Biomedical subjects

James J Dowling

Publications and source records attributed to James J Dowling.

10 recordsLinked to original sources

PubMed2025

Screening rare genetic diagnoses for amenability to bespoke antisense oligonucleotide therapy development: A retrospective cohort study.

PURPOSE: To estimate the proportion of molecular genetic diagnoses in a real-world, phenotypically heterogeneous patient cohort that are amenable to antisense oligonucleotide (ASO) treatment. METHODS: We retrospectively applied the N=1 Collaborative's Variant Assessments toward Eligibility for Antisense Oligonucleotide Treatment guidelines to all diagnostic variants found by clinical genome-wide sequencing at a single pediatric hospital in 532 patients over a 6-year period. Variants were classified as either "eligible," "likely eligible," "unlikely eligible," or "not eligible" in relation to the different ASO approaches, or "unable to assess." RESULTS: In total, 25 unique variants across 26 patients (4.9% of 532 patients) were eligible or likely eligible for ASO treatment at a molecular genetic level, via canonical exon skipping (4), splice correction (3), or messenger RNA knockdown (19). Only 8 of these molecular genetic diagnoses were made within a year of symptom onset. After considering disease and delivery related factors, 11 diagnoses were still considered candidates for bespoke ASO development. CONCLUSION: A meaningful proportion of genetic diagnoses identified by genome-wide sequencing may be amenable to ASO treatment. These results underscore the importance of timely diagnosis, and the proactive identification and accelerated functional testing of genetic variants amenable to ASO treatments.

Humans↗

PubMed2024

AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient.

There are more than 10,000 individual rare diseases and most are without therapy. Personalized genetic therapy represents one promising approach for their treatment. We present a road map for individualized treatment of an ultra-rare disease by establishing a gene replacement therapy developed for a single patient with hereditary spastic paraplegia type 50 (SPG50). Through a multicenter collaboration, an adeno-associated virus-based gene therapy product carrying the AP4M1 gene was created and successfully administered intrathecally to a 4-year-old patient within 3 years of diagnosis as part of a single-patient phase 1 trial. Primary endpoints were safety and tolerability, and secondary endpoints evaluated efficacy. At 12 months after dosing, the therapy was well tolerated. No serious adverse events were observed, with minor events, including transient neutropenia and Clostridioides difficile gastroenteritis, experienced but resolved. Preliminary efficacy measures suggest a stabilization of the disease course. Longer follow-up is needed to confirm the safety and provide additional insights on the efficacy of the therapy. Overall, this report supports the safety of gene therapy for SPG50 and provides insights into precision therapy development for rare diseases. Clinical trial registration: NCT06069687 .

Humans↗

PubMed2006

Body segment parameter estimation of the human lower leg using an elliptical model with validation from DEXA.

Accurate estimates of human body segment parameters (BSPs) are required for kinetic analyses of motion. The purpose of this study was to develop a geometric model of the human lower leg based on the mass distribution properties of the segment. Forty subjects were recruited from 4 human populations. Each population was randomly divided equally into model development (MD) and model validation (MV) groups. Participants underwent frontal and sagittal plane dual energy X-ray absorptiometry (DEXA) scans and anthropometric measurements. Leg BSPs were calculated from the scan information and mass distribution properties in the two planes were determined. Further, a geometric model was developed based on the ensemble averages of the mass distribution information from the MD groups. The model was applied to the MV groups and mean absolute errors were calculated for each BSP and each population. Finally, BSP estimates from literature sources were also determined and compared against DEXA. The model developed produced the lowest errors overall. Additionally, the results showed that the model developed estimated BSPs for all four populations with consistent accuracy whereas the other 4 models tested provided different levels of accuracy depending on the age and gender categories of the group tested. The results of this study present a model that accurately estimates BSPs of the lower leg for individuals varying in age, gender, race, and morphology. This study also presents a modelling technique that may successfully provide similar results for other body segments.

Absorptiometry, Photon↗

PubMed2006

The uncertainty of the pendulum method for the determination of the moment of inertia.

The purpose of this study was to quantify the uncertainty of the pendulum method for determining the moment of inertia of an object using various suspension distances. Experimental data were collected on a known geometric solid and partial differential equations were derived to calculate the uncertainty. Repeated measures were used to estimate the errors of the mass, period of oscillation, and distance measurements from the axis to the centre of mass. The results showed that the pendulum method was relatively insensitive to measurement errors of mass but was quite sensitive to errors in the period of oscillation. It was also found that the uncertainty of the pendulum method could be drastically reduced to less than 3% by suspending the object with the axis located at the radius of gyration. Most studies using the pendulum method to determine limb inertial properties have adopted a proximal suspension, including the often cited work by Dempster [Dempster WT. Space requirements for the seated operator. W ADC Technical Report 55-159. Ohio: Aero Medical Laboratory, Wright Air Development Centre, Air Research and Development Council, Wright-Patterson Air Force Base; 1955]. The results suggest that validation of imaging techniques to determine inertial properties should use geometric solids in addition to the pendulum method where the object is suspended at a distance estimated to be the radius of gyration. It is further recommended that the uncertainty be reported whenever it is necessary to use the pendulum method.

Acceleration↗

PubMed2005

Using mass distribution information to model the human thigh for body segment parameter estimation.

Accurate estimations of body segment inertial parameters (BSPs) are required to calculate the kinetics of motion. The purpose of this study was to develop a geometric model of the human thigh segment based on mass distribution properties determined from dual energy x ray absorptiometry (DEXA). One hundred subjects from four populations underwent a DEXA scan and anthropometric measurements were taken. The mass distribution properties of the thigh segment were determined for 20 subjects, a geometric model was developed, and the model was applied to the remaining 80 subjects. The model was validated by comparing to benchmark DEXA measurements. Four other popular models in the literature were also evaluated in the same manner No one set of predictors performed best for a particular group or BSP, however modeling the mass distribution properties of the segment allows the assumption of constant density while still accurately representing the inertial properties of the segment and provides promise for future development of BSP models.

Absorptiometry, Photon↗

PubMed2005

Predicting in vivo soft tissue masses of the lower extremity using segment anthropometric measures and DXA.

The purpose of this study was to derive and validate regression equations for the prediction of fat mass (FM), lean mass (LM), wobbling mass (WM), and bone mineral content (BMC) of the thigh, leg, and leg + foot segments of living people from easily measured segmental anthropometric measures. The segment masses of 68 university-age participants (26 M, 42 F) were obtained from full-body dual photon x-ray absorptiometry (DXA) scans, and were used as the criterion values against which predicted masses were compared. Comprehensive anthropometric measures (6 lengths, 6 circumferences, 8 breadths, 4 skinfolds) were taken bilaterally for the thigh and leg for each person. Stepwise multiple linear regression was used to derive a prediction equation for each mass type and segment. Prediction equations exhibited high adjusted R2 values in general (0.673 to 0.925), with higher correlations evident for the LM and WM equations than for FM and BMC. Predicted (equations) and measured (DXA) segment LM and WM were also found to be highly correlated (R2 = 0.85 to 0.96), and FM and BMC to a lesser extent (R2 = 0.49 to 0.78). Relative errors between predicted and measured masses ranged between 0.7% and -11.3% for all those in the validation sample (n = 16). These results on university-age men and women are encouraging and suggest that in vivo estimates of the soft tissue masses of the lower extremity can be made fairly accurately from simple segmental anthropometric measures.

Absorptiometry, Photon↗

PubMed2003

Design and responses of Butterworth and critically damped digital filters.

For many years the Butterworth lowpass filter has been used to smooth many kinds of biomechanical data, despite the fact that it is underdamped and therefore overshoots and/or undershoots data during rapid transitions. A comparison of the conventional Butterworth filter with a critically damped filter shows that the critically damped filter not only removes the undershooting and overshooting, but has a superior rise time during rapid transitions. While analog filters always create phase distortion, both the critically damped and Butterworth filters can be modified to become zero-lag filters when the data are processed in both the forward and reverse directions. In such cases little improvement is realized by applying multiple passes. The Butterworth filter has superior 'roll-off' (attenuation of noise above the cutoff frequency) than the critically damped filter, but by increasing the number of passes of the critically damped filter the same 'roll-off' can be achieved. In summary, the critically damped filter was shown to have superior performance in the time domain than the Butterworth filter, but for data that need to be double differentiated (e.g. displacement data) the Butterworth filter may still be the better choice.

Biomechanical Phenomena↗

PubMed2003

Analysis of body segment parameter differences between four human populations and the estimation errors of four popular mathematical models.

Calculating the kinetics of motion using inverse or forward dynamics methods requires the use of accurate body segment inertial parameters. The methods available for calculating these body segment parameters (BSPs) have several limitations and a main concern is the applicability of predictive equations to several different populations. This study examined the differences in BSPs between 4 human populations using dual energy x-ray absorptiometry (DEXA), developed linear regression equations to predict mass, center of mass location (CM) and radius of gyration (K) in the frontal plane on 5 body segments and examined the errors produced by using several BSP sources in the literature. Significant population differences were seen in all segments for all populations and all BSPs except hand mass, indicating that population specific BSP predictors are needed. The linear regression equations developed performed best overall when compared to the other sources, yet no one set of predictors performed best for all segments, populations or BSPs. Large errors were seen with all models which were attributed to large individual differences within groups. Equations which account for these differences, including measurements of limb circumferences and breadths may provide better estimations. Geometric models use these parameters, however the models examined in this study did not perform well, possibly due to the assumption of constant density or the use of an overly simple shape. Creating solids which account for density changes or which mimic the mass distribution characteristics of the segment may solve this problem. Otherwise, regression equations specific for populations according to age, gender, race, and morphology may be required to provide accurate estimations of BSPs for use in kinetic equations of motion.

Absorptiometry, Photon↗

PubMed2002

Clinical and molecular basis of classical lissencephaly: Mutations in the LIS1 gene (PAFAH1B1).

Classical lissencephaly (LIS) and subcortical band heterotopia (SBH) are related cortical malformations secondary to abnormal migration of neurons during early brain development. Approximately 60% of patients with classical LIS, and one patient with atypical SBH have been found to have deletions or mutations of the LIS1 gene, located on 17p13.3. This gene encodes the LIS1 or PAFAH1B1 protein with a coiled-coil domain at the N-terminus and seven WD40 repeats at the C-terminus. It is highly conserved between species and has been shown to interact with multiple proteins involved with cytoskeletal dynamics, playing a role in both cellular division and motility, as well as the regulation of brain levels of platelet activating factor. Here we report 65 large deletions of the LIS1 gene detected by FISH and 41 intragenic mutations, including four not previously reported, the majority of which have been found as a consequence of the investigation of 220 children with LIS or SBH by our group. All intragenic mutations are de novo, and there have been no familial recurrences. Eight-eight percent (36/41) of the mutations result in a truncated or internally deleted protein-with missense mutations found in only 12% (5/41) thus far. Mutations occurred throughout the gene except for exon 7, with clustering of three of the five missense mutations in exon 6. Only five intragenic mutations were recurrent. In general, the most severe LIS phenotype was seen in patients with large deletions of 17p13.3, with milder phenotypes seen with intragenic mutations. Of these, the mildest phenotypes were seen in patients with missense mutations.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed2002

The measurement of body segment inertial parameters using dual energy X-ray absorptiometry.

Accurate body segment parameter (BSP) information is required for dynamic analyses of motion and the current methods available for obtaining these BSPs have been criticized. The purpose of this study was to determine whether dual energy X-ray absorptiometry (DXA) could accurately measure the BSPs of scanned objects and thus be used as a tool for measuring the BSPs of human subjects. Whole body mass (WBM) of 11 males was measured from a DXA scan and the values were compared to criterion scale-measured values by calculating the mean percent error. Two objects (plastic cylinder, human cadaver leg) were also scanned and DXA measurements of mass, length, centre of mass location (CM) and moment of inertia about the centre of mass (I(CM)) were made using custom software. Criterion BSP measurements were then made and compared to DXA BSP values by calculating the percent error. Criterion I(CM) measurements of the two objects were made using a pendulum technique and a second criterion I(CM) calculation was made for the cylinder using a geometric formula. A mean percent error of -1.05% +/-1.32% was found for WBM measurements of the human subjects. Errors for the cylinder and cadaver leg were under 3.2% for all BSPs except for I(CM) when DXA was compared to the pendulum method (14.3% and 8.2% for cylinder and leg, respectively). The errors between DXA and the pendulum method were attributed to uncertainty in the pendulum technique (J. Biomech. 2002, in Review). I(CM) error of the cylinder when DXA was compared to the geometric calculation was 2.63%. This error, combined with the low errors for all other BSPs, indicated that DXA can be used as a simple and accurate means of obtaining direct BSP information on living humans.

Absorptiometry, Photon↗