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B A Kakulas

Publications and source records attributed to B A Kakulas.

At least 19 recordsLinked to original sources
PubMed2002

The mRNA of the NR1 subtype of glutamate receptor in Alzheimer's disease.

Glutamate has been implicated in the pathogenesis of Alzheimer's disease (AD). Controversial data exists regarding changes in the N-methyl-D-aspartate (NMDA) receptor complex in AD. We wished to elucidate the hypothesis that the NMDA receptor system is involved in the pathogenesis of AD using a gene expression approach targeting the mRNA of the universal subtype of the NMDA receptor NR1. This was performed using in situ hybridization and antisense 35S-labelled oligonucleotides on brain tissue collected at post-mortem. Relative mRNA expression was measured in standardised optical density units (OD units) using videodensitometry without knowledge of the diagnosis. The study population consisted of AD (n = 6) and neurodegenerative non-Alzheimer controls (non-AD, n = 14). Gene expression was measured in the frontal lobe, superior temporal gyrus and three areas within the hippocampus. We have observed no significant differences in the relative mRNA expression of the NR1 subtype of glutamate receptor in the following regions: frontal lobe AD = 60.7 +/- 14.1 OD units mRNA (x +/- 1SE) vs 52.6 +/- 1 in non-AD (Mann-Whitney test, p = 0.477); the superior temporal gyrus: AD = 53.3 +/- 13.9 vs 38.2 +/- 7 (p = 0.37); the CA1 region: AD = 37.8 +/- 7.75 vs 81.5 +/- 25.7 (p = 0.66); subiculum AD = 46.7 +/- 11.0 vs 105 +/- 43.3 (p = 0.82); parahippocampal gyrus AD = 36.6 +/- 9.3 vs 81.7 +/- 40.6 (p = 0.90). There were trends to a reduction in NR1 mRNA in the hippocampus and increased NR1 within the frontal and superficial temporal gyrus which were not significant. There was variation within and between all patients with and without AD in the magnitude of NR1 expression in all anatomical regions studied. The findings suggest heterogeneity in the involvement of the post-synaptic glutamatergic system in AD.

Adult↗
PubMed2002

Retropulsion of intervertebral discs associated with traumatic hyperextension of the cervical spine and absence of vertebral fracture: an uncommon mechanism of spinal cord injury.

STUDY DESIGN: Case report of a 68-year-old male who sustained cervical trauma following a bodysurfing accident. OBJECTIVE: To describe the pathology of a relatively uncommon mechanism of injury involving extradural cord compression associated with traumatic disc protrusion and herniation, following a cervical hyperextension injury in which there was no vertebral fracture or residual subluxation. SETTING: Department of Neuropathology, Royal Perth Hospital, West Australia. METHOD: Postmortem pathology report. RESULTS: Evidence of multiple ruptures of anterior longitudinal ligament with posterior intervertebral disc herniation and three discrete foci of central cord hemorrhage. CONCLUSION: Observations are consistent with cervical extension injury and an injury vector that involves intense axial loading sufficient to cause multiple disc failures, disc herniation and retropulsion leading to extradural disc compression and cord hemorrhage.

Aged↗
PubMed2001

A new PRNP mutation (G131V) associated with Gerstmann-Sträussler-Scheinker disease.

BACKGROUND: Gerstmann-Sträussler-Scheinker disease is a rare form of prion disease. OBJECTIVE: To determine the prion mutation in a 51-year-old man without a family history of neurologic disease who died from Gerstmann-Sträussler-Scheinker disease. PATIENT AND METHODS: The patient was a 51-year-old man who died after a 9-year illness characterized by dementia and eventually ataxia. Neuropathologic studies were performed, the results of which revealed abundant prion protein-immunopositive amyloid plaques in the cerebellum without spongiform degeneration. RESULTS: Genetic analysis of the prion protein gene showed a novel mutation at codon 131 that caused a valine-for-glycine substitution (G131V) and homozygosity at codon 129 (129M). Proteinase K-resistant prion protein was detected by Western blot analysis. CONCLUSIONS: This is the first mutation described in the short, antiparallel beta-sheet domain of the prion protein. This report highlights the importance of genetic analysis of patients with atypical dementia even in the absence of a family history.

Base Sequence↗
PubMed2000

Amyloid precursor protein gene isoforms in Alzheimer's disease and other neurodegenerative disorders.

Differential expression of the amyloid precursor protein gene (APP) may be important in the development of amyloidosis in Alzheimer's disease (AD) and experimentally in the brain's response to injury. Controversial data suggests that APP isoforms containing the Kunitz protease inhibitor isoform (APP KPI+) are over expressed in the brains of patients with AD when compared to the non-Kunitz protease inhibitor containing isoforms (APP KPI-). We have investigated this hypothesis using a quantitative analysis of gene expression on brain tissue collected at post-mortem. In situ hybridization has been used with synthetic oligonucleotide probes labelled with 35S to detect the two principal splice variants of APP: APP 695 (KPI-) and APP 751 (KPI+). A prospective brain bank of frozen brain specimens has been established and includes pathologically proven AD (n=15) and other neurodegenerative disorders as controls (n=18). The controls consist of frontal lobe atrophy (n=4), Huntington's disease (n=5), Parkinson's disease (n=4), motor neuron disease (n=2), multi-infarct dementia (n=1), multisystem atrophy (n=1), and subacute sclerosing panencephalitis (n=1). We have observed no significant differences in the expression of APP 695 KPI- mRNA in frontal lobe: 17.49+/-3.26 optical density (OD) units of mRNA expression in AD vs. 16.13+/-1.76 OD units mRNA in controls (P=0.80, linear regression); or temporal lobe: 14.73+/-2.96 in AD vs. 16.49+/-2.15 in controls (P=0.55). No significant differences have been found in APP 751 KPI+ in frontal lobe: 12.86+/-2.98 in AD vs. 13.70+/-2.88 in controls (P=0.97); and temporal lobe: 13.31+/-4.93 in AD vs. 11.07+/-1.99 in controls (P=0. 65). Analysis of the ratios of APP 751 KPI+ OD units of mRNA to APP 695 KPI- mRNA revealed a trend to an increased ratio which did not reach statistical significance: frontal lobe APP 751 KPI+/APP 695 KPI- 1.92+/-1.04 in AD vs. 0.86+/-0.17 in controls (P=0.54); temporal lobe 2.54+/-1.59 in AD vs. 0.96+/-0.11 controls (P=0.34). Our data has not revealed differential expression of APP mRNA isoforms in AD and supports the hypothesis that post-translational events in APP metabolism are important in amyloidogenesis and the pathogenesis of AD.

Adult↗
PubMed2000

Severe gamma-sarcoglycanopathy caused by a novel missense mutation and a large deletion.

We report two siblings with a relatively severe limb-girdle muscular dystrophy. The elder sister presented at 8 years of age with inability to climb and abnormal gait. At 12 years she was barely ambulant. Her sister followed a similar course. Serum creatine kinase was 8500-10000 IU (N 25-200) in the elder sister and 17000-19000 IU in the younger sister. Muscle biopsy of the elder sister at 8 years showed chronic myopathic changes with loss of muscle fibres, active necrosis and regeneration. Immunocytochemistry demonstrated normal spectrin and dystrophin, reduced alpha-sarcoglycan and absent gamma-sarcoglycan--indicating a gamma-sarcoglycanopathy. Haplotype analysis for the markers D13S115, D13S232, D13S292, D13S787, D13S1243 and D13S283 internal to and flanking the gamma-sarcoglycan gene showed the affected sisters shared haplotypes, indicating it was possible they were suffering from a gamma-sarcoglycanopathy. Non-inheritance of paternal alleles for D13S232, D13S292 and D13S1243 suggested the inheritance of a deletion, which was confirmed by FISH, using a genomic probe from the gamma-sarcoglycan gene. The gamma-sarcoglycan cDNA was amplified by reverse transcriptase PCR from the muscle biopsy of the elder sister and sequenced. A missense mutation changing codon 69 from GGC glycine to CGC arginine was identified. HhaI digestion of exon 3 genomic PCR products showed the two affected sisters were hemizygous for the mutation, while the mother and grandmother were heterozygotes. The mutation, identified by SSCP analysis, was not observed in 116 unrelated, unaffected individuals. Previously, only two other missense mutations, the Cys283Tyr missense mutation in Gypsies and the Leu193Ser mutation in a Dutch family, have been described in the gamma-sarcoglycan gene. The fact that the affected individuals in the current and Gypsy families are gamma-sarcoglycan negative may indicate that codons 69 and 283 are important in gamma-sarcoglycan function.

Adolescent↗
PubMed1999

Butyrycholinesterase K variant and Alzheimer's disease.

This study attempted to corroborate findings on the association between butyrylcholinesterase K variant and Alzheimer's disease. This was performed on an autopsy-confirmed series of patients with Alzheimer's disease and controls. The butyrylcholinesterase K variant was found to be of increased allele frequency in patients with sporadic Alzheimer's disease. When related to APOE epsilon4 typing the association was specific but not sensitive for the diagnosis of Alzheimer's disease.

Aged↗
PubMed1999

The contribution of molecular genetics in the diagnosis and management of neuromuscular disorders.

It is true that the recent advances in molecular genetics have generated a medical revolution. This is especially true for the inherited neuromuscular disorders. There have been many spectacular recent discoveries with new genes being found and their protein products identified. One of the most remarkable aspects of this progress is the nexus which has developed between the basic discovery and its clinical application. As soon as a new genetic mutation is reported, the information may be used immediately to establish the molecular diagnosis for that disorder in any part of the world which has a DNA laboratory. This is done by using primers derived from the published DNA sequences using the polymerase chain reaction (PCR). This development is of immense value for the clinician as it provides an exact molecular diagnosis often with prognostic information and the test results can be used for genetic counselling and prenatal diagnosis. One of the unexpected outcomes of this work has been the surprising variation which has been shown to exist between genotype and phenotype. Previously, one mutation was believed to be responsible for one clinical disorder. However, it is now known that one genotype may be responsible for a variety of phenotypes and vice versa. In the field of neuromuscular disorders the most notable advances have occurred for Duchenne muscular dystrophy and the related dystrophinopathies and for the group of limb girdle muscular dystrophies, especially the subgroup of sarcoglycanopathies. Other areas are the congenital myopathies, the 'channel-opathies' and the mitochondrial cytopathies. In this review the most commonly used molecular genetic and immunocytochemical methods using antibodies to the protein product are outlined together with the principles of their application in the neuromuscular clinic. Included are the provisos and pitfalls which need to be kept in mind in the interpretation of DNA results for each patient.

Female↗
PubMed1999

A review of the neuropathology of human spinal cord injury with emphasis on special features.

A judicious understanding of the basic neuropathology of spinal cord injuries (SCI) is essential knowledge for the clinician responsible for SCI management. An appreciation of the nature of human SCI is also necessary for the neuroscientist searching for a cure. The neuropathology of human SCI described here is derived from the study of 564 cases of spinal cord trauma held in a tissue bank and database of the Department of Neuropathology, Royal Perth Hospital in Australia. The main features of SCI neuropathology are reviewed and special aspects such as early axonal lesions, traumatic demyelination-remyelination, and quantification of white matter tracts are reported in more detail. One of the remarkable outcomes of this work is the finding that the majority of SCI patients have a proportion of spinal cord white matter maintained across the level of the lesion, an observation that has important therapeutic implications.

Adolescent↗
PubMed1999

Novel mutation in the myelin protein zero gene in a family with intermediate hereditary motor and sensory neuropathy.

OBJECTIVES: To determine the molecular basis for autosomal dominant intermediate hereditary motor and sensory neuropathy (HMSN) in a four generation family. The gene defects in families with intermediate HMSN are not known, but it has been suggested that most have X linked HMSN. METHODS: All participating family members were examined clinically. Genomic DNA was obtained from 10 affected and seven unaffected members. Linkage analysis for the known HMSN loci was first performed. Mutations in the peripheral myelin protein zero gene (PMP0) were sought in two affected members, using one unaffected member for comparison, by amplification of the six exons of the gene followed by single strand conformation polymorphism (SSCP) analysis, dideoxy fingerprinting (ddF), and sequencing. Subsequently, the mutation was screened for in all affected and unaffected members in the family using Alu I digestion and in 100 unrelated control subjects using "snap back" SSCP analysis. Sequencing of cDNA from a sural nerve biopsy from an affected member was also performed. RESULTS: The clinical phenotype was of variable severity, with motor nerve conduction velocities in the intermediate range. Linkage to PMP0 was demonstrated. Analysis of genomic DNA and cDNA for PMP0 identified a novel codon 35 GAC to TAC mutation. The mutation produces an inferred amino acid change of aspartate to tyrosine at codon six of the processed protein (Asp6Tyr) in the extracellular domain and was present in all affected family members but not in 100 unrelated controls. CONCLUSIONS: The present findings further extend the range of phenotypes associated with PMP0 mutations and indicate that families with "intermediate" HMSN need not necessarily be X-linked as previously suggested.

Adult↗
PubMed1998

High-level dystrophin expression after adenovirus-mediated dystrophin minigene transfer to skeletal muscle of dystrophic dogs: prolongation of expression with immunosuppression.

Replication-deficient adenovirus vectors (AdV) have been successfully used to transfer a truncated human dystrophin cDNA to skeletal muscle of dystrophin-deficient mdx mice. A dystrophin-deficient golden retriever dog model (GRMD) has been identified, which, unlike the mouse model, leads to a clinicopathological phenotype similar to that of Duchenne muscular dystrophy (DMD). We show for the first time that high-level dystrophin expression in skeletal muscle of GRMD dogs can be achieved by AdV-mediated gene transfer. However, a humoral and cellular immune response of the host against antigens of viral and transgene origin (similar to that occurring in mdx mice after AdV-mediated dystrophin gene transfer) leads to a decline of dystrophin expression over a 2-month period. Immunosuppression by cyclosporin significantly prolonged transgene expression. The GRMD model may help to solve the open questions pertaining to dystrophin gene transfer such as systemic delivery and improvement of muscle function before human trials for gene replacement therapy in DMD may be considered.

Adenoviridae↗
PubMed1998

Direct dystrophin and reporter gene transfer into dog muscle in vivo.

Bacterial beta-galactosidase cDNA was injected without lipofectin into 41 sites in dog muscle and expression was seen in 22 of them. The cDNA and lipofectin was injected into 35 similar sites and expression was seen in 21. Expression was seen in a maximum of 2.5% of muscle fibers and 23.21% of nonmuscle cells. A total of 106 muscle sites were injected with the minigene with and without lipofectin. In 4 of the 45 sites injected with the minigene without lipofectin human dystrophin was expressed around the periphery of 0.3% of the fibers. Bacterial beta-galactosidase cDNA was injected into the peritoneal cavity of 4 pups, 2 of which also received lipofectin. In all 4, expression was seen in liver, spleen, and mesenteric lymph node. In the 2 pups that received lipofectin, expression was also seen in the diaphragm, intercostal, and abdominal muscles of 1 and in the diagphragm and intercostal muscles of the other. These experiments show that human dystrophin transgene expression can be obtained in dog muscle. However, other methods will be required to increase the degree of expression before gene therapy trials can be undertaken.

Animals↗
PubMed1998

Dorsal root ganglion injuries in 109 blunt trauma fatalities.

In an autopsy study of 180 cervical spines, 109 were from victims of fatal blunt injury. A search was made for injuries to the dorsal root ganglia. The whole cervical spines, from the skull base to T1, were formalin fixed, deep frozen and sagittally sectioned on a specially adapted band saw in 2.5 mm thick slices. In 15 of the 109 fatally injured individuals, 44 examples of interstitial haemorrhage into a dorsal root ganglion (DRG) were found. This was sometimes accompanied by neural tissue disruption, visible only on histological study. The intraneural DRG haemorrhage was found in 13.8 per cent of all the injured individuals, but this prevalence rose to 34.5 per cent when only those (29) individuals surviving the injury between 2 h and 7 days were considered. The possible relevance of such injuries, in survivors of injury, to acute and chronic pain syndromes is discussed.

Adolescent↗
PubMed1998

Age-related congophilic inclusions in the brains of apolipoprotein E-deficient mice.

The hippocampal region of apolipoprotein E-deficient mice of varying ages was examined for any morphological changes by light and electron microscopy. Unusual periodic acid-Schiff-positive granules were seen in the hippocampal area of these animals as early as the fourth week of life and their numbers increased gradually with age. These granules were never found in control C57BL/6J (B6) mice before six months-of-age and their numbers were invariable low. They were strongly congophilic when stained with a modified Congo Red technique and reacted with a monoclonal antibody specific to amino acids 17-24 and 35-43 of the beta-amyloid peptide. The immunostaining of these granules with the beta-amyloid peptide was lost after specific adsorption with the appropriate synthetic peptide. These granules were identified ultrastructurally as non-membrane-bound fibrillogranular material in the cytoplasm of protoplasmic astrocytes. The data indicate that an amyloid-like protein accumulates in the protoplasmic astrocytes of the hippocampus of apolipoprotein E-deficient mice, especially in the brains of old animals.

Aging↗
PubMed1998

Arthrogryposis multiplex congenita in Western Australia.

OBJECTIVE: Determination of the prevalence of arthrogryposis multiplex congenita in Western Australia as well as the causes of the condition. Overseas reports varied considerably and no such survey had been conducted in Western Australia. METHODOLOGY: Case names were obtained from various registers and records as well as from private practitioners covering the 14 years birth cohort between 1980 and 1993. The records, and where possible the patients, were seen by one of the authors. Diagnosis was further established through relevant investigation where possible. RESULTS: Thirty cases were identified, giving a birth prevalence of approximately 1 in 12000. In nine cases there were significant abnormalities of the central nervous system, in seven cases anterior horn cell and/or peripheral nervous involvement was the cause and in three there was primary muscle disease. The remaining 11 had various syndromes for which no definite neuropathological lesions could be demonstrated, but most of these had syndromes such as distal arthrogryposis or amyoplasia. Mortality was 37%. Talipes occurred in 23 of 30 cases. Early intervention and, in more severe cases, radical surgical intervention was the management adopted in most cases. CONCLUSION: The birth prevalence of arthrogryposis in Western Australia is somewhat less than that reported in Canada and Finland but somewhat greater than the Edinburgh figures, which appear to be the extremes quoted in the literature. Prognosis is worse in cases with serious central nervous system involvement and/or chest involvement, and better in cases of localised arthrogryposis (e.g. distal), as well as in the specific syndrome of amyoplasia as described by Hall.

Arthrogryposis↗