Control of Pelvic Blood Flow Using a Novel Pneumatic Abdominal Binder.

Background Obstetrical hemorrhage continues to be the leading cause of maternal death; additional means of treatment are needed to reach women who are currently not being saved. We developed the "Ball and Binder", an inexpensive and innovative pneumatic abdominal-pelvic compression device made with a cloth binder and soccer ball. Objective To measure the change in distal aortic blood flow before and after placement of the device. Method A comparative study was done on nine healthy volunteers measuring the flow in the distal aorta before and after placement of a pneumatic abdominal binder. Result Distal aortic flow decreased by over half when the device was inflated. Conclusion An inexpensive pneumatic external abdominal compression "Ball and Binder" device was able to decrease flow to the pelvis by over half. This provides an additional tool for rapid treatment of postpartum hemorrhage unresponsive to routine initial measures.

Comparison of two- and three-dimensional transvaginal ultrasound in the visualisation of intrauterine devices.

The aims of the study were to evaluate whether three-dimensional transvaginal ultrasound (3D TV US) is superior to two-dimensional transvaginal ultrasound (2D TV US) at visualising intrauterine devices and determining their position. This prospective study included 52 participants with an intrauterine device fitted, who underwent 2D TV US and 3D TV US. 2D TV US and 3D-reconstructed coronal images were reviewed by two gynaecological radiologists to assess ease of visualisation and position of the intrauterine devices. Statistical analysis was performed using Wilcoxon signed-rank, McNemar and Chi-squared tests. The inter-observer agreement was measured using Cohen's Kappa. Intrauterine device visualisation scores were significantly higher with 2D TV US compared with 3D TV US (Radiologist 1 p = <0.001, Radiologist 2 p = 0.007). A significant number of T-arms appeared to perforate into the adjacent myometrium on the 3D-reconstructed coronal image, but were normal on the 2D images (Radiologist 1 p = <0.001, Radiologist 2 p = 0.008). Radiologist 1 found 19 perforated T-arms on 3D TV US compared with four on 2D TV US. Radiologist 2 found 13 perforated T-arms on 3D TV US compared with five on 2D TV US. Both radiologists agreed on the positions of the intrauterine devices substantially with 3D TV US (Kappa = 0.69) and moderately with 2D TV US (Kappa = 0.55). The 3D TV US did not visualise an intrauterine device better than 2D TV US. The 3D-reconstructed coronal image of the uterus can reliably display cases of T-arm perforation into the adjacent myometrium, which could be missed on 2D TV US images. The 3D TV US should be used in addition to 2D TV US in all cases where an intrauterine device is under evaluation.

SPAST mutations in Australian patients with hereditary spastic paraplegia.

BACKGROUND: Hereditary spastic paraplegia (HSP) is often caused by mutations in the SPAST gene. The frequency of SPAST mutations causing HSP in Australian patients is currently unknown. AIM: We aimed to determine the frequency of SPAST gene mutations in our cohort of HSP patients. METHODS: We recruited 30 unrelated patients with HSP for clinical and genetic assessment. DNA or RNA was extracted from patients' samples to perform direct DNA sequencing of the SPAST gene, multiplex ligation-dependent probe amplification (MLPA) and/or cDNA analysis. RESULTS: We identified 13 heterozygous SPAST mutations in 16 unrelated patients. Most mutations (75%) were detected by DNA sequence analysis. We identified nine-point mutations (n = 9), insertion (n = 1), one type of splice site mutation (n = 2), one type of exonic deletion (n = 2) and one type of exonic amplification (n = 2). Missense mutations (n = 7) were the most frequent mutation type (44%). Heterozygous exonic deletion (n = 2) and heterozygous exonic amplification (n = 2) were identified by MLPA and cDNA screening (25%). We also identified the single heterozygous p.Ser44Leu polymorphism in two other patients without pathogenic mutations in SPAST. CONCLUSION: We conclude that SPAST mutations are responsible for the majority of HSP in Australia. Most of the patients with SPAST mutations had pure forms of HSP and a positive family history to suggest autosomal dominant (AD) HSP. Not all mutations were identified by direct sequencing of the SPAST gene, necessitating further molecular analysis. Given that SPAST mutations cause AD-HSP, these findings are important when providing genetic counselling for affected patients.

Diagnostic accuracy of confrontation visual field tests.

OBJECTIVE: To determine the diagnostic accuracy of confrontation visual field testing and to compare the accuracy of confrontation tests both individually and in combination. METHODS: Patients were prospectively recruited from ophthalmology clinics over a 6-month period. All patients underwent SITA-standard 24-2 Humphrey visual field analysis. Two examiners, masked to the automated perimetry results and the results of the other examiner, assessed patients using 7 common confrontation visual field tests. The order of testing was randomized to reduce any learning effect. For each individual test and combination of tests, the sensitivity, specificity, positive predictive value, and negative predictive value were calculated. RESULTS: A total of 301 eyes from 163 patients were included in the study. The average mean deviation was -5.91 +/- 7.72 (SD) dB. Most confrontation tests were insensitive to the identification of field loss. The sensitivity and specificity varied depending on the type, density, and cause of the visual field defect. Kinetic testing with a red target provided the highest sensitivity (74.4%) and specificity (93.0%) of any individual test and when combined with static finger wiggle testing achieved a sensitivity of 78.3% while retaining a specificity of 90.1%. CONCLUSIONS: Confrontation visual field tests are insensitive at detecting visual field loss when performed individually and are therefore a poor screening test. Combining confrontation tests is a simple and practical method of improving the sensitivity of confrontation testing.

Galanin acts as a trophic factor to the central and peripheral nervous systems.

The neuropeptide galanin is widely, but not ubiquitously, expressed in the adult nervous system. Its expression is markedly up-regulated in many neuronal tissues after nerve injury or disease. Over the last 10 years, we have demonstrated that the peptide plays a developmental survival role to subsets of neurons in the peripheral and central nervous systems with resulting phenotypic changes in neuropathic pain and cognition. Galanin also appears to play a trophic role to adult sensory neurons following injury, via activation of GalR2, by stimulating neurite outgrowth. Furthermore, galanin also plays a neuroprotective role to the hippocampus following excitotoxic injury, again mediated by activation of GalR2. Most recently, we have shown that galanin expression is markedly up-regulated in multiple sclerosis (MS) lesions and in the experimental autoimmune encephalomyelitis (EAE) model of MS. Over-expression of galanin in transgenic mice abolishes disease in the EAE model, whilst loss-of-function mutations in galanin or GalR2 increase disease severity. In summary, these studies demonstrate that a GalR2 agonist might have clinical utility in a variety of human diseases that affect the nervous system.

Giant cell arteritis.

Giant cell arteritis (GCA) is an immune-mediated vasculitis affecting individuals over 50 years of age. It is characterised by granulomatous inflammation that affects medium-sized and large arteries. The wide spectrum of clinical manifestations can be divided into those related to tissue ischemia from vascular lesions and those related to a systemic inflammatory response. The pathogenesis of these groups also appears distinct, with vascular lesion formation thought to be an adaptive immune response, and the systemic inflammatory reaction an innate immune response. Clinical suspicion of GCA must remain especially high in those with neurological or visual symptoms and if warranted, prompt treatment with high-dose corticosteroids is invaluable in halting disease progression.

Novel mRNA isoforms of the sodium channels Na(v)1.2, Na(v)1.3 and Na(v)1.7 encode predicted two-domain, truncated proteins.

The expression of voltage-gated sodium channels is regulated at multiple levels, and in this study we addressed the potential for alternative splicing of the Na(v)1.2, Na(v)1.3, Na(v)1.6 and Na(v)1.7 mRNAs. We isolated novel mRNA isoforms of Na(v)1.2 and Na(v)1.3 from adult mouse and rat dorsal root ganglia (DRG), Na(v)1.3 and Na(v)1.7 from adult mouse brain, and Na(v)1.7 from neonatal rat brain. These alternatively spliced isoforms introduce an additional exon (Na(v)1.2 exon 17A and topologically equivalent Na(v)1.7 exon 16A) or exon pair (Na(v)1.3 exons 17A and 17B) that contain an in-frame stop codon and result in predicted two-domain, truncated proteins. The mouse and rat orthologous exon sequences are highly conserved (94-100% identities), as are the paralogous Na(v)1.2 and Na(v)1.3 exons (93% identity in mouse) to which the Na(v)1.7 exon has only 60% identity. Previously, Na(v)1.3 mRNA has been shown to be upregulated in rat DRG following peripheral nerve injury, unlike the downregulation of all other sodium channel transcripts. Here we show that the expression of Na(v)1.3 mRNA containing exons 17A and 17B is unchanged in mouse following peripheral nerve injury (axotomy), whereas total Na(v)1.3 mRNA expression is upregulated by 33% (P=0.003), suggesting differential regulation of the alternatively spliced transcripts. The alternatively spliced rodent exon sequences are highly conserved in both the human and chicken genomes, with 77-89% and 72-76% identities to mouse, respectively. The widespread conservation of these sequences strongly suggests an additional level of regulation in the expression of these channels, that is also tissue-specific.

Galanin acts as a trophic factor to the central and peripheral nervous systems.

The neuropeptide galanin is widely, but not ubiquitously, expressed in the adult nervous system. Its expression is markedly upregulated in many neuronal tissues after nerve injury or disease. Over the last 10 years we have demonstrated that the peptide plays a developmental survival role to subsets of neurons in the peripheral and central nervous systems with resulting phenotypic changes in neuropathic pain and cognition. Galanin also appears to play a trophic role to adult sensory neurons following injury, via activation of GalR2, by stimulating neurite outgrowth. Furthermore, galanin also plays a neuroprotective role to the hippocampus following excitotoxic injury, again mediated by activation of GalR2. In summary, these studies demonstrate that a GalR2 agonist might have clinical utility in a variety of human diseases that affect the nervous system.

Patterns of attentional deficits and emotional bias in bipolar and major depressive disorder.

OBJECTIVES: Previous studies have reported deficits in selective attention and specific emotional biases in patients with bipolar (BP) disorder. The extent to which these distinguish BP patients from those with major depressive disorder (MDD) remain unclear. We aimed to examine the relationship between selective attentional impairments and emotional biases in symptomatic and euthymic BP, and symptomatic MDD patients. DESIGN: A between-group design was used. The time taken for BP patients to perform on Stroop tasks was compared with that in patients with MDD, and a normal healthy control group. METHODS: BP patients during manic (N = 14) and depressed (N = 13) episodes, and euthymia (N = 15), together with symptomatic patients with MDD (N = 17) and normal healthy controls (N = 18) were matched for IQ, gender, and age. Selective attention was measured using the Golden (1978) version of the Stroop task, and emotional bias, using the Lyon, Startup, and Bentall (1999) version of the emotional Stroop task. RESULTS: On the Card Stroop, all patients were significantly slower than normal healthy controls on all three conditions. On the emotional Stroop Test, all patients were slower on neutral, positive, and negative conditions. CONCLUSIONS: Our findings suggest that both BP and MDD patients demonstrate impaired performance on neutral and emotionally salient attentionally demanding tasks. The finding of impaired performance in all patients on baseline conditions in each task, however, indicates the need for inclusion of additional baseline conditions in these tasks in order to elucidate the nature of attentional impairments specific to these patient populations.

Antitumour antibiotics with potent activity against multidrug resistant (MDR) Staphylococcus aureus: a new approach to targeting resistant bacteria.

As hospital reports of strains of resistant bacteria are continuing to increase, a new approach is required for the identification of small molecules with antibacterial activity. Natural products that bind covalently to their biological target have been largely unexplored, although in the field of cancer chemotherapy, such molecules have been shown to counter resistance developed through efflux mechanisms. The azinomycins are potent antitumour agents that alkylate DNA and one of the natural products, compound 1, is a mono-alkylator that has been reported to retain potent antitumour activity. All four diastereomers of 1 were synthesized via a route involving late stage introduction of the epoxide stereocentre and separation of the resulting compounds. A non-alkylating analogue and a potential alkylator that cannot intercalate were also made. All four diastereomers are potent antibacterial agents in cell lines containing efflux-based resistance mechanisms. MIC values in the range of 0.25-1.0 microg/ml were observed. Comparison with the antitumour activity of the compounds suggests that the antibacterial activity stems from a similar mechanism of action involving DNA alkylation. As the ultimate molecular target of the azinomycins is unknown, bacterial strains may represent an interesting route for the discovery of the downstream mechanisms affected by DNA alkylation.

Juvenile arthritis and autoimmunity to type II collagen.

OBJECTIVE: Joint inflammation in juvenile rheumatoid arthritis (JRA) is sometimes associated with an autoimmune response to type II collagen (CII), a cartilage-specific protein. To test the hypothesis that down-regulation of autoimmunity to CII can be accomplished in JRA by oral administration of CII, an open-label study of CII was performed in 9 patients with JRA. METHODS: Seven rheumatoid factor-negative JRA patients with polyarticular disease and 2 JRA patients with pauciarticular disease (1 with early onset and 1 with late onset) were treated for 3 months with oral bovine CII. Patients were examined for disease activity and underwent routine laboratory testing at monthly intervals. Two of the patients had flares of disease when treatment was discontinued, and these patients were re-treated for an additional 3 months. To test the hypothesis that oral tolerance induces an immune deviation of T cells, peripheral blood mononuclear cells from patients were collected before and after treatment and cultured with CII. Supernatants and RNA were collected and analyzed for the presence of various cytokines. RESULTS: Eight patient trials met the criteria for clinical improvement outlined by Giannini and coworkers in 1997. None of the patients had any side effects from the treatment. In 6 of the 8 patients who improved, interferon-gamma production decreased after oral CII therapy, correlating with clinical improvement, while 6 patients had increases in levels of transforming growth factor beta3. CONCLUSION: These results are encouraging. The possible beneficial effect of oral CII in JRA merits further investigation.

Botulinum toxin for sixth nerve palsies in children with brain tumors.

PURPOSE: Sixth nerve palsies in children with brain tumors have a low rate of spontaneous recovery. Botulinum toxin has been used to treat sixth nerve palsies. In this study, we review outcomes for children with brain tumors and sixth nerve palsies, some of whom were treated with botulinum toxin. METHODS: To determine whether botulinum toxin effected the outcome of children with sixth nerve palsies and brain tumors, a retrospective review of charts was conducted for patients identified as having brain tumors and sixth nerve palsies after evaluation at the St Jude Children's Research Hospital Eye Clinic between 1992 and 1999. Of 48 charts identified, 19 met our inclusion criteria, having a record of brain tumor associated with sixth nerve palsy and 2 or more eye clinic visits at least 6 months apart. Children were considered recovered if they had an esotropia of less than 10 PD in primary gaze at the last follow-up visit and did not require surgical correction. RESULTS: Of the 19 children included in the study, 10 were managed conservatively (no botulinum toxin or surgery for at least 6 months after diagnosis). Nine children received one or more botulinum toxin injections. Two (20%) of the 10 children in the conservatively managed group recovered without surgical intervention. Two (22%) of the 9 children in the botulinum toxin treatment group recovered without surgical intervention. CONCLUSIONS: Treatment with botulinum toxin did not improve the rate of recovery in our series of children with brain tumors and sixth nerve palsies.

Galanin-like peptide (GALP) is expressed in rat hypothalamus and pituitary, but not in DRG.

Galanin-like peptide (GALP) was recently purified on the basis of its preferential activation of galanin receptor subtype 2 (GALR2) compared with galanin receptor subtype 1 (GALR1). Using in situ hybridization of adult rat brain, pituitary and dorsal root ganglia (DRG) we demonstrate that GALP mRNA expression is restricted to the arcuate nucleus and median eminence of the hypothalamus, and to the posterior lobe of the pituitary. No expression was detected elsewhere in brain, or in the DRG. In adult mouse, no expression was detected in brain or in DRG either before or after axotomy, suggesting that GALP has no apparent role in the axotomy response of DRG.

Reversal of optic canal stenosis in osteopetrosis after bone marrow transplant.

PURPOSE: To describe a patient with infantile osteopetrosis and optic atrophy secondary to optic canal stenosis who demonstrated optic canal enlargement after bone marrow transplant. METHODS: Case report. A 3-month-old infant with infantile "malignant" osteopetrosis underwent ophthalmic examination, including visual evoked potentials, electroretinogram, and computed tomography (CT). Bone marrow transplant was performed at 8 months of age. RESULTS: Examination revealed visual loss and optic atrophy, left eye greater than right eye, secondary to optic canal stenosis. Flash visual evoked potentials revealed a normal waveform in both eyes with increased latency in the left eye. Electroretinogram was normal in both eyes. CT after bone marrow transplant showed enlargement of the optic canals. Vision remains stable 43 months after bone marrow transplant. CONCLUSIONS: Bone marrow transplant in infantile osteopetrosis may be followed by reversal of optic canal stenosis and preservation of vision.

Targeted disruption of the galanin gene reduces the number of sensory neurons and their regenerative capacity.

The neuropeptide galanin is expressed developmentally in the dorsal root ganglion (DRG) and is rapidly up-regulated 120-fold after peripheral nerve section in the adult. Here we report that adult mice carrying a loss-of-function mutation in the galanin gene have a 13% reduction in the number of cells in the DRG associated with a 24% decrease in the percentage of neurons that express substance P. These deficits are associated with a 2.8- and 2.6-fold increase in the number of apoptotic cells in the DRG at postnatal days 3 and 4, respectively. After crush injury to the sciatic nerve, the rate of peripheral nerve regeneration is reduced by 35% with associated long-term functional deficits. Cultured DRG neurons from adult mutant mice demonstrate similar deficits in neurite number and length. These results identify a critical role for galanin in the development and regeneration of sensory neurons.

Motivation gains in performance groups: paradigmatic and theoretical developments on the Köhler effect.

In contrast to many demonstrations of social loafing, relatively few studies have documented group motivation gains. One such exception was O. Köhler's (1926, 1927) finding that team members working together did better at a taxing persistence task than would be expected from their individual performances, particularly when there was a moderate discrepancy in coworkers' capabilities. In Experiment 1, we developed a paradigm within which Köhler's overall motivation gain effect could be replicated, although the discrepancy in coworkers' capabilities did not moderate these motivation gains (after statistical artifacts were taken into account). Experiment 2 indicated that this motivation gain occurred under conjunctive but not under additive task demands, suggesting that the instrumentality of one's contribution to valued outcomes is a more likely explanation of the Köhler effect than social comparison processes.

Frequency of microdeletions in the azoospermia factor region of the Y-chromosome of New Zealand men.

AIM: To determine the frequency of microdeletions in the azoospermic factor (AZF) genes on the Y-chromosome of New Zealand men attending the Fertility Centre. METHODS: World Health Organisation criteria were used to classify men as normospermic, oligozoospermic, severely oligozoospermic, and azoospermic. Microdeletions were detected from DNA of semen samples by the sequence-tagged site polymerase chain reaction. RESULTS: Microdeletions were detected in 20% (3/15) of azoospermic men, 4% (2/50) of severely oligozoospermic men, 3.2% (2/62) of oligozoospermic men, and 0.7% (1/141) normospermic men. One azoospermic man had multiple non-contiguous deletions. Overall, 5.5% of infertile men had at least one microdeletion in the long arm of the Y-chromosome. One severely oligozoospermic man and one oligozoospermic man had produced unassisted pregnancies. CONCLUSION: New Zealand men attending a Christchurch fertility centre have a similar frequency of microdeletions in the Y-chromosome to other populations. Azoospermic men have a higher frequency of microdeletions than men with less severe spermatogenic failure. Men with microdeletions can have reduced fertility, but are not necessarily sterile.

Relaxation of IGF2 imprinting in Wilms tumours associated with specific changes in IGF2 methylation.

Relaxation of IGF2 imprinting occurs in Wilms tumours and many other cancers, but the mechanism of loss of imprinting (LOI) remains unknown. To investigate the role of altered DNA methylation in LOI, we examined the pattern of methylation of the human insulin-IGF2 region in Wilms tumours and the normal kidney. The analysis included regions homologous to three 'differentially methylated regions' of the mouse Igf2 gene (dmrs 0, 1 and 2). In tumours displaying normal IGF2 imprinting, and in the normal kidney, maternal allele-specific DNA methylation was identified spanning exons 2 and 3. This region is homologous to dmr 0, a site of maternal-specific differential methylation in the mouse. In Wilms tumours with relaxed imprinting or 11p15.5 LOH this region was unmethylated. No other differential methylation was identified. In particular, two sites of paternal methylation in the mouse (dmrs 1 and 2), and all three imprinted IGF2 promoters were not methylated in the kidney or in Wilms tumours. We postulate that LOI in Wilms tumours is associated with loss of maternal allele-specific methylation from a region located upstream of the imprinted IGF2 promoters. This region may contain cis acting sequences that coordinately influence imprinting.