Allopurinol reduces brachial and central blood pressure, and carotid intima-media thickness progression after ischaemic stroke and transient ischaemic attack: a randomised controlled trial.

OBJECTIVE: Central blood pressure (CBP) and carotid intima-media thickness (CIMT) are surrogate measures of cardiovascular risk. Allopurinol reduces serum uric acid and oxidative stress and improves endothelial function and may therefore reduce CBP and CIMT progression. This study sought to ascertain whether allopurinol reduces CBP, arterial stiffness and CIMT progression in patients with ischaemic stroke or transient ischaemic attack (TIA). METHODS: We performed a randomised, double-blind, placebo-controlled study, examining the effect of 1-year treatment with allopurinol (300 mg daily), on change in CBP, arterial stiffness and CIMT progression at 1 year and change in endothelial function and circulating inflammatory markers at 6 months. Patients aged over 18 years with recent ischaemic stroke or TIA were eligible. RESULTS: Eighty participants were recruited, mean age 67.8 years (SD 9.4). Systolic CBP [-6.6 mm Hg (95% CI -13.0 to -0.3), p=0.042] and augmentation index [-4.4% (95% CI -7.9 to -1.0), p=0.013] were each lower following allopurinol treatment compared with placebo at 12 months. Progression in mean common CIMT at 1 year was less in allopurinol-treated patients compared with placebo [between-group difference [-0.097 mm (95% CI -0.175 to -0.019), p=0.015]. No difference was observed for measures of endothelial function. CONCLUSIONS: Allopurinol lowered CBP and reduced CIMT progression at 1 year compared with placebo in patients with recent ischaemic stroke and TIA. This extends the evidence of sustained beneficial effects of allopurinol to these prognostically significant outcomes and to the stroke population, highlighting the potential for reduction in cardiovascular events with this treatment strategy. TRIAL REGISTRATION NUMBER: ISRCTN11970568.

Effect of early introduction of microencapsulated diet to larval Atlantic halibut, Hippoglossus hippoglossus L. assessed by microarray analysis.

An experimental microdiet prepared using an internal gelation method was used to partially replace the traditional live feed (Artemia) for larval Atlantic halibut, Hippoglossus hippoglossus L. Three trials were conducted with microdiet introduced at 20, 32, and 43 days post first feeding and larvae were sampled at approximately 2, 13, 23, and 33 days after microdiet introduction in each trial. The success of feeding was assessed by morphometrics and histological analysis of gut contents. Microdiet particles were readily consumed after a period of adaptation and provided an adequate source of nutrients with no significant increase in mortality in the microdiet-fed group compared to the control group. However, growth was limited and there was an increased incidence of malpigmentation of the eye and skin. Subtle changes in underlying digestive and developmental physiology were revealed by microarray analysis of RNA from control and experimental fish given microdiet from day 20 post first feeding. Fifty-eight genes were differentially expressed over the four sampling times in the course of the trial and the 28 genes with annotated functions fell into five major categories: metabolism and biosynthesis, cell division and proliferation, protein trafficking, cell structure, and stress. Interestingly, several of these genes were involved in pigmentation and eye development, in agreement with the phenotypic abnormalities seen in the larvae.

Are elevated circulating intercellular adhesion molecule 1 levels more strongly predictive of diabetes than vascular risk? Outcome of a prospective study in the elderly.

AIMS/HYPOTHESIS: The aim of this prospective study was to determine whether circulating intercellular adhesion molecule (ICAM) 1, as a potential surrogate of 'endothelial activation', is more strongly associated with risk of vascular events than with incident diabetes. METHODS: We related baseline ICAM-1 levels to vascular events (866 CHD and stroke events in 5,685 participants) and incident diabetes (292 in 4,945 without baseline diabetes) in the elderly over 3.2 years of follow-up. RESULTS: ICAM-1 levels correlated positively with triacylglycerol but negatively with LDL- and HDL-cholesterol. ICAM-1 levels were higher in those who developed diabetes (388.6 +/- 1.42 vs 369.4 +/- 1.39 ng/ml [mean+/-SD], p = 0.011) and remained independently associated with new-onset diabetes (HR 1.84, 95% CI 1.26-2.69, p = 0.0015 per unit increase in log[ICAM-1] after adjusting for classical risk factors and C-reactive protein). By contrast, ICAM-1 levels were not significantly (p = 0.40) elevated in those who had an incident vascular event compared with those who remained event-free, and corresponding adjusted risk associations were null (HR 0.98, 95% CI 0.80-1.22, p = 0.89) in analyses adjusted for other risk factors. CONCLUSIONS/INTERPRETATION: We show that elevated ICAM-1 levels are associated with risk of incident diabetes in the elderly at risk, despite no association with incident cardiovascular disease risk. We suggest that perturbations in circulating ICAM-1 levels are aligned more towards diabetes risk.

Characterization of a partial alpha-amylase clone from red porgy (Pagrus pagrus): expression during larval development.

A partial alpha-amylase cDNA was isolated from red porgy (Pagrus pagrus, Teleostei: Sparidae) and its tissue specific expression during larval development was examined. The cDNA was 949 bp long and showed 90% identity with other fish amylases. A 545 bp fragment was used to study amylase expression using in situ hybridization and RT-PCR techniques. Both methods showed a similar pattern: high and relatively constant expression for the first 30 days after hatching (dah), subsequently decreasing until the end of the experiment at 60 dah. The goal of this work was to extend the existing knowledge of the functionality of larval fish digestive systems and to provide new information about alpha-amylase gene expression.

Increase in periventricular white matter hyperintensities parallels decline in mental processing speed in a non-demented elderly population.

OBJECTIVE: To investigate the influence of deep white matter hyperintensities (DWMH) and periventricular white matter hyperintensities (PVWMH) on progression of cognitive decline in non-demented elderly people. METHODS: All data come from the nested MRI sub-study of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). We performed a 3 year follow up study on 554 subjects of the PROSPER study using both repeated magnetic resonance imaging and cognitive testing. Cognitive decline and its dependency on WMH severity was assessed using linear regression models adjusted for sex, age, education, treatment group, and test version when applicable. RESULTS: We found that the volume of PVWMH at baseline was longitudinally associated with reduced mental processing speed (p = 0.0075). In addition, we found that the progression in PVWMH volume paralleled the decline in mental processing speed (p = 0.024). In contrast, neither presence nor progression of DWMH was associated with change in performance on any of the cognitive tests. CONCLUSION: PVWMH should not be considered benign but probably underlie impairment in cognitive processing speed.

Treatment and outcome of adult patients with primary focal segmental glomerulosclerosis in five UK renal units.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is the least studied of the causes of idiopathic nephrotic syndrome, and there are few specific guidelines for treatment. AIM: To review data from five UK renal units to investigate whether adult patients with FSGS were treated uniformly, and to examine the effect of treatment on proteinuria and survival. DESIGN: Retrospective record review. METHODS: We examined electronic records of patients with idiopathic FSGS for information on baseline clinical parameters, treatment regimens and outcomes. RESULTS: Of 136 patients with primary FSGS and nephrotic range proteinuria, 76 (56%) were treated with prednisolone and of this group, 59% were treated with additional immunosuppression. Among the treated patients, the total remission rate (complete and partial) was 67%, and one hospital achieved a remission rate of 80%. Treated patients had a significantly higher remission rate than those who were not treated. Remission was associated with a 5-year survival off dialysis of 94%, compared with 53% if remission was not achieved. Baseline serum creatinine and remission were independently associated with survival off dialysis in a multivariate Cox proportional hazards model. DISCUSSION: Patients with primary FSGS and nephrotic range proteinuria, who are treated with corticosteroids, are more likely to enter remission than those who are not treated. Remission rates of up to 80% can be achieved with prolonged treatment, and remission is an independent predictor of survival off dialysis. Patients who do not achieve remission have a poor prognosis. Further clarification of optimal treatment regimens requires additional, prospective studies.

Different progression rates for deep white matter hyperintensities in elderly men and women.

The authors investigated the progression of white matter hyperintensities (WMHs) in a large population of elderly men and women. After 3 years of follow-up, women had accumulated approximately twice as much deep WMH (DWMH) as men. The progression of periventricular WMH was the same for men and women. Gender differences may affect the pathogenesis of DWMH, which in turn may result in different clinical consequences in women.

Trypsinogen expression during the development of the exocrine pancreas in winter flounder (Pleuronectes americanus).

Histological, biochemical and molecular techniques were used to describe the functional development of the pancreas in winter flounder (Pleuronectes americanus) with specific reference to the expression of three trypsinogen genes. The pancreas was identified shortly following hatch, appearing as a compact structure situated dorsal and slightly posterior to the liver. As the larval fish approached metamorphosis, the pancreas became diffuse, spreading throughout the mesentery surrounding the stomach, the upper intestine and the pyloric caecae. Trypsin 2 expression was detected from 5 days post-hatch (dph). Two other related trypsinogen genes isolated from the pyloric caecae (Trypsin 1) and the intestine (Trypsin 3) showed contrasting results. Trypsin 1 showed very low levels of expression and only in late larval stages and metamorphosis. Trypsin 3 showed expression only after 20 dph. In order to determine tissue-specific expression of the three trypsinogen genes, the RNA from seven gastrointestinal-associated tissues was examined. Trypsin 1 and Trypsin 2 expression was most notably associated with the pyloric caecae, cardiac stomach, pyloric stomach and the rectum, although some variation in expression level between tissues was observed. Trypsin 3 expression had a narrower tissue distribution and was only associated with the pyloric caecae and the rectum. The tissue expression patterns observed here are likely due in part to the diffuse nature of the pancreas. Trypsin-like activity was evident from hatch and continued at significant levels through to at least 25 dph.

Molecular cloning of trypsin cDNAs and trypsin gene expression in the salmon louse Lepeophtheirus salmonis (Copepoda: Caligidae).

The salmon louse, Lepeophtheirus salmonis, is a marine ectoparasitic copepod that infects salmonid fishes. We are studying the interactions between this parasite and its salmonid hosts, as it is a common cause of disease in both wild and farmed stocks of salmon. In this paper, we report on the cloning and sequencing of seven trypsin-like enzymes from a cDNA library prepared from whole body preadult female and male L. salmonis. The predicted trypsin activation peptides are 23 or 24 residues in length, considerably longer than previously reported activation peptides of other animals. Differences in the putative signal and activation peptide sequences of the trypsin isoforms suggest that these forms differ in their regulation and function. The calculated molecular weights of the trypsins range from 23.6 to 23.7 kDa. There are eight cysteine residues, which suggest the presence of four disulfide bridges. These trypsins are very similar (>or=46% aa identity) to other crustacean trypsins and insect hypodermins. Using in situ hybridization techniques trypsinogen expression could be identified in all three cell types of the midgut.

Pulsing electromagnetic field therapy in nerve regeneration: an experimental study in the cat.

A multidisciplinary approach to the study of peripheral nerve regeneration in the cat has been presented. The purpose of this work has been to determine if pulsing electromagnetic field (PEMF) therapy can enhance peripheral nerve regeneration after injury. In equal groups of animals, two types of pulsing electromagnetic field treatment were compared with untreated controls. All animals underwent quantitative electrophysiologic and morphologic assessment at the area of injury. In addition, muscle fiber sizing in the periphery and retrograde labeling of anterior horn motoneurons with horseradish peroxidase were studied. Results have shown no statistical differences between the groups in electrophysiologic or morphologic parameters. However, in animals treated with a pulse-burst electromagnetic field there was a statistically significant improvement in the labeling and localization of anterior horn cells in the central nervous system. These results indicate that pulse-burst electromagnetic radiation can increase the numbers of motor neurons that reestablish appropriate connections to the periphery after nerve injury. It remains to be seen if this improved spinal cord organization can translate to improved peripheral functional return.

Effects of maternal administration of alcohol on fetal brain development.

The effects of oral administration of alcohol during pregnancy and lactation on fetal and neonatal development were determined. Female Wistar rats were pair-fed nutritionally adequate liquid diets containing either alcohol or isocaloric carbohydrates starting on day 1 of gestation. Blood alcohol levels were determined in the pregnant animals throughout the experiment. On the day of parturition the litters were culled to six. The pups were sacrificed on day 30 and gamma-glutamyl transpeptidase (gamma GTP) activity determined in liver and brain. gamma GTP activity was determined to be elevated in the alcohol treated rats in all areas of brain studied except in the cortex and striatum. Additionally, the alcohol treated animals were smaller than the controls and exhibited higher serum and liver gamma GTP activities. Routine light microscopic plastic sections revealed large vacuolated spaces mainly confined to cortical layer V in the alcoholic rats. Golgi studies also revealed a decreased number of dendritic spines on pyramidal cell dendrites in the alcohol treated animals. These data suggest that exposure to alcohol in utero and in the postnatal period has a dramatic effect on neurons and processes in the cerebral cortex as well as on the membrane bound enzyme, gamma GTP.

Catecholamine neurons in the brain stem of tree shrew (Tupaia).

Glyoxylic acid-paraformaldehyde-induced histofluorescence was used to determine locations of catecholamine-containing neurons in the brain stem of Tupaia. Fluorescent cells in the medulla were located ventrolaterally in association with the lateral reticular nucleus; another group was found dorsolateral to the hypoglossal nucleus and extended laterally toward the solitary nucleus. In the pons, fluorescent cells were found in locus coeruleus, subcoeruleus and in association with the superior olivary nucleus. At caudal midbrain levels, catecholamine neurons were seen within the reticular formation and in association with the dorsal raphe nucleus, while more rostrally fluorescent neurons were located in substantia nigra, ventral tegmental area, among root fibers of the oculomotor nerve and in periaqueductal gray. The locations of catecholamine-containing neurons in tree shrew conform to the general mammalian pattern. Additionally, tree shrew has catecholamine neurons in the rostral mesencephalic periaqueductal gray as described in rat, opossum, rabbit and some primate; catecholamine neurons are also associated with the dorsal raphe nucleus in Tupaia, a finding previously reported only in primates.

Responses to cortical injury: I. Methodology and local effects of contusions in the rat.

In order to develop some understanding of the evolution of cortical contusions, interdisciplinary studies including behavior, morphology and histochemistry were conducted at varying intervals after standardized injuries. A method for producing graded and reproducible focal cortical contusions in the rat is described. When these impact injuries are made in the "hindpaw cortical area,' specific trauma dose dependent behavioral deficits can be readily observed in the contralateral hindlimb. While most functional recovery occurs in the first two weeks after trauma, with severe contusions, deficits persist beyond 90 days. Morphologically these injuries progress from hemorrhages in white matter directly under contused cortex during the first hours after injury to the development of a necrotic cavity by 24 hours. The cavitation appears to expand over the subsequent two weeks and by 15 days is lined with fibroblast-like elements and macrophages. Intense acid phosphatase activity is seen on the borders of the area of necrosis. This lysosomal enzyme may participate in autolysis and development of focal cavitation following cortical contusion.

Responses to cortical injury: II. Widespread depression of the activity of an enzyme in cortex remote from a focal injury.

As a part of a broader study of the reaction of the brain to injury, we report here an interesting loss of the activity of an enzyme in areas quite remote from the site of direct injury. At 36 h following a laceration or contusion injury to the hindpaw area of the motor cortex, a peculiar loss of staining for the enzyme alpha glycerophosphate dehydrogenase (alpha-GPDH) was noted. alpha-GPDH activity was markedly depressed in cortical layers II and III throughout the hemisphere on the side of the injury. The depression of alpha-GPDH activity extended far laterally across the rhinal fissure into the pyriform cortex. The decrease in alpha-GPDH staining was prominent 4 days after the injury: however, the staining pattern had returned to normal at 9 days. Enzyme changes in animals lesioned in the occipital cortex paralleled that seen in animals with a lesion in the motor cortex. Animals which had received an undercut lesion in the motor cortex 56 days earlier were contused in the occipital cortex. The old injury site presented the same sequelae of changes as seen in other lesioned animals. Additionally, a suction ablation injury involving only a small part of motor cortex resulted in the same widespread reduction of staining for alpha-GPDH in layers II and III. The derangement in energy metabolism suggests that cells in layers II and III of the cerebral cortex may be particularly vulnerable to perturbations induced by cortical trauma. These findings may be related to the diffuse and transient functional losses observed after head injury in man.

Origin of the rubrospinal tract of the rat.

The location of cells of origin of the rat rubrospinal tract has been determined by the use of retrograde axonal transport of horseradish peroxidase. Rubral neurons projecting to cervical spinal levels are found in dorsal and medial portions of the nucleus while those sending fibers to lumbar cord levels are located ventrally and ventrolaterally within the nucleus. No cells in the rostral one-half of the nucleus were labelled in this study. The results indicate that the rat rubrospinal tract originates from somatotopically-organized groups of neurons in the caudal one-half of the red nucleus.

Benign polypoid adenoma of the ampulla of vater. Treatment by double sphincteroplasty.

A patient with a symptomatic duodenal polyp was found at operation to have a 4 cm diameter adenomatous polyp of the ampulla of Vater, with both the common bile duct and pancreatic duct passing through the stalk and emptying from the polyp. The polyp was excised at the base of the stalk, and the two ducts reconstructed by a double spincteroplasty technique. The postoperative course and 2 1/2 year follow-up have been uneventful.

Axillary-axillary bovine arteriovenous fistula for hemodialysis.

A preliminary evaluation of bovine carotid artery heterografts as axillary-axillary arteriovenous fistulas suggests that this graft may be an easily constructed and easily utilized portal for hemodialysis cannulation. At present, this fistula should be reserved for use when all other commonly employed peripheral sites and methods of constructing arteriovenous fistulas have been exhausted.

The rubrospinal tract in a prosimian primate, Galago senegalensis.

The spinal distribution of rubrospinal fibers is described in the lesser bushbaby (Galago senegalensis), a prosimian primate. The tract is composed of thick and thin fibers, extends the length of the cord in the lateral funiculus, and is located ventral and ventrolateral to the lateral corticospinal tract and medial to the dorsal spincerebellar tract. There is a topographical relationship between origin and termination of rubrospinal fibers in Galago. Dorsomedial areas of the red nucleus project primarily to contralateral lumbar and sacral levels. Thoracic fibers arise from intermediate regions of the nucleus. Rubrospinal fibers in Galago terminate in basilar regions of the dorsal horn mainly at cervical and lumbar levels. Degeneration is most concentrated in medial and lateral portions of lamina V-VII. Although degenerated fibers approached the midline, none could be traced to the contralateral side. Lesions of more extensive portion of the nucleus resulted in degeneration in Clarke's column especially evident in low thoracic and upper lumbar levels. The latter connection may represent one rubrocerebellar feedback loop in the lesser bushbaby.