Rising incidence, progression and changing patterns of liver disease in Wales 1999-2019.

BACKGROUND: Liver disease incidence and hence demand on hepatology services is increasing. AIM: To describe trends in incidence and natural history of liver diseases in Wales to inform effective provision of hepatology services. METHODS: The registry is populated by International Classification of Diseases-10 (ICD-10) code diagnoses for residents derived from mortality data and inpatient/day case activity between 1999-2019. Pseudo-anonymised linkage of: (1) Causative diagnoses; (2) Cirrhosis; (3) Portal hypertension; (4) Decompensation; and (5) Liver cancer diagnoses enabled tracking liver disease progression. RESULTS: The population of Wales in 2019 was 3.1 million. Between 1999 and 2019 73054 individuals were diagnosed with a hepatic disorder, including 18633 diagnosed with cirrhosis, 10965 with liver decompensation and 2316 with hepatocellular carcinoma (HCC). Over 21 years the incidence of liver diseases increased 3.6 fold, predominantly driven by a 10 fold increase in non-alcoholic fatty liver disease (NAFLD); the leading cause of liver disease from 2014. The incidence of cirrhosis, decompensation, HCC, and all-cause mortality tripled. Liver-related mortality doubled. Alcohol-related liver disease (ArLD), autoimmune liver disease and congestive hepatopathy were associated with the highest rates of decompensation and all-cause mortality. CONCLUSION: A 10 fold increase in NAFLD incidence is driving a 3.6 fold increase in liver disease in Wales over 21 years. Liver-related morbidity and mortality rose more slowly reflecting the lower progression rate in NAFLD. Incidence of ArLD remained stable but was associated with the highest rates of liver-related and all-cause mortality.

Congenital myasthenic syndrome due to a TOR1AIP1 mutation: a new disease pathway for impaired synaptic transmission.

Congenital myasthenic syndromes are inherited disorders characterized by fatiguable muscle weakness resulting from impaired signal transmission at the neuromuscular junction. Causative mutations have been identified in genes that can affect the synaptic function or structure. We identified a homozygous frameshift deletion c.127delC, p. Pro43fs in TOR1AIP1 in two siblings with limb-girdle weakness and impaired transmission at the neuromuscular synapse. TOR1AIP1 encodes the inner nuclear membrane protein lamin-associated protein 1. On muscle biopsy from the index case, lamin-associated protein 1 was absent from myonuclei. A mouse model with lamin-associated protein 1 conditionally knocked out in striated muscle was used to analyse the role of lamin-associated protein 1 in synaptic dysfunction. Model mice develop fatiguable muscle weakness as demonstrated by using an inverted screen hang test. Electromyography on the mice revealed a decrement on repetitive nerve stimulation. Ex vivo analysis of hemi-diaphragm preparations showed both miniature and evoked end-plate potential half-widths were prolonged which was associated with upregulation of the foetal acetylcholine receptor γ subunit. Neuromuscular junctions on extensor digitorum longus muscles were enlarged and fragmented, and the number of subsynaptic nuclei was significantly increased. Following these findings, electromyography was performed on cases of other nuclear envelopathies caused by mutations in LaminA/C or emerin, but decrement on repetitive nerve stimulation or other indications of defective neuromuscular transmission were not seen. Thus, this report highlights the first nuclear membrane protein in which defective function can lead to impaired synaptic transmission.

Autophagy is a gatekeeper of hepatic differentiation and carcinogenesis by controlling the degradation of Yap.

Activation of the Hippo pathway effector Yap underlies many liver cancers, however no germline or somatic mutations have been identified. Autophagy maintains essential metabolic functions of the liver, and autophagy-deficient murine models develop benign adenomas and hepatomegaly, which have been attributed to activation of the p62/Sqstm1-Nrf2 axis. Here, we show that Yap is an autophagy substrate and mediator of tissue remodeling and hepatocarcinogenesis independent of the p62/Sqstm1-Nrf2 axis. Hepatocyte-specific deletion of Atg7 promotes liver size, fibrosis, progenitor cell expansion, and hepatocarcinogenesis, which is rescued by concurrent deletion of Yap. Our results shed new light on mechanisms of Yap degradation and the sequence of events that follow disruption of autophagy, which is impaired in chronic liver disease.

The Transcriptional Activator Krüppel-like Factor-6 Is Required for CNS Myelination.

Growth factors of the gp130 family promote oligodendrocyte differentiation, and viability, and myelination, but their mechanisms of action are incompletely understood. Here, we show that these effects are coordinated, in part, by the transcriptional activator Krüppel-like factor-6 (Klf6). Klf6 is rapidly induced in oligodendrocyte progenitors (OLP) by gp130 factors, and promotes differentiation. Conversely, in mice with lineage-selective Klf6 inactivation, OLP undergo maturation arrest followed by apoptosis, and CNS myelination fails. Overlapping transcriptional and chromatin occupancy analyses place Klf6 at the nexus of a novel gp130-Klf-importin axis, which promotes differentiation and viability in part via control of nuclear trafficking. Klf6 acts as a gp130-sensitive transactivator of the nuclear import factor importin-α5 (Impα5), and interfering with this mechanism interrupts step-wise differentiation. Underscoring the significance of this axis in vivo, mice with conditional inactivation of gp130 signaling display defective Klf6 and Impα5 expression, OLP maturation arrest and apoptosis, and failure of CNS myelination.

Astrocytic TYMP and VEGFA drive blood-brain barrier opening in inflammatory central nervous system lesions.

In inflammatory central nervous system conditions such as multiple sclerosis, breakdown of the blood-brain barrier is a key event in lesion pathogenesis, predisposing to oedema, excitotoxicity, and ingress of plasma proteins and inflammatory cells. Recently, we showed that reactive astrocytes drive blood-brain barrier opening, via production of vascular endothelial growth factor A (VEGFA). Here, we now identify thymidine phosphorylase (TYMP; previously known as endothelial cell growth factor 1, ECGF1) as a second key astrocyte-derived permeability factor, which interacts with VEGFA to induce blood-brain barrier disruption. The two are co-induced NFκB1-dependently in human astrocytes by the cytokine interleukin 1 beta (IL1B), and inactivation of Vegfa in vivo potentiates TYMP induction. In human central nervous system microvascular endothelial cells, VEGFA and the TYMP product 2-deoxy-d-ribose cooperatively repress tight junction proteins, driving permeability. Notably, this response represents part of a wider pattern of endothelial plasticity: 2-deoxy-d-ribose and VEGFA produce transcriptional programs encompassing angiogenic and permeability genes, and together regulate a third unique cohort. Functionally, each promotes proliferation and viability, and they cooperatively drive motility and angiogenesis. Importantly, introduction of either into mouse cortex promotes blood-brain barrier breakdown, and together they induce severe barrier disruption. In the multiple sclerosis model experimental autoimmune encephalitis, TYMP and VEGFA co-localize to reactive astrocytes, and correlate with blood-brain barrier permeability. Critically, blockade of either reduces neurologic deficit, blood-brain barrier disruption and pathology, and inhibiting both in combination enhances tissue preservation. Suggesting importance in human disease, TYMP and VEGFA both localize to reactive astrocytes in multiple sclerosis lesion samples. Collectively, these data identify TYMP as an astrocyte-derived permeability factor, and suggest TYMP and VEGFA together promote blood-brain barrier breakdown.

The Welsh study of mothers and babies: protocol for a population-based cohort study to investigate the clinical significance of defined ultrasound findings of uncertain significance.

BACKGROUND: Improvement in ultrasound imaging has led to the identification of subtle non-structural markers during the 18 - 20 week fetal anomaly scan, such as echogenic bowel, mild cerebral ventriculomegaly, renal pelvicalyceal dilatation, and nuchal thickening. These markers are estimated to occur in between 0.6% and 4.3% of pregnancies. Their clinical significance, for pregnancy outcomes or childhood morbidity, is largely unknown. The aim of this study is to estimate the prevalence of seven markers in the general obstetric population and establish a cohort of children for longer terms follow-up to assess the clinical significance of these markers. METHODS/DESIGN: All women receiving antenatal care within six of seven Welsh Health Boards who had an 18 to 20 week ultrasound scan in Welsh NHS Trusts between July 2008 and March 2011 were eligible for inclusion. Data were collected on seven markers (echogenic bowel, cerebral ventriculomegaly, renal pelvicalyceal dilatation, nuchal thickening, cardiac echogenic foci, choroid plexus cysts, and short femur) at the time of 18 - 20 week fetal anomaly scan. Ultrasound records were linked to routinely collected data on pregnancy outcomes (work completed during 2012 and 2013). Images were stored and reviewed by an expert panel.The prevalence of each marker (reported and validated) will be estimated. A projected sample size of 23,000 will allow the prevalence of each marker to be estimated with the following precision: a marker with 0.50% prevalence to within 0.10%; a marker with 1.00% prevalence to within 0.13%; and a marker with 4.50% prevalence to within 0.27%. The relative risk of major congenital abnormalities, stillbirths, pre-term birth and small for gestational age, given the presence of a validated marker, will be reported. DISCUSSION: This is a large, prospective study designed to estimate the prevalence of markers in a population-based cohort of pregnant women and to investigate associations with adverse pregnancy outcomes. The study will also establish a cohort of children that can be followed-up to explore associations between specific markers and longer-term health and social outcomes.

"Until the trial is complete you can't really say whether it helped you or not, can you?": exploring cancer patients' perceptions of taking part in a trial of acupressure wristbands.

BACKGROUND: Nested qualitative studies within clinical trials provide data on patients' experiences of receiving trial interventions and can inform and improve trial designs. The present study explored patients' experiences of participating in a randomised controlled trial of acupressure wristbands for chemotherapy related nausea. METHODS: A randomised three-group sham-controlled trial was carried out to evaluate the effectiveness of acupressure wristbands in the management of chemotherapy-related nausea. A convenience sample of 26 patients volunteered to participate in a qualitative study to explore their experiences of using acupressure wristbands, and taking part in the clinical trial. Participants were recruited from each of the three UK geographical sites from which the trial was conducted: Manchester, Liverpool and Plymouth. In-depth semi-structured interviews were conducted with the participants in their own homes or other location convenient for participating patients. Interviews were audio-taped, transcribed verbatim and analysed using Framework methodology. RESULTS: The main motivational factors influencing participants to take part in the trial were a desire to 'give something back' and limit their own experience of nausea. Participants were largely satisfied with the organisation and running of the acupressure wristband trial. Many participants experienced positive outcomes as a result of taking part in the trial. Lapses in memory, or poor health as a result of their chemotherapy treatment, led to some participants failing to complete trial paperwork on designated days. Two sham wristband participants reported wearing the bands inappropriately resulting in pressure being applied to the acupoint. Almost all of the participants interviewed had only experienced mild nausea or vomiting during the trial. Participants were pragmatic on the extent to which the wristbands were responsible for this lack of nausea and vomiting during the trial. However, many participants, including some patients receiving sham acupressure, believed the wristbands to have had a positive impact on their nausea and vomiting; there was a perception that the wristbands were, at least in part, responsible for the lack of nausea and vomiting they had experienced. CONCLUSIONS: Participants perceive acupressure wristbands as reducing the level of nausea and vomiting experienced during chemotherapy treatment. Reports that some participants wore wristbands inappropriately, and/or delayed completion of trial paperwork could represent confounding variables and have implications for the trial results, and the design of clinical trials within the field of cancer.

Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease.

In inflammatory CNS conditions such as multiple sclerosis (MS), current options to treat clinical relapse are limited, and more selective agents are needed. Disruption of the blood-brain barrier (BBB) is an early feature of lesion formation that correlates with clinical exacerbation, leading to edema, excitotoxicity, and entry of serum proteins and inflammatory cells. Here, we identify astrocytic expression of VEGF-A as a key driver of BBB permeability in mice. Inactivation of astrocytic Vegfa expression reduced BBB breakdown, decreased lymphocyte infiltration and neuropathology in inflammatory and demyelinating lesions, and reduced paralysis in a mouse model of MS. Knockdown studies in CNS endothelium indicated activation of the downstream effector eNOS as the principal mechanism underlying the effects of VEGF-A on the BBB. Systemic administration of the selective eNOS inhibitor cavtratin in mice abrogated VEGF-A-induced BBB disruption and pathology and protected against neurologic deficit in the MS model system. Collectively, these data identify blockade of VEGF-A signaling as a protective strategy to treat inflammatory CNS disease.

Proapoptotic and antiapoptotic actions of Stat1 versus Stat3 underlie neuroprotective and immunoregulatory functions of IL-11.

Current therapies for multiple sclerosis target inflammation but do not directly address oligodendrocyte protection or myelin repair. The gp130 family cytokines ciliary neurotrophic factor, leukemia inhibitory factor, and IL-11 have been identified as oligodendrocyte growth factors, and IL-11 is also strongly immunoregulatory, but their underlying mechanisms of action are incompletely characterized. In this study, we demonstrate that these effects of IL-11 are mediated via differential regulation of apoptosis in oligodendrocytes versus Ag-presenting dendritic cells (DCs), and are dependent on lineage-specific activity of the transcription factors Stat1 versus Stat3. Focal demyelinating lesions induced in cerebral cortices of IL-11Rα(-/-) mice using stereotactic microinjection of lysolecithin were larger than in controls, and remyelination was delayed. In IL-11Rα(-/-) mice, lesions displayed extensive oligodendrocyte loss and axonal transection, and increased infiltration by inflammatory cells including CD11c(+) DCs, CD3(+) lymphocytes, and CD11b(+) phagocytes. In oligodendrocyte progenitor cell (OPC) cultures, IL-11 restricted caspase 9 activation and apoptosis, and it increased myelination in OPC-neuron cocultures. Importantly, siRNA inhibition of Stat1 enhanced the antiapoptotic effects of IL-11 on OPCs, but IL-11 induced apoptosis in the presence of Stat3 silencing. In contrast, IL-11 augmented caspase activation and apoptosis in cultures of CD11c(+) DCs, but not in CD11b(+) or CD3(+) cells. Inhibition of Stat3 exacerbated the proapoptotic effects of IL-11 on DCs, whereas they were ablated in Stat1(-/-) cultures. Collectively, these findings reveal novel mechanisms underlying the actions of a neuroprotective and immunoregulatory member of the gp130 cytokine family, suggesting avenues to enhance oligodendrocyte viability and restrict CNS inflammation in multiple sclerosis.

Population based absolute and relative survival to 1 year of people with diabetes following a myocardial infarction: a cohort study using hospital admissions data.

BACKGROUND: People with diabetes who experience an acute myocardial infarction (AMI) have a higher risk of death and recurrence of AMI. This study was commissioned by the Department for Transport to develop survival tables for people with diabetes following an AMI in order to inform vehicle licensing. METHODS: A cohort study using data obtained from national hospital admission datasets for England and Wales was carried out selecting all patients attending hospital with an MI for 2003-2006 (inclusion criteria: aged 30+ years, hospital admission for MI (defined using ICD 10 code I21-I22). STATA was used to create survival tables and factors associated with survival were examined using Cox regression. RESULTS: Of 157,142 people with an MI in England and Wales between 2003-2006, the relative risk of death or recurrence of MI for those with diabetes (n = 30,407) in the first 90 days was 1.3 (95%CI: 1.26-1.33) crude rates and 1.16 (95%CI: 1.1-1.2) when controlling for age, gender, heart failure and surgery for MI) compared with those without diabetes (n = 129,960). At 91-365 days post AMI the risk was 1.7 (95% CI 1.6-1.8) crude and 1.50 (95%CI: 1.4-1.6) adjusted. The relative risk of death or re-infarction was higher at younger ages for those with diabetes and directly after the AMI (Relative risk; RR: 62.1 for those with diabetes and 28.2 for those without diabetes aged 40-49 [compared with population risk]). CONCLUSIONS: This is the first study to provide population based tables of age stratified risk of re-infarction or death for people with diabetes compared with those without diabetes. These tables can be used for giving advice to patients, developing a baseline to compare intervention studies or developing license or health insurance guidelines.

VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown.

Breakdown of the blood-brain barrier (BBB) is an early and significant event in CNS inflammation. Astrocyte-derived VEGF-A has been implicated in this response, but the underlying mechanisms remain unresolved. Here, we identify the endothelial transmembrane tight junction proteins claudin-5 (CLN-5) and occludin (OCLN) as targets of VEGF-A action. Down-regulation of CLN-5 and OCLN accompanied up-regulation of VEGF-A and correlated with BBB breakdown in experimental autoimmune encephalomyelitis, an animal model of CNS inflammatory disease. In cultures of brain microvascular endothelial cells, VEGF-A specifically down-regulated CLN-5 and OCLN protein and mRNA. In mouse cerebral cortex, microinjection of VEGF-A disrupted CLN-5 and OCLN and induced loss of barrier function. Importantly, functional studies revealed that expression of recombinant CLN-5 protected brain microvascular endothelial cell cultures from a VEGF-induced increase in paracellular permeability, whereas recombinant OCLN expressed under the same promoter was not protective. Previous studies have shown CLN-5 to be a key determinant of trans-endothelial resistance at the BBB. Our findings suggest that its down-regulation by VEGF-A constitutes a significant mechanism in BBB breakdown.

Effects of Alchemilla vulgaris and glycerine on epithelial and myofibroblast cell growth and cutaneous lesion healing in rats.

Wound-healing properties have been suggested for Alchemilla vulgaris. Since epithelial and myofibroblast cell growth is required for wound healing, the effects of A. vulgaris on cell growth were investigated in Chang liver and Madin Darby Bovine Kidney (MDBK) epithelial cell lines and rat aortic myofibroblast cultures. Putative healing properties were investigated on dorsal circular 8 mm excisional skin lesions in adult male rats. Cell numbers increased with 0.1-1% A. vulgaris, attaining 21.3 +/- 2.1%, 15.5 +/- 2.25% and 10.6 +/- 0.6% in MDBK, myofibroblast and Chang liver cells, respectively (p < 0.005). No morphological changes or cytotoxicity were noted. In rats A. vulgaris (3%)-treated lesions were significantly decreased in diameter by 10.0 +/- 0.7% (p < 0.005) after 2 days of treatment. On day 3 of treatment, the lesion diameter was significantly reduced by 15.9 +/- 1.1% in glycerine vehicle-treated rats compared with distilled water (p < 0.005), whereas that in A. vulgaris-treated rats was reduced further by 23.2 +/- 1.4% (p < 0.005). Glycerine alone significantly reduced the lesion diameter between days 3 and 5 but complete healing occurred a day earlier in A. vulgaris-treated rats. The results demonstrate wound-healing properties of A. vulgaris associated with promitotic activity in epithelial cells and myofibroblasts.

IL-1beta regulates blood-brain barrier permeability via reactivation of the hypoxia-angiogenesis program.

Loss of blood-brain barrier (BBB) integrity is believed to be an early and significant event in lesion pathogenesis in the inflammatory demyelinating disease multiple sclerosis (MS), and understanding mechanisms involved may lead to novel therapeutic avenues for this disorder. Well-differentiated endothelium forms the basis of the BBB, while astrocytes control the balance between barrier stability and permeability via production of factors that restrict or promote vessel plasticity. In this study, we report that the proinflammatory cytokine IL-1beta, which is prominently expressed in active MS lesions, causes a shift in the expression of these factors to favor plasticity and permeability. The transcription factor, hypoxia inducible factor-1 (HIF-1), plays a significant role in this switch. Using a microarray-based approach, we found that in human astrocytes, IL-1beta induced the expression of genes favoring vessel plasticity, including HIF-1alpha and its target, vascular endothelial growth factor-A (VEGF-A). Demonstrating relevance to MS, we showed that HIF-1alpha and VEGF-A were expressed by reactive astrocytes in active MS lesions, while the VEGF receptor VEGFR2/flk-1 localized to endothelium and IL-1 to microglia/macrophages. Suggesting functional significance, we found that expression of IL-1beta in the brain induced astrocytic expression of HIF-1alpha, VEGF-A, and BBB permeability. In addition, we confirmed VEGF-A to be a potent inducer of BBB permeability and angiogenesis, and demonstrated the importance of IL-1beta-induced HIF-1alpha in its regulation. These results suggest that IL-1beta contributes to BBB permeability in MS via reactivation of the HIF-VEGF axis. This pathway may represent a potential therapeutic target to restrict lesion formation.

Methodological issues in the identification of hip fractures using routine hospital data: a database study.

The proportion of the population over the age of retirement has risen in many countries, and this means there is a corresponding rise in the incidence of hip fractures. However, in order to reliably investigate the ability of interventions to prevent fracture, there needs to be a reliable measure of the incidence of hip fracture. The purpose of this study was to examine the inclusion and exclusion criteria used to identify hip fracture from hospital admission data and to examine the impact that these criteria have on estimated incidence of hip fracture. We examine the influence of: individual compared to consultant episode data; primary data compared to any diagnosis of hip fracture; emergency compared to elective admissions; and the influence of type and rate of surgery on incidence estimates. The results showed that classifying hip fractures by use of consultant episodes overestimated the rate of hip fracture by 6-31%, and this overestimation has increased in recent years. The use of primary diagnosis as opposed to any diagnosis underestimates hip fracture by 5%. Two percent (2%) of the people studied had an operation for a hip fracture but did not have a hip fracture diagnosis (many had a multiple fracture diagnosis), and 5.5% of the people studied had an elective admission for the hip fracture (perhaps falling in hospital during an elective admission). We conclude that the selection criteria can have a great influence on the number of hip fractures identified using routine data. There should be a standardized selection procedure for the identification of hip fracture, as this would enable interventions and preventive measures to be evaluated over time and facilitate comparisons of rates in different regions and countries, in order to examine factors associated with hip fracture.

Role for CXCR2 and CXCL1 on glia in multiple sclerosis.

As part of a need to understand myelin repair mechanisms, molecular pathways underlying oligodendrocyte behavior and central nervous system (CNS) remyelination are currently key topics in multiple sclerosis (MS). In the present study, we report expression of a chemoattractant receptor of the immune system, the chemokine receptor, CXCR2, on normal and proliferating oligodendrocytes in active MS lesions. Proliferating oligodendrocytes were occasionally associated with reactive astrocytes positive for CXCL1 (GRO-alpha), the ligand for CXCR2. CXCL1 expression was not seen on astrocytes in control and normal CNS tissue, while CXCR2 expression was constitutive on oligodendrocytes. At the functional level, following stimulation with the proinflammatory cytokine, interleukin-1beta (IL-1beta), we found high-level synthesis of CXCL1 by human fetal astrocytes in vitro. In contrast, human oligodendrocytes in culture expressed the receptor, CXCR2, constitutively. We propose that the concurrence of CXCR2 on oligodendrocytes and induced CXCL1 on hypertrophic astrocytes in MS provides a novel mechanism for recruitment of oligodendrocytes to areas of damage, an essential prerequisite for lesion repair in this devastating human condition.

The cytokine IL-1beta activates IFN response factor 3 in human fetal astrocytes in culture.

The cytokine IL-1beta is a major activator of primary human fetal astrocytes in culture, leading to the production of a wide range of cytokines and chemokines important in the host defense against pathogens. IL-1beta, like TLR4, signals via the MyD88/IL-1betaR-associated kinase-1 pathway linked to activation of NF-kappaB and AP-1. Recent studies have shown that TLR4 also signals independently of MyD88, resulting in the activation of IFN regulatory factor 3 (IRF3), a transcription factor required for the production of primary antiviral response genes such as IFN-beta. Using a functional genomics approach, we observed that IL-1beta induced in astrocytes a group of genes considered to be IFN-stimulated genes (ISG), suggesting that IL-1beta may also signal via IRF3 in these cells. We now show, using real-time PCR, that in astrocytes IL-1beta induces the expression of IFN-beta, IRF7, CXCL10/IFN-gamma-inducible protein-10, and CCL5/RANTES. Chemokine expression was confirmed by ELISA. We also show that IL-1beta induces phosphorylation and nuclear translocation of IRF3 and delayed phosphorylation of STAT1. The dependency of IFN-beta, IRF7, and CXCL10/IFN-gamma-inducible protein-10 gene expression on IRF3 was confirmed using a dominant negative IRF3-expressing adenovirus. The robust induction by IL-1beta of additional ISG noted on the microarrays, such as STAT1, 2'5'-oligoadenylate synthetase 2, and ISG15, also supports an active signaling role for IL-1beta via this pathway in human fetal astrocytes. These data are the first to show that IL-1beta, in addition to TLRs, can stimulate IRF3, implicating this cytokine as an activator of genes involved in innate antiviral responses in astrocytes.

Evidence for growth-promoting effects of omega n - 3 fatty acids alone and in combination with a specific vitamin and mineral complex in rat neuroblastoma cells.

The beneficial effects of Omega n - 3 polyunsaturated fatty acids (n - 3 PUFA) in situations of cognitive impairment may be associated with enhanced neuronal growth. Since neuronal growth is impaired in n - 3 PUFA deficiency, and enhanced by certain vitamins and trace elements, the effects of n - 3 PUFA, vitamin and mineral cell complex (VMC) and their association on neuronal growth were investigated in cultured rat neuroblastoma cells. Treatment of cells for 3 days with n - 3 PUFA significantly enhanced neurite length without affecting the number of neurites or cells. VMC significantly increased cell number without affecting neurite length or their number. Combined n - 3 PUFA and VMC significantly enhanced all three growth parameters. The data confirm the growth promoting effects of n - 3 PUFA and VMC in cultured neurons over a relatively short time frame.

Cytokines: powerful regulators of glial cell activation.

It is now clear that cytokines function as powerful regulators of glial cell function in the central nervous system (CNS), either inhibiting or promoting their contribution to CNS pathology. Although these interactions are complex, the availability of animals with targeted deletions of these genes and/or their receptors, as well as transgenic mice in which cytokine expression has been targeted to specific cell types, and the availability of purified populations of glia that can be studied in vitro, has provided a wealth of interesting and frequently surprising data relevant to this activity. A particular feature of many of these studies is that it is the nature of the receptor that is expressed, rather than the cytokine itself, that regulates the functional properties of these cytokines. Because cytokine receptors are themselves modulated by cytokines, it becomes evident that the effects of these cytokines may change dramatically depending upon the cytokine milieu present in the immediate environment. An additional exciting aspect of these studies is the previously underappreciated role of these factors in repair to the CNS. In this review, we focus on current information that has helped to define the role of cytokines in regulating glial cell function as it relates to the properties of microglia and astrocytes.

Cement, cancers and clusters: an investigation of a claim of a local excess cancer risk related to a cement works.

BACKGROUND: We investigated claims by a campaigning group of a cancer cluster associated with a local cement works. METHODS: To investigate cancer rates in the town we defined the study area as the Census wards matching the geographical area code supplied to the campaigning group. Standard methods were applied to registered cases of cancer for the area for the years 1974-1989 to derive observed and expected numbers. The significance of the relative risk was assessed using the Poisson distribution. By selecting a different denominator population we attempted to reproduce the results of the campaign group. Cancer rates around the cement works were investigated for four cancer types plausibly associated with emissions, using cancer registrations for the years 1985-1994. Cases were mapped to 1981 Census ward boundaries, and the same statistical methods were used, but expected counts were also adjusted for deprivation. Rates were calculated for an inner 2 km zone and outer zone 2-5 km from the works. Relative risk was calculated and the ratio of risks was examined for evidence of increased risk closer to the works. RESULTS: Relative risks were not significantly elevated either in the town or around the cement works itself. We were able to reproduce the likely errors that resulted in the elevated relative risks for five cancer groups claimed by the campaigning group. CONCLUSIONS: We found no evidence of increased incidence of cancer around the cement works. Incorrect handling of cancer registration data can result in spurious cancer clusters and unnecessary public alarm.