Heterozygote effects in mice with partial truncations in the growth hormone receptor cytoplasmic domain: Assessment of growth parameters and phenotype

The GH receptor (GHR) is essential for normal postnatal growth and development, and the molecular basis of GHR action has been studied intensively. Clinical case studies and more recently mouse models have revealed the extensive phenotype of impaired GH action. We recently reported two new mouse models, possessing cytoplasmic truncations at position 569 (plus Y539/545-F) and 391, which were created to identify functional subdomains within the cytoplasmic signaling domain. In the homozygous state, these animals show progressively impaired postnatal growth coupled with complex changes in gene expression. We describe here an extended phenotype analysis encompassing the heterozygote state to identify whether single copies of these mutant receptors bring about partial or dominant-negative phenotypes. It appears that the retention of the ubiquitin-dependent endocytosis motif the N-terminal cytoplasmic domain permits turnover of these mutant receptors because no dominant-negative phenotype is seen. Nonetheless, we do observe partial impairment of postnatal growth in heterozygotes supporting limited haploinsufficiency. Reproductive function is impaired in these models in a progressive manner, in parallel with loss of signal transducer and activator of transcription-5 activation ability. In summary, we describe a more comprehensive phenotypic analysis of these mouse models, encompassing overall and longitudinal body growth, reproductive function, and hormonal status in both the heterozygote and homozygote state. Our results suggest that patients expressing single copies of similarly mutated GHRs would not display an obvious clinical phenotype.

Variability in Cobb angle measurements using reformatted computerized tomography scans

Study Design. Survey of intraobserver and interobserver measurement variability. Objective. To assess the use of reformatted computerized tomography (CT) images for manual measurement of coronal Cobb angles in idiopathic scoliosis. Summary of Background Data. Cobb angle measurements in idiopathic scoliosis are traditionally made from standing radiographs, whereas CT is often used for assessment of vertebral rotation. Correlating Cobb angles from standing radiographs with vertebral rotations from supine CT is problematic because the geometry of the spine changes significantly from standing to supine positions, and 2 different imaging methods are involved. Methods. We assessed the use of reformatted thoracolumbar CT images for Cobb angle measurement. Preoperative CT of 12 patients with idiopathic scoliosis were used to generate reformatted coronal images. Five observers measured coronal Cobb angles on 3 occasions from each of the images. Intraobserver and interobserver variability associated with Cobb measurement from reformatted CT scans was assessed and compared with previous studies of measurement variability using plain radiographs. Results. For major curves, 95% confidence intervals for intraobserver and interobserver variability were +/- 6.6 degrees and +/- 7.7 degrees, respectively. For minor curves, the intervals were +/- 7.5 degrees and +/- 8.2 degrees, respectively. Intraobserver and interobserver technical error of measurement was 2.4 degrees and 2.7 degrees, with reliability coefficients of 88% and 84%, respectively. There was no correlation between measurement variability and curve severity. Conclusions. Reformatted CT images may be used for manual measurement of coronal Cobb angles in idiopathic scoliosis with similar variability to manual measurement of plain radiographs.

The epileptology of William Aldren Turner

William Aldren Turner (1864-1945), in his day Physician to the National Hospital, Queen Square, and to King's College Hospital, London, was one of the major figures in the world of epileptology in the period between Hughlings Jackson in the latter part of the 19th century and the advent of electroencephalography in the 1930s. Although he also made contributions to knowledge in other areas of neurology, and with Grainger Stewart wrote a competent textbook on that subject, Turner's main professional interest throughout his career seems to have been epilepsy. On the basis of a series of earlier, rather heavily statistical, personal publications dealing with various aspects of the disorder, he authored what became a well-accepted monograph entitled Epilepsy-a study of the idiopathic disorder, which appeared in 1907, and he also gave the 1910 Morison lectures in Edinburgh on the topic. His writings on epilepsy over a period of three decades consolidated knowledge rather than led to significant advances, but helped maintain interest in the disorder during a rather long fallow phase in the development of the understanding of its nature. (C) 2005 Elsevier Ltd. All rights reserved.

Characterization of tumour-infiltrating lymphocytes and apoptosis in colitis-associated neoplasia: comparison with sporadic colorectal cancer

The development of colorectal cancer is a major complication for patients with chronic idiopathic colitis. Colitis-associated tumours tend to occur at a younger age and be more aggressive than sporadic colorectal cancers. While we have previously associated the presence of tumour-infiltrating lymphocytes (TILs) and increased apoptosis in sporadic colorectal cancer with high-level microsatellite instability and improved prognosis, little is known of the relationship between these variables in colitis-associated colorectal cancer. The aim of this study was to correlate TILs and tumour cell apoptosis in colitis-associated neoplasms stratified according to microsatellite instability. Twenty tumour and 11 dysplastic samples resected from 21 patients with long-standing colitis were analysed for microsatellite instability at 10 microsatellite markers. TIL distribution (CD3, CD8) and function (granzyme B) were quantified by immunohistochemistry. Neoplastic cell apoptosis was assessed using the M30 CytoDEATH antibody. These findings were compared with 40 microsatellite stable (MSS) sporadic colorectal cancers previously evaluated for TILs and neoplastic apoptosis. Low-level microsatellite instability was found in 1/20 colitis-associated tumours. All other colitis-associated lesions were designated MSS. CD3(+) and CD8(+) TIL counts were significantly higher in colitis-associated lesions compared with NISS sporadic colorectal cancer (p < 0.0001, p = 0.001 respectively). Despite their higher TIL density, colitis-associated tumours were more likely to present late (Dukes' stage C or D) (P = 0.02). Functionally, colitis-associated TILs demonstrated significantly less granzyme B expression compared to sporadic cancers (p = 0.002). The level of tumour cell apoptosis was similar between the two groups (sporadic, 1.53%; colitis cancers, 1.45%). In conclusion, NISS colitis-associated tumours have a higher prevalence of CD3(+)/CD8(+) TILs but no associated increase in tumour cell killing by apoptosis. Unlike cytotoxic T cells in sporadic colorectal cancer, TILs do not appear to enhance the prognosis of colitis-associated colorectal cancer. This may be related to an impairment of granzyme B expression within these lesions. Copyright (c) 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Molecular genetics of sudden cardiac death in small animals - A review

Sudden cardiac death in small animals is uncommon but often occurs due to cardiac conduction defects or myocardial diseases. Primary cardiac conduction defects are mainly caused by mutations in genes involved in impulse conduction processes (e.g., gapjunction genes and transcription factors) or repolarisation processes (e.g., ion-channel genes), whereas primary cardiomyopathies are mainly caused by defective force generation or force transmission due to gene mutations in either sarcomeric or cytoskeleton proteins. Although over 50 genes have been identified in humans directly or indirectly related to sudden cardiac death, no genetic aetiologies have been identified in small animals. Sudden cardiac deaths have been also reported in German Shepherds and Boxers. A better understanding of molecular genetic aetiologies for sudden cardiac death will be required for future study toward unveiling actiology in sudden cardiac death in small animals. (c) 2005 Elsevier Ltd. All rights reserved.

Guidelines for the prevention, detection and management of people with chronic heart failure in Australia 2006

* Chronic heart failure (CHF) is found in 1.5%–2.0% of Australians. Considered rare in people aged less than 45 years, its prevalence increases to over 10% in people aged ≥ 65 years. * CHF is one of the most common reasons for hospital admission and general practitioner consultation in the elderly (≥ 70 years). * Common causes of CHF are ischaemic heart disease (present in > 50% of new cases), hypertension (about two-thirds of cases) and idiopathic dilated cardiomyopathy (around 5%–10% of cases). * Diagnosis is based on clinical features, chest x-ray and objective measurement of ventricular function (eg, echocardiography). Plasma levels of B-type natriuretic peptide (BNP) may have a role in diagnosis, primarily as a test for exclusion. Diagnosis may be strengthened by a beneficial clinical response to treatment(s) directed towards amelioration of symptoms. * Management involves prevention, early detection, amelioration of disease progression, relief of symptoms, minimisation of exacerbations, and prolongation of survival.

Allergy - 5: Allergy and the skin: eczema and chronic urticaria

Eczema is common, occurring in 15%-20% of infants and young children. For some infants it can be a severe chronic illness with a major impact on the child's general health and on the family. A minority of children will continue to have eczema as adults. The exact cause of eczema is not clear, but precipitating or aggravating factors may include food allergens (most commonly, egg) or environmental allergens/irritants, climatic conditions, stress. and genetic predisposition. Management of eczema consists of education; avoidance of triggers and allergens; liberal use of emollients or topical steroids to control inflammation; use of antihistamines to reduce itch; and treatment of infection if present. Treatment with systemic agents may be required in severe cases, but must be supervised by an immunologist. Urticaria (hives) may affect up to a quarter of people at some time in their lives. Acute urticaria is more common in children, while chronic urticaria is more common in adults. Chronic urticaria is not life-threatening, but the associated pruritus and unsightly weals can cause patients much distress and significantly affect their daily lives. Angioedema coexists with urticaria in about 50% of patients. It typically affects the lips, eyelids, palms, soles and genitalia. Management of urticaria is through education; avoidance of triggers and allergens (where relevant); use of antihistamines to reduce itch; and short-term use of corticosteroids when antihistamine therapy is ineffective. Referral is indicated for patients with resistant disease.

Alveolar haemorrhage in anti-glomerular basement membrane disease without detectable antibodies by conventional assays

Anti-glomerular basement membrane (anti-GBM) disease represents the spectrum of disease attributable to circulating anti-GBM antibodies. While active anti-GBM disease in the absence of circulating anti-GBM antibodies has been described, it is considered rare with the use of current routinely available assays. We report four subjects with features consistent with active anti-GBM antibody disease without detectable antibodies by routinely available enzyme linked immunosorbent assay (ELISA) and immunoblot techniques. All were smokers who presented with diffuse alveolar haemorrhage, minimal renal involvement, and undetectable anti-GBM antibodies. Seronegative anti-GBM disease with predominant pulmonary involvement may be more common than previously appreciated and should be part of the differential diagnosis for otherwise unexplained diffuse alveolar haemorrhage. Renal biopsy with immunofluorescent studies should be considered in the diagnostic evaluation of such subjects, including those with idiopathic pulmonary haemosiderosis.

A prospective assessment of SRS-24 scores after endoscopic anterior instrumentation for scoliosis

Study Design. Prospective clinical case series. Objective. To evaluate the clinical outcome of anterior endoscopic instrumention for scoliosis using the SRS-24 questionnaire and to examine how these scores change over a 2-year follow-up period. Summary of Background Data. Anterior endoscopic instrumentation correction has several advantages compared with open procedures. However, the clinical results of this technique using a validated outcome measure have rarely been reported in the literature. Methods. A total of 83 consecutive patients underwent endoscopic anterior instrumentation performed at a single unit. Patients completed the SRS-24 questionnaire before surgery and at 3, 6, 12, and 24 months after surgery. The SRS-24 scores were compared between each of the follow-up intervals. Results. The pain, general self-image, and function from back condition domains improved after surgery (P < 0.05). Activity level significantly improved between 3 and 6 months, and both function domains improved between 6 and 12 months (P < 0.05). None of the domains increased significantly after 1 year. Conclusions. Endoscopic anterior instrumentation for scoliosis significantly improved pain, self-image, and function. The greatest improvement in function occurred between 6 and 12 months after surgery. The SRS-24 scores at 1 year from surgery may provide a good indicator of patient outcome in the long-term.

Subthalamic nucleus neurones in slices from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mice show irregular, dopamine-reversible firing pattern changes, but without synchronous activity

The loss of dopamine in idiopathic or animal models of Parkinson's disease induces synchronized low-frequency oscillatory burst-firing in subthalamic nucleus neurones. We sought to establish whether these firing patterns observed in vivo were preserved in slices taken from dopamine-depleted animals, thus establishing a role for the isolated subthalamic-globus pallidus complex in generating the pathological activity. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) showed significant reductions of over 90% in levels of dopamine as measured in striatum by high pressure liquid chromatography. Likewise, significant reductions in tyrosine hydroxylase immunostaining within the striatum (>90%) and tyrosine hydroxylase positive cell numbers (65%) in substantia nigra were observed. Compared with slices from intact mice, neurones in slices from MPTP-lesioned mice fired significantly more slowly (mean rate of 4.2 Hz, cf. 7.2 Hz in control) and more irregularly (mean coefficient of variation of inter-spike interval of 94.4%, cf. 37.9% in control). Application of ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 2-amino-5-phosphonopentanoic acid (AP5) and the GABAA receptor antagonist picrotoxin caused no change in firing pattern. Bath application of dopamine significantly increased cell firing rate and regularized the pattern of activity in cells from slices from both MPTP-treated and control animals. Although the absolute change was more modest in control slices, the maximum dopamine effect in the two groups was comparable. Indeed, when taking into account the basal firing rate, no differences in the sensitivity to dopamine were observed between these two cohorts. Furthermore, pairs of subthalamic nucleus cells showed no correlated activity in slices from either control (21 pairs) or MPTP-treated animals (20 pairs). These results indicate that the isolated but interconnected subthalamic-globus pallidus network is not itself sufficient to generate the aberrant firing patterns in dopamine-depleted animals. More likely, inputs from other regions, such as the cortex, are needed to generate pathological oscillatory activity. © 2006 IBRO.

Abnormal visual habituation in pediatric photosensitive epilepsy

Objective - To investigate visual habituation – a measure of visual cortical excitability – in photosensitive patients in pediatric age and compare the findings with a matched sample with idiopathic generalized epilepsies without photosensitivity and with normally developing children. Methods - We presented a full-field black-and-white checkerboard pattern, at 3 reversal/s with 100% contrast binocularly for 600 consecutive trials and measured the N75–P100 and P100–N145 pattern-reversal visual evoked potential inter-peak amplitudes and N75, P100, N145 latencies for the six blocks of 100 responses. As a measure of habituation we used the slope of the linear regression line of the N75–P100 and P100–N145 peak-to-peak amplitudes. The slope of the linear regression line of the N75–P100 and P100–N145 latencies was also analyzed. Results - Statistical analysis revealed significant differences between the three groups in the slope index of N75–P100 PR-VEP amplitude, with increased or constant amplitude in the PS group compare to the IGE and ND across the six blocks. Conclusions - Our results support the notion that photosensitivity is associated with altered control of excitatory and inhibitory cortical processes. The causal relationship between habituation deficit and photo-paroxysmal response needs to be further investigated with longitudinal studies. Significance This study supports the hypothesis that suppression of PR-VEP is a sensitive intermediate phenotype, which discriminates patients with photosensitivity from those with generalized epilepsies in pediatric age.

Oculo-visual dysfunction in Parkinson's disease

This review describes the oculo-visual problems likely to be encountered in Parkinson's disease (PD) with special reference to three questions: (1) are there visual symptoms characteristic of the prodromal phase of PD, (2) is PD dementia associated with specific visual changes, and (3) can visual symptoms help in the differential diagnosis of the parkinsonian syndromes, viz. PD, progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and corticobasal degeneration (CBD)? Oculo-visual dysfunction in PD can involve visual acuity, dynamic contrast sensitivity, colour discrimination, pupil reactivity, eye movement, motion perception, and visual processing speeds. In addition, disturbance of visuo-spatial orientation, facial recognition problems, and chronic visual hallucinations may be present. Prodromal features of PD may include autonomic system dysfunction potentially affecting pupil reactivity, abnormal colour vision, abnormal stereopsis associated with postural instability, defects in smooth pursuit eye movements, and deficits in visuo-motor adaptation, especially when accompanied by idiopathic rapid eye movement (REM) sleep behaviour disorder. PD dementia is associated with the exacerbation of many oculo-visual problems but those involving eye movements, visuo-spatial function, and visual hallucinations are most characteristic. Useful diagnostic features in differentiating the parkinsonian symptoms are the presence of visual hallucinations, visuo-spatial problems, and variation in saccadic eye movement dysfunction.

Photodynamic therapy:a treatment option in choroidal neovascularisation secondary to punctate inner choroidopathy

Punctate inner choroidopathy is an idiopathic inflammatory ocular disorder characteristically seen in young myopic women. Visual prognosis is generally good but sight threatening choroidal neovascularisation may develop in up to 40% patients.1 We discuss verteporfin photodynamic therapy in subfoveal choroidal neovascularisation secondary to punctate inner choroidopathy that failed to respond to oral corticosteroids and had poor results with submacular surgery in the contralateral eye.