the urea distribution volume Vf. The protein catabolic rate (PCR) is obtained using the ratio G/Vf. The sensitivity of the predictions of the model to small errors in the experimentally estimated model parameters is evaluated and suggests that the model prediction of Cf is relatively insensitive to errors in the estimate of G, but more sensitive to errors in Vf and dialyser clearance K. The determination of G from urea concentration measurements made during dialysis alone is very sensitive to errors. The accurate estimation of G requires the use of concentration measurements made between dialyses. The calculation of the PCR is very sensitive to errors in G and Vf since these are not independent and must be used with caution, particularly when used to compare values between patients.

Humans↗