Evidence for a neuroanatomical difference within the olivo-cerebellar pathway of adults with dyslexia

Recent behavioural evidence has indicated that cerebellar impairment may be strongly associated with dyslexia. Previous neuroanatomical research has shown the presence of anomalies within the cerebral cortex of brains of dyslexic people. This paper reports equivalent analyses on the cerebella of the same brain specimens. Cross sectional areas and cell packing densities of Purkinje cells in the cerebellar cortex, and cells in the inferior olivary and dentate nuclei of four dyslexic and four control brains were measured using the dissector method. A significant difference in mean cell area in medial posterior cerebellar cortex was identified, with the dyslexic cells having larger mean area. Furthermore, analysis of cell size distributions not only confirmed the significant differences in the posterior lobe, with an increased proportion of large neurons and fewer small neurons for the dyslexics, but also revealed significant differences in the anterior lobe, again with a pattern of more large and fewer small cells. Similar distributional differences were seen in the inferior olive. No differences were found in the flocculonodular lobe or the dentate nucleus. While caution is necessary in generalising from the results given the small number of specimens, together with the age difference, the neuroanatomical data established here provides further converging evidence of cerebellar abnormality in dyslexia.     

JunB negatively regulates AP-1 activity and cell proliferation of malignant mouse keratinocytes

OBJECTIVE: Previously we have shown that a malignant mouse keratinocyte cell line, 10Gy5, has elevated AP-1 transactivation and reduced JunB protein levels compared to its parental benign cell line, 308, and that the tumorigenicity in the 10Gy5 cells could be blocked by a dominant negative c-Jun mutant protein. We wished to determine whether the change in JunB protein levels could account for the elevated AP-1 activity and whether re-expression of JunB in malignant 10Gy5 cells altered their proliferative capacity. DESIGN: In the current study, we reduced JunB expression in benign 308 cells with antisense oligonucleotides and increased JunB expression in malignant 10Gy5 cells by stable transfection of a JunB expression vector. RESULTS: Increased AP-1 activity was detected after treatment of the benign 308 cell line with JunB antisense oligonucleotides that reduced JunB protein levels. Stably JunB-transfected clones of malignant 10Gy5 cells showed decreased AP-1 activity, slowed in vitro cell proliferation and reduced tumor growth when xenografted to athymic nude mice. CONCLUSION: These findings suggest that expression of JunB protein has a negative effect on malignant tumor cell proliferation in part through its ability to inhibit AP-1 transactivation.     

Intra-ureteric capsaicin in loin pain haematuria syndrome: efficacy and complications

OBJECTIVE: To evaluate the safety and efficacy of intra-ureteric capsaicin for loin pain haematuria syndrome (LPHS). PATIENTS AND METHODS: In an open prospective pilot study, four middle-aged patients (three women and one man) with LPHS resistant to therapies such as splanchnic nerve block, psychological treatment or renal autotransplantation (one) were assessed. An intra-ureteric infusion of capsaicin (30 mg/100 mL of 30% alcohol in saline) for 30 min with bladder irrigation was administered under general anaesthesia, with a subsequent intravenous patient-controlled narcotic analgesic pump for pain control. Double-concentration capsaicin was used for second infusions, if necessary when the response to the earlier infusion was inadequate or incomplete. RESULTS: The first patient had experienced reduced pain levels for the first 3 months only, with no benefit from the subsequent treatments with higher doses of capsaicin (60 mg). The second patient with recurrent pain in an autotransplanted kidney had no benefit from either a 30 or 60 mg capsaicin infusion a month apart, but developed a fibrotic stricture at the transplant pelvi-ureteric junction, requiring pyelocystoplasty. The third patient with concurrent depression had no benefit from a 30-mg infusion of capsaicin. The fourth patient experienced no pain relief from a 30 mg infusion of capsaicin but developed proteinuria secondary to mesangial proliferative glomerulonephritis, ureteric inflammation needing stenting within 7 days of treatment and subsequently nephrectomy for a nonfunctioning kidney at 3 months. CONCLUSION: Intra-ureteric capsaicin was neither effective nor safe in LPHS; the contribution of the alcohol diluent cannot be excluded.     

Identification and use of biomarkers in Gaucher disease and other lysosomal storage diseases

The value of biomarkers in the clinical management of lysosomal storage diseases is best illustrated by the present use of plasma chitotriosidase levels in the diagnosis and monitoring of Gaucher disease. The enzyme chitotriosidase is specifically produced and secreted by the pathological storage macrophages (Gaucher cells). Plasma chitotriosidase levels are elevated on average 1000-fold in symptomatic patients with Gaucher disease and reflect the body burden on storage cells. Changes in plasma chitotriosidase reflect changes in clinical symptoms. Monitoring of plasma chitotriosidase levels is nowadays commonly used in decision making regarding initiation and optimization of costly therapeutic interventions (enzyme replacement therapy or substrate reduction therapy). A novel substrate has been developed that further facilitates the measurement of chitotriosidase in plasma samples. Moreover, an alternative Gaucher-cell marker, CCL18, has been very recently identified and can also be employed to monitor the disease, particularly in those patients lacking chitotriosidase due to a genetic mutation. There is a need for comparable surrogate markers for other lysosomal storage diseases and the search for such molecules is an area of intense investigation.
Conclusion: The use of biomarkers can provide valuable insight into the molecular pathogenesis of LSDs, such as Gaucher disease and Fabry disease.     

Warm up practices of golfers: are they adequate?

BACKGROUND: Although it is widely recommended that golfers warm up before play or practice to enhance their physical performance and reduce their injury risk, it is not known to what extent they actually undertake such warm up procedures. OBJECTIVE: To collect information about the proportion of golfers who actively warm up and to determine the types of warm up behaviours. METHODS: This study was conducted over three weeks at three different golfing venues: a private golf course, a public golf course, and a golf driving range. Golfers' warm up behaviours, defined as any form of preparative exercise, were recorded by direct observation by two independent observers. RESULTS: The sample consisted of 1040 amateur golfers (852 men and 188 women) aged at least 18 years. Only 54.3% (95% confidence interval 49.8 to 58.8) performed some form of warm up activity. Air swings on the tee were the most commonly observed warm up activity, with 88.7% (95% confidence interval 85.9 to 91.5) of golfers who warmed up performing these. CONCLUSIONS: Only a small proportion of amateur golfers perform appropriate warm up exercises. To improve on this, golfers should be educated about the possible benefits of warming up and be shown how to perform an appropriate warm up routine.     

Injury prevention and the promotion of physical activity: What is the nexus?

The promotion of physical activity is a public health priority for Australia. The new "National Physical Activity Guidelines for Australians" include a statement on additional health benefits of vigorous sporting and fitness activities. However, injury associated with sport and physical activity can lead to significant health care costs and consequent disabilities and reduced mobility may result in inactivity, this increasing the risk of cardiovascular disease and other health problems. Consideration of injury prevention principles when promoting physical activity is therefore crucial. There are several areas of research needed in this new field. These include the importance of good quality population monitoring and the use of other data sources to determine the population-wide consequences and health costs of injury sustained during sport and physical activity. The goal is to have evidence based, educational, regulatory and other preventive strategies that can be systematically evaluated by drawing on well organised, representative population-based injury data.     

SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis

BACKGROUND & AIMS: Gain-of-function trypsin mutations cause acute pancreatitis and chronic pancreatitis. Loss of trypsin inhibitor function may have similar effects. We investigated the prevalence of SPINK1 (PSTI) mutations in familial pancreatitis, idiopathic chronic pancreatitis, and controls. METHODS: Genetic-linkage studies were performed in 5 familial pancreatitis families. The entire SPINK1 gene was sequenced in 112 affected individuals and 95 control DNA samples, and exon 3 was sequenced in 95 additional controls. X-ray crystallography-based model building and statistical studies were performed. RESULTS: Significant linkage between pancreatitis and 5q31.1-2 was excluded. Novel SPINK1 mutations, one D50E mutation, one IVS3+125 C>A, and five IVS3+184 T>A intronic polymorphisms were identified. The N34S and P55S mutations were observed in 29 of 112 patients (25%) as N34S/N34S (n = 7), N34S/wt (n = 19), N34S/P55S (n = 2), and N34S/D50E (n = 1). Three hundred eighty control alleles revealed 3 N34S (0.77%), 2 P55S (0.53%), and no D50E mutations. Age of disease onset and severity were similar between homozygous and heterozygous patients. Structural modeling revealed several possible pathophysiologic mechanisms for the N34S mutation. CONCLUSIONS: SPINK1 mutations are common in the population (approximately 2%), but are clearly associated with pancreatitis. The mutation-associated risk is low. Modeling and familial clustering suggest that SPINK1 mutations are disease modifying, possibly by lowering the threshold for pancreatitis from other genetic or environmental factors, but by themselves do not cause disease.     

Antibodies to tumor necrosis factor alpha prevent increases in cell replication in liver due to the potent peroxisome proliferator, WY- 14,643

Several structurally dissimilar hypolipidemic drugs, plasticizers and halogenated hydrocarbons induce peroxisomes in hepatocytes, and cause hepatocellular adenoma and carcinoma in rats and mice. The mechanism by which these agents act is unknown, although recent studies have suggested a link between increased cell proliferation and hepatic cancer caused by peroxisome proliferators. Here, we demonstrate that neutralizing antibodies to tumor necrosis factor alpha (TNF alpha) block increases in protein kinase C and cell proliferation due to [4- chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (WY-14,643), a hypolipidemic drug and potent peroxisome proliferator that causes tumors. WY-14,643 moderately elevated the level of TNF alpha mRNA in the liver. TNF alpha was detected immunohistochemically exclusively in Kupffer cells. These results demonstrate that WY-14,643 acts as an indirect mitogen on hepatocytes via TNF alpha. We propose that the Kupffer cell, a major source of TNF alpha in the liver, is involved in the mechanism of the mitogenic effect of WY-14,643.