Genome-wide study of familial juvenile hyperuricaemic (gouty) nephropathy (FJHN) indicates a new locus, FJHN3, linked to chromosome 2p22.1-p21

Familial juvenile hyperuricaemic (gouty) nephropathy (FJHN), is an autosomal dominant disease associated with a reduced fractional excretion of urate, and progressive renal failure. FJHN is genetically heterogeneous and due to mutations of three genes: uromodulin (UMOD), renin (REN) and hepatocyte nuclear factor-1beta (HNF-1β) on chromosomes 16p12, 1q32.1, and 17q12, respectively. However, UMOD, REN or HNF-1β mutations are found in only ~45% of FJHN probands, indicating the involvement of other genetic loci in ~55% of probands. To identify other FJHN loci, we performed a single nucleotide polymorphism (SNP)-based genome-wide linkage analysis, in six FJHN families in whom UMOD, HNF-1β and REN mutations had been excluded. Parametric linkage analysis using a 'rare dominant' model established linkage in five of the six FJHN families, with a LOD score >+3, at 0% recombination, between FJHN and SNPs at chromosome 2p22.1-p21. Analysis of individual recombinants in two unrelated affected individuals defined a ~5.5 Mbp interval, flanked telomerically by SNP RS372139 and centromerically by RS896986 that contained the locus, designated FJHN3. The interval contains 28 genes, and DNA sequence analysis of the most likely candidate, solute carrier family 8 member 1 (SLC8A1), did not identify any abnormalities in the FJHN3 probands. FJHN3 is likely located within a ~5.5 Mbp interval on chromosome 2p22.1-p21, and identifying the genetic abnormality will help to further elucidate mechanisms predisposing to gout and renal failure.

Perinatal nutrition and gastrointestinal disorders : Working Group Report of the Second World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition

Metabolic programming during the perinatal period as a consequence of early nutrition is an emerging area of great interest. This concept is known as the "fetal origins of adult disease" theory (1). Numerous epidemiological studies published over the past 20 years or so have suggested that small body size at birth and during infancy and, more specifically, intrauterine growth retardation are associated later in life with lowered cognitive performance and increased rates of coronary heart disease and its major biological risk factors, ie, raised blood pressure, insulin resistance, coronary artery disease, and abnormalities in lipid metabolism. The molecular mechanisms that govern this phenomenon in humans, however, are unknown and need to be elucidated.

Nutritional rehabilitation in cystic fibrosis: A 5 year follow-up study

Previously, we reported catch-up weight gain, growth, and improved lung function in a group of malnourished cystic fibrosis (CF) children receiving aggressive nutritional supplementation for 1 year compared with a forced expiratory volume in 1 s (FEV1)-, height-, and sex-matched comparison group receiving standard therapy. To evaluate long-term effects, the clinical progress of both groups has been studied over a 5 year period. The supplemented group (n = 10) received supplements for a median of 1.35 years to achieve nutritional rehabilitation. Compared with the nonsupplemented group (n = 14), the previously supplemented group had lower mortality (2 vs. 4, N.S.) and significantly greater weight and height z scores at 4 and 5 years. The progression of pulmonary function abnormalities as measured by FEV, and forced vital capacity (FVC) slopes was greater at 3 years in the nonsupplemented group (FEV1, p < 0.05) but no significant differences in rates of deterioration of pulmonary function were seen after 5 years in the two groups of survivors. We conclude that intensive nutritional support for 1 year has both short-and long-term effects on nutrition and growth, still evident some years after the cessation of this therapeutic modality. Supplementation for periods of longer than 1 year may produce greater gains and possibly prolong the improvement in pulmonary function observed in the earlier study. © 1992 Raven Press, Ltd., New York.

Curvedness study on atherosclerosis plaques and its implications to plaque stress

Atherosclerosis plaque rupture has been considered to be a mechanical failure of the thin fibrous cap, resulted from extreme plaque stress. Plaque stress was affected by many factors from morphological features to biological abnormalities. In this study, geometrical factors (curvedness, fibrous cap thickness) were studied on assessing plaque vulnerability in comparison with stress analysis results obtained by fluid structure interaction from 20 human carotid atherosclerosis plaques. The results show that plaque surface curvedness could contribute to extreme stress level, especially in plaque shoulder region. General plaque stress distribution could be predicted by fibrous cap thickness and curvedness with multi-regression model. With more features included in the regression model, plaque stress could be easily calculated and used to assess plaque vulnerability.

Evaluation of growth and changes in body composition following neonatal diagnosis of cystic fibrosis

Early deficits in nutritional status that might require specific treatment and early response to nutritional therapy were studied longitudinally in 25 infants with cystic fibrosis (CF) diagnosed by neonatal screening, using anthropometric and research body composition methodology, and evaluation of pancreatic function. At the time of confirmed diagnosis (mean 5.4 weeks), body mass, length, total body fat (TBF), and total body potassium (TBK) were all significantly reduced. Following diagnosis and commencement of therapy there was a normalization of weight, length, and TBK by 6-12 months of age, indicating catch-up growth. But in some individuals the response was incomplete, and as a group, mean total body fat remained significantly lower than normal at 1 year of age. Seven of 25 (28%) were pancreatic sufficient at diagnosis, and all but one had evidence of declining pancreatic function requiring the institution of pancreatic enzyme therapy during the next 1-9 months. The median age of commencement of enzyme therapy was 10 weeks (range 5 weeks to 11 months). These longitudinal assessments emphasize the dynamic changes occurring in absorptive function, body composition, and nutritional status following neonatal diagnosis of cystic fibrosis and may reflect previously described abnormalities of energy metabolism in this age group. Abnormal body composition is evident in most CF infants following diagnosis by neonatal screening but pancreatic damage may still be evolving. We suggest that early active nutritional therapy and surveillance for changes in pancreatic function are warranted in CF infants diagnosed by neonatal screening.

Short-term nutritional supplementation during management of pulmonary exacerbations in cystic fibosis: A controlled study, including effects of protein turnover

Effects of nutritional supplements on minimizing weight loss and abnormalities of protein turnover during pulmonary exacerbations in cystic fibrosis (CF) were studied by controlled trial. Patients received pulmonary therapy and either standard diet (n = 10) or adjunctive enteral supplements (n = 12). Initial protein turnover, measured by [15N]glycine kinetics, showed alterations of protein synthesis (P Syn) and catabolism (P Cat), which correlated with the degree of underweight, and negligible net protein deposition (P Dep). With treatment both groups had significant increases in mean body weight and forced expiratory volume in 1 s, expressed as percent predicted value for height (FEV1) by 3 wk, but a significant correlation between initial underweight and subsequent weight gain was observed only in supplemented patients. Mean P Syn and P Dep increased significantly (p < 0.001) only in the supplemented group. Pulmonary exacerbations in CF have important adverse effects on body-protein metabolism, similar to changes in protein-energy malnutrition and infection. These effects are reversed by short-term nutritional support. Strategic nutritional intervention should thus be considered in management, especially in malnourished patients.

Pattern visual evoked potentials in dyslexic versus normal children

Purpose: Presence of neurophysiological abnormalities in dyslexia has been a conflicting issue. This study was performed to evaluate the role of sensory visual deficits in the pathogenesis of dyslexia. Methods: Pattern visual evoked potentials (PVEP) were recorded in 72 children including 36 children with dyslexia and 36 children without dyslexia (controls) who were matched for age, sex and intelligence. Two check sizes of 15 and 60 min of arc were used with temporal frequencies of 1.5 Hz for transient and 6 Hz for steady‑state methods. Results: Mean latency and amplitude values for 15 min arc and 60 min arc check sizes using steady state and transient methods showed no significant difference between the two study groups (P values: 0.139/0.481/0.356/0.062).Furthermore, no significant difference was observed between two methods of PVEPs in dyslexic and normal children using 60min arc with high contrast(Pvalues: 0.116, 0.402, 0.343 and 0.106). Conclusion: The sensitivity of PVEP has high validity to detect visual deficits in children with dyslexic problem. However, no significant difference was found between dyslexia and normal children using high contrast stimuli.

Determinants of vascular cognitive impairment : White matter lesions, brain atrophy and their neuropsychological correlates

The concept of vascular cognitive impairment (VCI) covers a wide spectrum of cognitive dysfunctions related to cerebrovascular disease. Among the pathophysiological determinants of VCI are cerebral stroke, white matter lesions and brain atrophy, which are known to be important risk factors for dementia. However, the specific mechanisms behind the brain abnormalities and cognitive decline are still poorly understood. The present study investigated the neuropsychological correlates of particular magnetic resonance imaging (MRI) findings, namely, medial temporal lobe atrophy (MTA), white matter hyperintensities (WMH), general cortical atrophy and corpus callosum (CC) atrophy in subjects with cerebrovascular disease. Furthermore, the cognitive profile of subcortical ischaemic vascular disease (SIVD) was examined. This study was conducted as part of two large multidisciplinary study projects, the Helsinki Stroke Aging Memory (SAM) Study and the multinational Leukoaraiosis and Disability (LADIS) Study. The SAM cohort consisted of 486 patients, between 55 and 85 years old, with ischaemic stroke from the Helsinki University Hospital, Helsinki, Finland. The LADIS Study included a mixed sample of subjects (n=639) with age-related WMH, between 65 and 84 years old, gathered from 11 centres around Europe. Both studies included comprehensive clinical and neuropsychological assessments and detailed brain MRI. The relationships between the MRI findings and the neuropsychological test performance were analysed by controlling for relevant confounding factors such as age, education and other coexisting brain lesions. The results revealed that in elderly patients with ischaemic stroke, moderate to severe MTA was specifically related to impairment of memory and visuospatial functions, but mild MTA had no clinical relevance. Instead, WMH were primarily associated with executive deficits and mental slowing. These deficits mediated the relationship between WMH and other, secondary cognitive deficits. Cognitive decline was best predicted by the overall degree of WMH, whereas the independent contribution of regional WMH measures was low. Executive deficits were the most prominent cognitive characteristic in SIVD. Compared to other stroke patients, the patients with SIVD also presented more severe memory deficits, which were related to MTA. The cognitive decline in SIVD occurred independently of depressive symptoms and, relative to healthy control subjects, it was substantial in severity. In stroke patients, general cortical atrophy also turned out to be a strong predictor of cognitive decline in a wide range of cognitive domains. Moreover, in elderly subjects with WMH, overall CC atrophy was related to reduction in mental speed, while anterior CC atrophy was independently associated with frontal lobe-mediated executive functions and attention. The present study provides cross-sectional evidence for the involvement of WMH, MTA, general cortical atrophy and CC atrophy in VCI. The results suggest that there are multifaceted pathophysiological mechanisms behind VCI in the elderly, including both vascular ischaemic lesions and neurodegenerative changes. The different pathological changes are highly interrelated processes and together they may produce cumulative effects on cognitive decline.

Oscillatory brain activity in memory disorders

Neuronal oscillations are thought to underlie interactions between distinct brain regions required for normal memory functioning. This study aimed at elucidating the neuronal basis of memory abnormalities in neurodegenerative disorders. Magnetoencephalography (MEG) was used to measure oscillatory brain signals in patients with Alzheimer s disease (AD), a neurodegenerative disease causing progressive cognitive decline, and mild cognitive impairment (MCI), a disorder characterized by mild but clinically significant complaints of memory loss without apparent impairment in other cognitive domains. Furthermore, to help interpret our AD/MCI results and to develop more powerful oscillatory MEG paradigms for clinical memory studies, oscillatory neuronal activity underlying declarative memory, the function which is afflicted first in both AD and MCI, was investigated in a group of healthy subjects. An increased temporal-lobe contribution coinciding with parieto-occipital deficits in oscillatory activity was observed in AD patients: sources in the 6 12.5 Hz range were significantly stronger in the parieto-occipital and significantly weaker in the right temporal region in AD patients, as compared to MCI patients and healthy elderly subjects. Further, the auditory steady-state response, thought to represent both evoked and induced activity, was enhanced in AD patients, as compared to controls, possibly reflecting decreased inhibition in auditory processing and deficits in adaptation to repetitive stimulation with low relevance. Finally, the methodological study revealed that successful declarative encoding and retrieval is associated with increases in occipital gamma and right hemisphere theta power in healthy unmedicated subjects. This result suggests that investigation of neuronal oscillations during cognitive performance could potentially be used to investigate declarative memory deficits in AD patients. Taken together, the present results provide an insight on the role of brain oscillatory activity in memory function and memory disorders.

Subtypes of psychotic-like experiences are differentially associated with suicidal ideation, plans and attempts in young adults

Psychotic-like experiences (PLEs) have been associated with increased risk of suicidality, but it is unclear whether the level of risk varies with different types of PLE. A cross-sectional online survey was completed by 1610 university students. Respondents completed the Community Assessment of Psychic Experiences-15 (CAPE-P15) assessing PLEs on three subscales: Perceptual Abnormalities (PA), Persecutory Ideation (PI) and Bizarre Experiences (BE). Lifetime suicidal ideation, plans and attempts, cannabis, ecstasy and methamphetamine use and family history of mental disorder were also assessed. Multinomal logistic regression was used to examine unique determinants of lifetime suicidality, defined as any history of (i) suicidal ideation or plans and (ii) any attempt, relative to no lifetime history of suicidality. A lifetime history of PA and PI provided significant unique contributions to the prediction of suicide risk, after control for other significant predictors. BE were not associated with any suicide variable demonstrating the variation in risk of suicidality with different types of PLEs. Perceptual abnormalities and persecutory ideation as measured by the CAPE-P15 are the PLEs associated with a higher risk of lifetime suicidality.

Current CAPE-15: A measure of recent psychotic-like experiences and associated distress

Aim Psychotic-like experiences (PLEs) are common in young people and are associated with both distress and adverse outcomes. The Community Assessment of Psychic Experiences-Positive Scale (CAPE-P) provides a 20-item measure of lifetime PLEs. A 15-item revision of this scale was recently published (CAPE-P15). Although the CAPE-P has been used to assess PLEs in the last 12 months, there is no version of the CAPE for assessing more recent PLEs (e.g. 3 months). This study aimed to determine the reliability and validity of the current CAPE-P15 and assess its relationship with current distress. Method A cross-sectional online survey of 489 university students (17–25 years) assessed lifetime and current substance use, current distress, and lifetime and 3-month PLEs on the CAPE-P15. Results Confirmatory factor analysis indicated that the current CAPE-P15 retained the same three-factor structure as the lifetime version consisting of persecutory ideation, bizarre experiences and perceptual abnormalities. The total score of the current version was lower than the lifetime version, but the two were strongly correlated (r = .64). The current version was highly predictive of generalized distress (r = .52) and indices that combined symptom frequency with associated distress did not confer greater predictive power than frequency alone. Conclusion This study provided preliminary data that the current CAPE-P15 provides a valid and reliable measure of current PLEs. The current CAPE-P15 is likely to have substantial practical utility if it is later shown to be sensitive to change, especially in prevention and early intervention for mental disorders in young people.

Cathepsin D Deficiency - Molecular and Cellular Mechanisms of Neurodegeneration

Cathepsin D (CTSD) is a lysosomal protease, the deficiency of which is fatal and associated with neurodegeneration. CTSD knock-out mice, which die at the age of four weeks, show intestinal necrosis, loss of lymphoid cells and moderate pathological changes in the brain. An active-site mutation in the CTSD gene underlies a neurodegenerative disease in newborn sheep, characterized by brain atrophy without any changes to visceral tissues. The CTSD deficiences belong to the group of neuronal ceroid-lipofuscinoses (NCLs), severe neurodegenerative lysosomal storage disorders. The aim of this thesis was to examine the molecular and cellular mechanisms behind neurodegeneration in CTSD deficiency. We found the developmental expression pattern of CTSD to resemble that of synaptophysin and the increasing expression of CTSD to coincide with the active period of myelination in the rat brain, suggesting a role for CTSD in early rat brain development. An active-site mutation underlying the congenital ovine NCL not only affected enzymatic activity, but also changed the stability, processing and transport of the mutant protein, possibly contributing to the disease pathogenesis. We also provide CTSD deficiency as a first molecular explanation for human congenital NCL, a lysosomal storage disorder, characterized by neuronal loss and demyelination in the central nervous system. Finally, we show the first evidence for synaptic abnormalities and thalamocortical changes in CTSD-deficient mice at the molecular and ultrastructural levels. Keywords: cathepsin D, congenital, cortex, lysosomal storage disorder, lysosome, mutation, neurodegeneration, neuronal ceroid-lipofuscinosis, overexpression, synapse, thalamus

Expression and function of angiotensins in the regulation of intraocular pressure - an experimental study

Glaucoma is a multifactorial long-term ocular neuropathy associated with progressive loss of the visual field, retinal nerve fiber structural abnormalities and optic disc changes. Like arterial hypertension it is usually a symptomless disease, but if left untreated leads to visual disability and eventual blindness. All therapies currently used aim to lower intraocular pressure (IOP) in order to minimize cell death. Drugs with new mechanisms of action could protect glaucomatous eyes against blindness. Renin-angiotensin system (RAS) is known to regulate systemic blood pressure and compounds acting on it are in wide clinical use in the treatment of hypertension and heart failure but not yet in ophthalmological use. There are only few previous studies concerning intraocular RAS, though evidence is accumulating that drugs antagonizing RAS can also lower IOP, the only treatable risk factor in glaucoma. The main aim of this experimental study was to clarify the expression of the renin-angiotensin system in the eye tissues and to test its potential oculohypotensive effects and mechanisms. In addition, the possible relationship between the development of hypertension and IOP was evaluated in animal models. In conclusion, a novel angiotensin receptor type (Mas), as well as ACE2 enzyme- producing agonists for Mas, were described for the first time in the eye structures participating in the regulation of IOP. In addition, a Mas receptor agonist significantly reduced even normal IOP. The effect was abolished by a specific receptor antagonist. Intraocular, local RAS would thus to be involved in the regulation of IOP, probably even more in pathological conditions such as glaucoma though there was no unambiguous relationship between arterial and ocular hypertension. The findings suggest the potential as antiglaucomatous drugs of agents which increase ACE2 activity and the formation of angiotensin (1-7), or activate Mas receptors.

Successful fertility experiments with cryopreserved spermatozoa of barramundi, Lates calcarifer (Bloch), using dimethylsulfoxide and glycerol as cryoprotectants

The fertility of cryopreserved Lates calcarifer sperm was studied to increase the availability of semen for routine fertilization of stripped eggs and to provide a tool for selective breeding. Semen diluted (1:4 v/v) and frozen (-196 degrees C) with 5% dimethylsulfoxide (DMSO) or 10% glycerol (final concentration) as cryoprotectants was used to inseminate freshly stripped ova. Frozen-thawed sperm were motile for about 4 min after being mixed with seawater. In the DMSO medium, post-thaw sperm activation was immediate after dilution with seawater, but in the glycerol medium maximum motility intensity was delayed for up to 1 min. When eggs and sperm were mixed before the addition of seawater, semen frozen with DMSO as cryoprotectant gave a mean hatch rate (84.1%) no different (P > 0.05) from that of unfrozen semen diluted with Ringer's solution (80.7%) or with DMSO (83.7%), but higher (P < 0.05) than that of semen frozen with glycerol (60.9%). Adding sperm to seawater 30 s before mixing with eggs did not improve the fertility of sperm cryopreserved with glycerol. Eggs inseminated with glycerol-cryoprotected sperm showed higher mortality during incubation than those inseminated with DMSO-cryoprotected sperm. Sperm held in liquid nitrogen for 90 days with DMSO as cryoprotectant yielded acceptable fertilization and hatching rates with semen-to-ova ratios of up to 1:100 (v/v) , and produced fish with no apparent abnormalities over a 29-day period after hatch. These results show that cryopreservation of L. calcarifer sperm is feasible and well suited to a variety of hatchery purposes.

Rhythm Analysis Using Vectorcardiograms

Fourier shape descriptors of vectorcardiograms have been proposed for cardiac rhythm analysis. The technique characterizes the differences in shape and size of the normal and abnormal vectorcardiograms. The specific abnormalities considered are premature ventricular contractions (PVC's) and supraventricular premature contractions (SVPC's).