Biomedical subjects

M M Ryan

Publications and source records attributed to M M Ryan.

At least 19 recordsLinked to original sources

PubMed2007

Outcome of noninvasive ventilation in children with neuromuscular disease.

OBJECTIVE: To assess the effect of institution of noninvasive ventilation (NIV) on clinical outcome and quality of life (QOL) in a cohort of children with severe neuromuscular disorders. METHODS: We reviewed records and obtained clinical data from the year prior to commencing NIV and annually thereafter. Data obtained included diagnosis, patient symptoms, mortality, NIV adverse effects, pulmonary function tests, polysomnographic data, length of hospitalizations, and health care costs. Patients and parents completed questionnaires assessing QOL with NIV and recalling QOL before NIV. RESULTS: Fourteen of 17 (82%) suitable patients were enrolled. Follow-up ranged from 6 to 84 months (median 30). Symptoms of daytime sleepiness (p = 0.003) and headache (p = 0.046) improved after initiation of NIV. Sleep quality assessed by polysomnography also improved. Hospitalization rates (p = 0.002) and health care costs (p = 0.003) decreased. QOL remained stable after NIV, despite disease progression. CONCLUSION: Treatment of respiratory failure, in children with neuromuscular disease, with noninvasive ventilation results in a reduction in symptoms, hospitalizations, and health care costs without adverse effects on quality of life.

Child↗

PubMed2006

Gene expression analysis of bipolar disorder reveals downregulation of the ubiquitin cycle and alterations in synaptic genes.

Bipolar affective disorder is a severe psychiatric disorder with a strong genetic component but unknown pathophysiology. We used microarray technology to determine the expression of approximately 22,000 mRNA transcripts in post-mortem tissue from two brain regions in patients with bipolar disorder and matched healthy controls. Dorsolateral prefrontal cortex tissue from a cohort of 70 subjects and orbitofrontal cortex tissue from a separate cohort of 30 subjects was investigated. The final analysis included 30 bipolar and 31 control subjects for the dorsolateral prefrontal cortex and 10 bipolar and 11 control subjects for the orbitofrontal cortex. Differences between disease and control groups were identified using a rigorous statistical analysis with correction for confounding variables and multiple testing. In the orbitofrontal cortex, 393 differentially expressed transcripts were identified by microarray analysis and a representative subset was validated by quantitative real-time PCR. Pathway analysis revealed significant upregulation of genes involved in G-protein coupled receptor signalling and response to stimulus (in particular the immune response), while genes relating to the ubiquitin cycle and intracellular transport showed coordinated downregulation in bipolar disorder. Additionally, several genes involved in synaptic function were significantly downregulated in bipolar disorder. No significant changes in gene expression were observed in the dorsolateral prefrontal cortex using microarray analysis or quantitative real-time PCR. Our findings implicate the orbitofrontal cortex as a region prominently involved in bipolar disorder and indicate that diverse processes are affected. Overall, our results suggest that dysregulation of the ubiquitin pathway and synaptic function may be central to the disease process.

Adult↗

PubMed2006

Sec14p-like proteins regulate phosphoinositide homoeostasis and intracellular protein and lipid trafficking in yeast.

The major PI (phosphatidylinositol)/PC (phosphatidylcholine)-transfer protein in yeast, Sec14p, co-ordinates lipid metabolism with protein transport from the Golgi complex. Yeast also express five additional gene products that share 24-65% primary sequence identity with Sec14p. These Sec14p-like proteins are termed SFH (Sec Fourteen Homologue) proteins, and overexpression of certain individual SFH gene products rescues sec14-1(ts)-associated growth and secretory defects. SFH proteins are atypical in that these stimulate the transfer of PI, but not PC, between distinct membrane bilayer systems in vitro. Further analysis reveals that SFH proteins functionally interact with the Stt4p phosphoinositide 4-kinase to stimulate PtdIns(4,5)P(2) synthesis which in turn activates phospholipase D. Finally, genetic analyses indicate that Sfh5p interfaces with the function of specific subunits of the exocyst complex as well as the yeast SNAP-25 (25 kDa synaptosome-associated protein) homologue, Sec9p. Our current view is that Sfh5p regulates PtdIns(4,5)P(2) homoeostasis at the plasma membrane, and that Sec9p responds to that regulation. Thus SFH proteins individually regulate specific aspects of lipid metabolism that couple, with exquisite specificity, with key cellular functions.

Biological Transport, Active↗

PubMed2004

Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress.

The etiology and pathophysiology of schizophrenia remain unknown. A parallel transcriptomics, proteomics and metabolomics approach was employed on human brain tissue to explore the molecular disease signatures. Almost half the altered proteins identified by proteomics were associated with mitochondrial function and oxidative stress responses. This was mirrored by transcriptional and metabolite perturbations. Cluster analysis of transcriptional alterations showed that genes related to energy metabolism and oxidative stress differentiated almost 90% of schizophrenia patients from controls, while confounding drug effects could be ruled out. We propose that oxidative stress and the ensuing cellular adaptations are linked to the schizophrenia disease process and hope that this new disease concept may advance the approach to treatment, diagnosis and disease prevention of schizophrenia and related syndromes.

Brain↗

PubMed2004

Functional genomics and proteomics: application in neurosciences.

The sequencing of the complete genome for many organisms, including man, has opened the door to the systematic understanding of how complex structures such as the brain integrate and function, not only in health but also in disease. This blueprint, however, means that the piecemeal analysis regimes of the past are being rapidly superseded by new methods that analyse not just tens of genes or proteins at any one time, but thousands, if not the entire repertoire of a cell population or tissue under investigation. Using the most appropriate method of analysis to maximise the available data therefore becomes vital if a complete picture is to be obtained of how a system or individual cell is affected by a treatment or disease. This review examines what methods are currently available for the large scale analysis of gene and protein expression, and what are their limitations.

Brain↗

PubMed2003

Clinical course correlates poorly with muscle pathology in nemaline myopathy.

OBJECTIVE: To report pathologic findings in 124 Australian and North American cases of primary nemaline myopathy. METHODS: Results of 164 muscle biopsies from 124 Australian and North American patients with primary nemaline myopathy were reviewed, including biopsies from 19 patients with nemaline myopathy due to alpha-actin (ACTA1) mutations and three with mutations in alpha-tropomyosin(SLOW) (TPM3). For each biopsy rod number per fiber, percentage of fibers with rods, fiber-type distribution of rods, and presence or absence of intranuclear rods were documented. RESULTS: Rods were present in all skeletal muscles and diagnosis was possible at all ages. Most biopsies contained nemaline bodies in more than 50% of fibers, although rods were seen only on electron microscopy in 10 patients. Rod numbers and localization correlated poorly with clinical severity. Frequent findings included internal nuclei and increased fiber size variation, type 1 fiber predominance and atrophy, and altered expression of fiber type specific proteins. Marked sarcomeric disruption, increased glycogen deposition, and intranuclear rods were associated with more severe clinical phenotypes. Serial biopsies showed progressive fiber size variation and increasing numbers of rods with time. Pathologic findings varied widely in families with multiple affected members. CONCLUSIONS: Very numerous nemaline bodies, glycogen accumulation, and marked sarcomeric disruption were common in nemaline myopathy associated with mutations in skeletal alpha-actin. Nemaline myopathy due to mutations in alpha-tropomyosin(SLOW) was characterized by preferential rod formation in, and atrophy of, type 1 fibers. Light microscopic features of nemaline myopathy correlate poorly with disease course. Electron microscopy may correlate better with disease severity and genotype.

Actins↗

PubMed2001

Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene.

Nemaline myopathy (NM) is a clinically and genetically heterogeneous disorder characterized by muscle weakness and the presence of nemaline bodies (rods) in skeletal muscle. Disease-causing mutations have been reported in five genes, each encoding a protein component of the sarcomeric thin filament. Recently, we identified mutations in the muscle alpha-skeletal-actin gene (ACTA1) in a subset of patients with NM. In the present study, we evaluated a new series of 35 patients with NM. We identified five novel missense mutations in ACTA1, which suggested that mutations in muscle alpha-skeletal actin account for the disease in approximately 15% of patients with NM. The mutations appeared de novo and represent new dominant mutations. One proband subsequently had two affected children, a result consistent with autosomal dominant transmission. The seven patients exhibited marked clinical variability, ranging from severe congenital-onset weakness, with death from respiratory failure during the 1st year of life, to a mild childhood-onset myopathy, with survival into adulthood. There was marked variation in both age at onset and clinical severity in the three affected members of one family. Common pathological features included abnormal fiber type differentiation, glycogen accumulation, myofibrillar disruption, and "whorling" of actin thin filaments. The percentage of fibers with rods did not correlate with clinical severity; however, the severe, lethal phenotype was associated with both severe, generalized disorganization of sarcomeric structure and abnormal localization of sarcomeric actin. The marked variability, in clinical phenotype, among patients with different mutations in ACTA1 suggests that both the site of the mutation and the nature of the amino acid change have differential effects on thin-filament formation and protein-protein interactions. The intrafamilial variability suggests that alpha-actin genotype is not the sole determinant of phenotype.

Actins↗

PubMed2001

Nemaline myopathy: a clinical study of 143 cases.

We report 143 Australian and North American cases of primary nemaline myopathy. As classified by the European Neuromuscular Centre guidelines, 23 patients had severe congenital, 29 intermediate congenital, 66 typical congenital, 19 childhood-onset, and 6 adult-onset nemaline myopathy. Inheritance was autosomal recessive in 29 patients, autosomal dominant in 41, sporadic in 72, and indeterminate in 1. Twenty-two patients had skeletal muscle actin mutations and 4 had mutations in the alpha-tropomyosin(slow) gene. Obstetric complications occurred in 49 cases. Seventy-five patients had significant respiratory disease during the first year of life, and 79 had feeding difficulties. Atypical features in a minority of cases included arthrogryposis, central nervous system involvement, and congenital fractures. Progressive distal weakness developed in a minority of patients. Thirty patients died, the majority during the first 12 months of life. All deaths were due to respiratory insufficiency, which was frequently underrecognized in older patients. Arthrogryposis, neonatal respiratory failure, and failure to achieve early motor milestones were associated with early mortality. Morbidity from respiratory tract infections and feeding difficulties frequently diminished with increasing age. Aggressive early management is warranted in most cases of congenital nemaline myopathy.

Adult↗

PubMed2000

Anterior horn cell disease and olivopontocerebellar hypoplasia.

To date, fewer than 30 cases of anterior horn cell disease with associated olivopontocerebellar hypoplasia have been reported. We describe five patients and review the literature on this uncommon disorder. In addition to a syndrome of progressive spinal muscular atrophy similar to that seen in Werdnig-Hoffmann disease, this disorder is characterised by hypoplasia of the olivary nuclei, pons, and cerebellum. Additional clinical features may include dysmorphism, abnormal eye movements, stridor, congenital joint contractures, and enlarged kidneys. Pontocerebellar hypoplasia may be associated with posterior fossa cystic malformations, cerebral atrophy, and a demyelinating neuropathy.

Cerebellar Diseases↗

PubMed2000

Childhood chronic inflammatory demyelinating polyneuropathy: clinical course and long-term outcome.

We reviewed the clinical history, electrophysiologic and pathologic findings, and response to therapy of 16 children with chronic inflammatory demyelinating polyneuropathy. The majority presented with lower limb weakness. Sensory loss was uncommon. The illness was monophasic in seven children, relapsing in six, and three had a slowly progressive course. All patients were treated with immunosuppressive agents. In 11, the initial treatment was prednisolone. All had at least a short-term response but five went on to develop a relapsing course. Intravenous immunoglobulin was the initial treatment in four patients. Three responded rapidly, with treatment being stopped after a maximum of 5 months. In resistant chronic inflammatory demyelinating neuropathy, in addition to prednisolone and immunoglobulin, plasma exchange, azathioprine, cyclosporine, methotrexate, cyclophosphamide and pulse methylprednisolone were tried at different times in different patients. On serial neurophysiologic testing slowing of nerve conduction persisted for long periods after clinical recovery. Follow-up was for an average of 10 years. When last seen 14 patients were asymptomatic, two having mild residual deficits. Childhood chronic inflammatory demyelinating neuropathy responds to conventional treatment and generally has a favourable long-term outcome.

Adolescent↗

PubMed2000

Persistent or severe back pain and stiffness are ominous symptoms requiring prompt attention.

BACKGROUND: Children with severe or persistent back pain and stiffness often have an underlying organic cause but there is a large differential diagnosis, examination may be difficult and the problem is relatively rare in general paediatric practice. These difficulties appeared to lead to delays in diagnosis and management of children with this problem. OBJECTIVES: To provide an approach to the diagnosis and management children with severe or persistent back pain or stiffness based on our clinical experience and the literature. METHODOLOGY: The case histories of 10 children with severe back pain seen by the authors over a 5-year period were reviewed. They were chosen as illustrative examples of the diagnostic and management problems and did not represent a systematic review of all cases seen by the authors over that time. RESULTS: Underlying causes included infection, inflammation, neoplasm, trauma and vascular malformation. Four of the children had spinal cord compression which required urgent decompression. There was one child with a conversion disorder but three children with organic disease were initially felt to have a conversion disorder. Investigations generally proceeded relatively slowly and the problem was not regarded as a semi-urgent situation carrying the risk of permanent paraplegia. Magnetic resonance imaging (MRI) scan of the spine was the investigation of choice. CONCLUSION: Children with severe or persistent back pain and stiffness have a wide variety of underlying causes. The possibility of underlying spinal cord compression should always be considered in children with this presentation. If the diagnosis is not obvious, MRI scan of the spine should be arranged without delay.

Back Pain↗

PubMed1999

Influenza A encephalitis with movement disorder.

Influenza A is an uncommon but well-recognized cause of viral encephalitis in childhood, occurring most commonly during community influenza outbreaks. The authors report four cases of influenza A encephalitis that occurred during an Australian epidemic in 1997-1998. Choreoathetosis during the acute phase of infection or basal ganglia involvement on neuroimaging was observed in three of the four patients. These findings in pediatric encephalitis are suggestive of influenza A infection and may guide investigation and early diagnosis.

Basal Ganglia↗

PubMed1999

A novel syndrome of episodic muscle weakness maps to xp22.3.

We describe a family with a novel disorder characterized by episodic muscle weakness and X-linked inheritance. Eight males in three generations demonstrate the characteristic features of the disorder. Episodes of severe muscle weakness are typically precipitated by febrile illness and affect the facial and extraocular musculature, as well as the trunk and limbs, and resolve spontaneously over a period of weeks to months. Younger members of the family are normal between episodes but during relapses show generalized weakness, ptosis, and fluctuations in strength. In some cases, fatigability can be demonstrated. The proband has late-onset chronic weakness and fatigability. The clinical phenotype has features suggestive both of the congenital myasthenic syndromes and of ion-channel disorders such as the periodic paralyses. We have localized the responsible gene to chromosome Xp22.3, with a maximum two-point LOD score of 4. 52 at a recombination fraction of.0, between OACA2 and DXS9985.

Adolescent↗

PubMed1999

Cerebral vasculitis in a case of Sydenham's chorea.

A 10-year-old girl with acute-onset hemichorea had multiple areas of abnormal signal seen on magnetic resonance imaging of the brain, associated with middle and anterior cerebral artery vasculitis seen on cerebral angiography. Her serology and clinical course were supportive of the diagnosis of Sydenham's chorea. Other causes of cerebral vasculitis were excluded. Follow-up studies revealed resolution of changes seen on magnetic resonance imaging and partial resolution of angiographic abnormalities. This is the first report of abnormal cerebral angiography in Sydenham's chorea.

Anterior Cerebral Artery↗

PubMed1998

Coordination of two-joint rectus femoris and hamstrings during the swing phase of human walking and running.

It has been hypothesized previously that because a strong correlation was found between the difference in electromyographic activity (EMG) of rectus femoris (RF) and hamstrings (HA; EMG(RF)-EMG(HA)) and the difference in the resultant moments at the knee and hip (Mk-Mh) during exertion of external forces on the ground by the leg, input from skin receptors of the foot may play an important role in the control of the distribution of the resultant moments between the knee and hip by modulating activation of the two-joint RF and HA. In the present study, we examined the coordination of RF and HA during the swing phase of walking and running at different speeds, where activity of foot mechanoreceptors is not modulated by an external force. Four subjects walked at speeds of 1.8 m/s and 2.7 m/s and ran at speeds of 2.7 m/s and 3.6 m/s on a motor-driven treadmill. Surface EMG of RF, semimembranosus (SM), and long head of biceps femoris (BF) and coordinates of the four leg joints were recorded. An inverse dynamics analysis was used to calculate the resultant moments at the ankle, knee, and hip during the swing phase. EMG signals were rectified and low-pass filtered to obtain linear envelopes and then shifted in time to account for electromechanical delay between EMG and joint moments. During walking and running at all studied speeds, mean EMG envelope values of RF were statistically (P<0.05) higher in the first half of the swing (or at hip flexion/knee extension combinations of joint moments) than in the second half (or at hip extension/knee flexion combinations of joint moments). Mean EMG values of BF and SM were higher (P<0.05) in the second half of the swing than in the first half. EMG and joint moment peaks were substantially higher (P<0.05) in the swing phase of walking at 2.7 m/s than during the swing phase of running at the same speed. Correlation coefficients calculated between the differences (EMG(RF)-EMG(HA)) and (Mk-Mh), taken every 1% of the swing phase, were higher than 0.90 for all speeds of walking and running. Since the close relationship between EMG and joint moments was obtained in the absence of an external force applied to the foot, it was suggested that the observed coordination of RF and HA can be regulated without a stance-specific modulation of cutaneous afferent input from the foot. The functional role of the observed coordination of RF and HA was suggested to reduce muscle fatigue.

Adult↗

PubMed1997

Hysterectomy: social and psychosexual aspects.

Studies of the psychological and sexual outcome of hysterectomy have often arrived at conflicting conclusions and this has resulted in some confusion among health professionals as well as among women themselves. This situation should cause concern, since the incidence of this surgery is high in most countries of the western world. The confusion about outcome arises out of the methodological problems that plagued earlier research. Some of the more recent studies using prospective design, standardized measures and appropriate statistical analysis have not implicated hysterectomy with increased psychological or sexual disorders. However, both before and after hysterectomy in samples studied, the rate of psychological disorder was higher than would have been expected in a normal population, although a clearer picture has emerged from the most recent study. In this paper, risk factors are identified, and the need to include women's own evaluation of the procedure is emphasized.

Female↗

PubMed1995

Antenatal HIV antibody testing in Australia.

OBJECTIVE: To evaluate the role of voluntary antenatal testing in HIV surveillance and prevention by examining antenatal HIV antibody testing practice and policy in Australia. DESIGN: Cross-sectional study using a self-administered questionnaire. SUBJECTS AND SETTING: Specialist obstetricians and gynaecologists and general practitioners (GPs) affiliated with the Royal Australian College of Obstetricians and Gynaecologists and Australian public hospital antenatal clinics, August-November 1992. MAIN OUTCOME MEASURES: The percentage of public hospital antenatal clinics and specialist and GP obstetricians in Australia who tested pregnant women for HIV antibody as part of their antenatal care, and the proportion of pregnant women in Australia who had an antenatal HIV antibody test in the 1991-92 financial year. RESULTS: Questionnaires concerning antenatal HIV antibody testing were completed by 90% (993/1108) of specialists, 87% (2134/2461) of GPs and 93% (215/230) of public hospitals surveyed. Of the 706 specialists and 1503 GPs who reported that they were currently engaged in obstetric care, approximately 60% (430/706) and 935/1503, respectively) offered antenatal HIV testing either to all pregnant women or to selected groups at risk. There were significant differences in testing patterns between States and Territories. For the 95 public hospitals with antenatal clinics, 81% (77) offered the HIV antibody test to all or selected groups of pregnant women; these percentages did not differ significantly between States and Territories. It was estimated that 25% of pregnant women seen by specialists, 29% seen by GPs and 9% seen in public hospital clinics were tested for HIV antibody as part of their antenatal care in 1991-92. CONCLUSIONS: In Australia approximately one in five pregnant women were tested for HIV antibody as part of their antenatal care in 1991-92. Voluntary HIV testing in pregnancy may provide unrepresentative data for measuring the prevalence of HIV infection in pregnant women.

AIDS Serodiagnosis↗

PubMed1994

The polyurethane nasotracheal tube.

An uncuffed nasotracheal tube for use in minor maxillofacial surgery has been developed using polyurethane. The suitability of this tube as an alternative to the existing soft red rubber and harder polyvinyl chloride materials has been assessed at four centres during anaesthesia for routine oral surgery. The tube was found to be satisfactory.

Anesthesia, General↗