Biomedical subjects

J Masel

Publications and source records attributed to J Masel.

At least 19 recordsLinked to original sources

PubMed2006

Transplantation of hNT neurons into the ischemic cortex: cell survival and effect on sensorimotor behavior.

Cell transplantation offers a potential new treatment for stroke. Animal studies using models that produce ischemic damage in both the striatum and the frontal cortex have shown beneficial effects when hNT cells (postmitotic immature neurons) were transplanted into the ischemic striatum. In this study, we investigated the effect of hNT cells in a model of stroke in which the striatum remains intact and damage is restricted to the cortex. hNT cells were transplanted into the ischemic cortex 1 week after stroke induced by distal middle cerebral artery occlusion (dMCAo). The cells exhibited robust survival at 4 weeks posttransplant even at the lesion border. hNT cells did not migrate, but they did extend long neurites into the surrounding parenchyma mainly through the white matter. Neurite extension was predominantly toward the lesion in ischemic animals but was bidirectional in uninjured animals. Extension of neurites through the cortex toward the lesion was also seen when there was some surviving cortical tissue between the graft and the infarct. Prolonged deficits were obtained in four tests of sensory-motor function. hNT-transplanted animals showed a significant improvement in functional recovery on one motor test, but there was no effect on the other three tests relative to control animals. Thus, despite clear evidence of graft survival and neurite extension, the functional benefit of hNT cells after ischemia is not guaranteed. Functional benefit could depend on other variables, such as infarct location, whether the cells mature, the behavioral tests employed, rehabilitation training, or as yet unidentified factors.

Analysis of Variance↗

PubMed2004

Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex.

We characterize the survival, migration, and differentiation of human neurospheres derived from CNS stem cells transplanted into the ischemic cortex of rats 7 days after distal middle cerebral artery occlusion. Transplanted neurospheres survived robustly in naive and ischemic brains 4 wk posttransplant. Survival was influenced by proximity of the graft to the stroke lesion and was negatively correlated with the number of IB4-positive inflammatory cells. Targeted migration of the human cells was seen in ischemic animals, with many human cells migrating long distances ( approximately 1.2 mm) predominantly toward the lesion; in naive rats, cells migrated radially from the injection site in smaller number and over shorter distances (0.2 mm). The majority of migrating cells in ischemic rats had a neuronal phenotype. Migrating cells between the graft and the lesion expressed the neuroblast marker doublecortin, whereas human cells at the lesion border expressed the immature neuronal marker beta-tubulin, although a small percentage of cells at the lesion border also expressed glial fibrillary acid protein (GFAP). Thus, transplanted human CNS (hCNS)-derived neurospheres survived robustly in naive and ischemic brains, and the microenvironment influenced their migration and fate.

Animals↗

PubMed2004

Genetic assimilation can occur in the absence of selection for the assimilating phenotype, suggesting a role for the canalization heuristic.

Genetic assimilation occurs when an acquired trait loses dependency on its environmental trigger and becomes an inherited trait. According to the standard quantitative genetic model for genetic assimilation, the trait is determined by the contributions of multiple genes. Trait expression occurs at a lower threshold with the trigger. Selection for the trait in the presence of the trigger increases the frequency of the trait-determining alleles. Eventually these alleles become frequent enough to breach the higher threshold for expression in the absence of the trigger. This loss of dependence on the trigger signifies genetic assimilation. Here I show that genetic assimilation can occur in the absence of selection for the trait in an evolutionary simulation of a gene network model. This contradicts the prediction of the standard quantitative genetic model, but is consistent with an explanation in terms of the canalization heuristic.

Biological Evolution↗

PubMed2002

Distinctive enchondromatosis with spine abnormality, regressive lesions, short stature, and coxa vara: importance of long-term follow-up.

We report a girl with a unique type of enchondromatosis observed from birth to puberty. Radiographic abnormalities documented at the age of 14 months included distinctive spondylometaphyseal enchondromatous types of lesions with minimal involvement of the short tubular and flat bones. Follow-up radiographic examinations documented progressive coxa vara and hypoplasia/dysplasia of the left ulna. At puberty, the short tubular bones appeared normal. There was marked regression of the flat bone, rib, and spinal lesions. This case shows the importance of long-term observation of unclassified forms of skeletal dysplasia.

Abnormalities, Multiple↗

PubMed2001

Premature calvarial synostosis and epidermal hyperplasia (Beare-Stevenson syndrome-like anomalies) resulting from a P250R missense mutation in the gene encoding fibroblast growth factor receptor 3.

We report on a patient with a severe premature calvarial synostosis and epidermal hyperplasia. The phenotype was consistent with that of a mild presentation of Beare-Stevenson syndrome but molecular analysis of the IgIII-transmembrane linker region and the transmembrane domain of the gene encoding the FGFR2 receptor, revealed wild-type sequence only. Subsequently, molecular analysis of the FGFR3 receptor gene identified a heterozygous P250R missense mutation in both the proposita and her mildly affected father. This communication extends the clinical spectrum of the FGFR3 P250R mutation to encompass epidermal hyperplasia and documents the phenomenon of activated FGFR receptors stimulating common downstream developmental pathways, resulting in overlapping clinical outcomes.

Amino Acid Substitution↗

PubMed2001

The measured level of prion infectivity varies in a predictable way according to the aggregation state of the infectious agent.

Transmissible spongiform encephalopathies are believed to be caused by an infectious form of the prion protein, designated PrP(Sc). The concentration of PrP(Sc) is often poorly correlated to the level of infectivity. Infectivity can be measured in two ways, namely endpoint titration and the incubation time assay, but patterns of infectivity vary depending on which method is used. These discrepancies can be explained by variation in the aggregation state of PrP(Sc). Both methods of measuring infectivity are modelled mathematically, and the theoretical results are in agreement with published data. It was found to be theoretically impossible to characterise prion infectivity by a multiple of a single quantity representing 'one prion', no matter how it is measured. Infectivity is instead characterised by both the number and sizes of the PrP(Sc) aggregates. Apparent discrepancies arise when these complexities are reduced to a single number.

Animals↗

PubMed2000

Designing drugs to stop the formation of prion aggregates and other amyloids.

Amyloid protein aggregates are implicated in many neurodegenerative diseases, including Alzheimer's disease and the prion diseases. Therapeutics to block amyloid formation are often tested in vitro, but it is not clear how to extrapolate from these experiments to a clinical setting, where the effective drug dose may be much lower. Here we address this question using a theoretical kinetic model to calculate the growth rate of protein aggregates as a function of the dose of each of three categories of drug. We find that therapeutics which block the growing ends of amyloids are the most promising, as alternative strategies may be ineffective or even accelerate amyloid formation at low drug concentrations. Our mathematical model can be used to identify and optimise an end-blocking drug in vitro. Our model also suggests an alternative explanation for data previously thought to prove the existence of an entity known as protein X.

Amyloid↗

PubMed2000

Clinical findings in a patient with FGFR1 P252R mutation and comparison with the literature.

We report on a patient with the skeletal findings of Jackson-Weiss syndrome, who manifests only mild craniofacial anomalies. Molecular analysis of her fibroblast growth factor receptor 1 gene (FGFR1) identified a heterozygous P252R missense mutation, previously only reported with FGFR1-Pfeiffer syndrome like manifestations. Mutations in the immunoglobulin-like, II-III (IgII-III) linker region of FGFR1 and FGFR3 molecules may present as a skeletal dysplasia affecting the appendicular skeleton including, brachydactyly, short broad middle phalanges, phalangeal epiphyseal coning and broad halluces. This communication is a further example of the phenomenon of an activated FGFR molecule resulting in overlapping manifestations in FGFR syndromes.

Abnormalities, Multiple↗

PubMed2000

Fluctuations in HIV-1 viral load are correlated to CD4+ T-lymphocyte count during the natural course of infection.

Viral load fluctuates during the natural course of asymptomatic HIV-1 infection. It is often assumed that these fluctuations are random around a set point or underlying growth trend. Using longitudinal data, we tested whether fluctuations in viral load can be better explained by changes in CD4+ T-cell count than by a set point or trend of exponential growth. The correspondence between viral load and CD4+ T-cell count could be described by a simple mathematical relation. Using a bootstrapping approach, the hypothesis that viral load fluctuations are random around a set point was rejected with p < .00005. The hypothesis that viral load fluctuations are random around a trend of exponential growth was rejected with p < .005. Viral load data was explained better by changes in CD4+ T-cell counts than by a set point or by a trend of exponential growth. The implications of this finding for improved prognostication are discussed.

CD4 Lymphocyte Count↗

PubMed2000

Evaluation and management of mechanical dysfunction in continent colonic urinary reservoirs.

PURPOSE: We analyze a group of patients who presented with mechanical dysfunction of the reservoir and/or efferent limb of a continent colonic urinary diversion, and establish an evaluation and management algorithm. MATERIALS AND METHODS: A total of 16 patients with a mean age of 58 years and 1 or more symptoms related to continent colonic urinary diversion were evaluated. Presenting symptomatology included difficult catheterization in 8 cases (50%), disabling incontinence in 8 (50%) and recurrent urinary tract infections in 6 (37.5%). All patients had normal, nonobstructed, nonrefluxing upper tracts and none presented with stone disease. Urological evaluation consisted of catheterization, fluoroscopy and urography of the pouch, retrograde urography of the external limb and urodynamics (enterocystometrogram and outlet pressure profilometry). RESULTS: Of the 8 patients with difficulty with catheterization 4 had stomal stenosis, 2 had an elongated and redundant external limb, and 2 had a false passage. Diagnosis was established by the inability to catheterize, fluoroscopy of the pouch and retrograde urography. Disabling incontinence occurred in 8 patients, including 7 who presented with an incompetent outlet and 2 with high pressure intestinal contractions of the reservoir. The aforementioned abnormalities were diagnosed by a combination of retrograde urography, urography of the pouch and urodynamics. Recurrent symptomatic urinary infections were observed in 5 patients of the previous groups and in another with an hourglass reservoir, which was primarily diagnosed by urography of the pouch. Surgical correction in 15 patients included outlet reinforcement, reservoir revision, stomal or external limb revision and conversion to a urinary conduit. Surgical treatment was successful in 14 of 15 patients (93%). CONCLUSIONS: Catheterization difficulty requires retrograde urography to define possible anatomical abnormalities (false passage, conduit elongation) if catheterization and fluoroscopy of the pouch do not demonstrate stomal stenosis. Urinary incontinence benefits from enterocystometry and outlet pressure measurement to determine reservoir and external limb function. Recurrent urinary tract infections not related to ureteral obstruction or reflux requires fluoroscopy of the pouch and external limb to determine abnormalities in patients with detubularization and localization of areas of urine pooling.

Adult↗

PubMed1999

The kinetics of proteinase K digestion of linear prion polymers.

Transmissible spongiform encephalopathies such as scrapie are caused by a protein-only infectious agent, known as a prion. It is not clear how a protein can be capable of replicating itself, and the mechanism remains controversial. One influential model hypothesizes that prions are nucleated, macroscopically linear polymers. We investigated the theoretical kinetics of this model and derived predictions which could be used to test the model. In the model, the polymerization and depolymerization rates are independent polymer size. This leads to an exponential size distribution at equilibrium. In agreement with a prediction stemming from this size distribution, the average size of PrP-res polymers was proportional to the square root of the concentration of PrP-res in a published study of in vitro conversion. Prion digestion by proteinase K (PK) is predicted to be biphasic. The second phase of digestion should be virtually independent of the PK concentration and should depend on the initial size distribution of prion polymers. For initially equilibrated polymers with an exponential size distribution, phase two digestion is exponential at a predicted rate. This rate varies in a defined way with the concentration used for equilibration and with other parameters which affect the average polymer size.

Biopolymers↗

PubMed1999

Quantifying the kinetic parameters of prion replication.

The mechanism of protein-only prion replication is controversial. A detailed mathematical model of prion replication by nucleated polymerisation is developed, and its parameters are estimated from published data. PrP-res decay is around two orders of magnitude slower than PrP-sen decay, a plausible ratio of two parameters estimated from very different experiments. By varying the polymer breakage rate, we reveal that systems of short polymers grow the fastest. Drugs which break polymers could therefore accelerate disease progression. Growth in PrP-res seems slower than growth in infectious titre. This can be explained either by a novel hypothesis concerning inoculum clearance from a newly infected brain, or by the faster growth of compartments containing smaller polymers. The existence of compartments can also explain why prion growth sometimes reaches a plateau. Published kinetic data are all compatible with our mathematical model, so the nucleated polymerisation hypothesis cannot be ruled out on dynamic grounds.

Animals↗

PubMed1999

Variability in kyphomelic dysplasia.

Four infants with kyphomelic dysplasia ascertained from three families demonstrate variability within the syndrome. In the first family, sibling recurrence in female sibs was noted with atypical kyphomelic dysplasias, suggesting autosomal recessive inheritance. In the second family, with a male affected with the 'typical findings' of lethal kyphomelic dysplasia, diagnosis of a skeletal dysplasia was suspected at 29-30 weeks' gestation following US detection of short, bent femurs. In the third family, with a female affected, severe radiographic changes were documented at birth. The clinical course of the disease was mild with almost complete regression of the radiographic findings at the age of 7 years.

Abortion, Induced↗

PubMed1999

Mesomelic dysplasia with periosteal thickening, radio-humeral dislocation, osteoporosis and multiple fractures.

UNLABELLED: We report a boy with a new form of mesomelic dysplasia characterised by short stature, multifocal periosteal thickening, radio-humeral dislocation, osteoporosis and multiple fractures with minimal trauma. Electrophoresis of fibroblast collagens detected defects in type III and type V collagen. CONCLUSION: Bone dysplasias presenting with osteopenia, abnormal trabecular pattern, bone fragility, and periosteal thickening suggest a collagenopathy. A possible collagen defect requires biochemical investigations.

Abnormalities, Multiple↗

PubMed1999

Antenatal detection and management of suprarenal masses.

The indications for, and timing of, surgical intervention for suprarenal masses detected prenatally are unclear. Also, the definitive diagnosis of suprarenal masses using imaging studies is difficult at best. We report 2 cases of antenatally detected suprarenal masses. One case represents an initial cystic mass expanding and becoming solid that had benign pathologic features. The second case was a stable solid mass that, on exploration, was malignant. Management options are discussed.

Adrenal Gland Diseases↗

PubMed1999

Feeding problems in infants with gastro-oesophageal reflux disease: a controlled study.

OBJECTIVE: Gastro-oesophageal reflux disease (GORD) in infants is commonly associated with feeding problems but has not been subject to systematic controlled study. We evaluated feeding, dietary, behavioural data obtained from systematic objective studies of six-month old infants with and without GORD. METHODS: Infants with GORD (defined by 24-h pH monitoring, n = 20), and age, gender, gestation, and socio-economic matched healthy infants (n = 20) had standardised assessments of dietary intake, oromotor function by videoanalysis (Feeding Assessment Schedule, FAS), and infant feeding behaviour by Testers and Maternal Ratings (TRIB and MRIB). Videofluoroscopic analyses of swallowing was undertaken in 11/20 GORD infants and analysed by standardised paediatric check list. RESULTS: Compared with control data: GORD infants had significantly lower energy intakes; the FAS showed GORD infants to have significantly fewer adaptive skills and readiness behaviour for solids, significantly more food refusal and food loss; the TRIB showed GORD infants to be significantly more demanding and difficult with feeds; and the MRIB revealed that mothers of GORD infants had significantly more negative feelings, significantly less enjoyment of feeds, and reported significantly more crying behaviour. On videofluoroscopy, oral-preparatory and oral phase problems predominated, particularly with solids, silent aspiration occurred during the pharyngeal phase in 2/11, and delayed oesophageal transit occurred in 4/11. CONCLUSIONS: Feeding problems affecting behaviour, swallowing, food intake, and mother-child interaction occur in infants with GORD, who displayed a lack of development of age-appropriate feeding skills. The contribution of feeding problems to morbidity in GORD in infants has been underestimated in the past.

Bottle Feeding↗

PubMed1997

Measurement of radiation dose received by the hands and thyroid of staff performing gridless fluoroscopic procedures in children.

The aim of this study was to confirm that the radiation doses received by attendants who manually restrain infants during fluoroscopic procedures are low. Doses to the hands and neck of three radiologists and three nurses performing or assisting at all the fluoroscopic procedures in a children's hospital were measured for 1 month using thermoluminescent dosemeters. All fluoroscopy on children at this hospital is performed without an antiscatter grid. Total doses for the neck ranged from 20 to 50 microSv per week and for hands from 40 to 210 microSv per week. These doses were shared by the three radiologists and the three nurses. Individual doses received per staff member are very small when compared with the doses received by interventional radiology staff. Doses received by staff in this study were of the order of 5% of the limit advised by the National Health and Medical Research Council of Australia (NHMRC) for radiation workers. Nurses received larger doses than radiologists and steps will be taken to reduce this dose further.

Adolescent↗

PubMed1996

Dysosteosclerosis.

A 5 1/2 year old boy presented with delayed development and loss of vision. A skeletal survey showed osteosclerosis consistent with dysosteosclerosis. Some unusual features of dysosteosclerosis are discussed.

Bone and Bones↗