Enhanced levels of leukotriene B4 in synovial fluid in Lyme disease

The purpose of this study was to evaluate the potential role of LTB4 and cysteinyl leukotrienes in Lyme disease (LD). Therefore, a total number of 34 patients divided into four groups was studied. The patients were classified as having Lyme arthritis (n = 7) or Lyme meningitis (n = 10), and as control groups patients with a noninflammatory arthropathy (NIA) (n = 7) and healthy subjects (n = 10). LTB4 as well as LTC4 secretion from stimulated polymorphonuclear leukocytes (PMNL) from all groups of patients showed no statistical differences. LTB4 levels in synovial fluid were significantly increased in patients with Lyme arthritis (median 142 ng/ml, range 88–296) when compared to the control subjects with NIA (median 46 ng/ml, range 28–72) (p < 0.05). No statistical difference of urinary LTE4 levels between all the different groups of patients was observed. These results show that cysteinyl leukotrienes do not play an important role in the pathogenesis of LD. In contrast to previous findings in rheumatoid arthritis, LTB4 production from stimulated PMNL was not found to be increased in LD. However, the significantly elevated levels of LTB4 in synovial fluid of patients with Lyme arthritis underline the involvement of LTB4 in the pathogenesis of this disease

Natural selection on the regulation of foraging in harvester ants

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Cultural Influences on Academic Performance in Fiji: A Case Study in the Nadroga/Navosa Province

At an upper level of education, especially Forms 5, 6 and 7 of secondary school and in tertiary institutions, Indo-Fijian students often perform better than their ethnic Fijian counterparts. This pattern of ethnic difference in academic performance is a long standing one, lasting over 70 years. However, both ethnic groups have been participants in the same educational system in Fiji. Educational policies have been implemented to reduce this difference. This present case study argues that there are cultural differences of values, beliefs and practices with respect to educational achievement among Indo-Fijians and ethnic Fijians. The achievement ethic of the two ethnic groups differs. Indo-Fijian culture respects and values education highly. Generally speaking, educating children has been always the top priority of Indo-Fijian culture. They believe that education changes people for the better, and the only way to “success” is through education. Thus, Indo- Fijian parents believe that helping children to strive for academic excellence is one of the most important tasks for them. The priority attached by such parents to educational success is one of the strongest forces behind academic success. By contrast, ethnic Fijian culture encourages children to have a strong sense of loyalty to their community and of becoming good members of their koro (i.e., village). Indeed, one’s total commitment to communal activities and cultural requirements is of vital importance. Although ethnic Fijian parents generally understand the importance of their children’s education and wish to support their education, ethnic Fijian communal demands are enormous in terms of time and labour. The pressure to maintain their moral and social obligations within the community tends to make ethnic Fijians spend a large amount of time, energy and money on functions such as ceremonial events and church activities, at the possible expense of providing for the formal education of their children. These demands mean that parents are often absent from home, and unable to supervise children’s homework. Ethnic Fijian children, upper secondary schoolers, feel strong pressure from their peers within their koro to conform to social activities, such as attending church, playing sports such as rugby and volleyball, and hanging around in the koro and town. Besides, the layout of the typical ethnic Fijian home is a more difficult environment than Indo-Fijian households for children’s study, largely due to the limited space to study independently. The socio-cultural background of ethnic Fijians, especially their home environment including family values and priorities, is one of the major barriers to their children’s educational progress. In addition, school leadership, teachers’ expectations, colonial policies and legacies, e.g., land tenure issues, play important roles in affecting differences in the academic performance of these two ethnic groups. Consequently, the educational achievement differences between ethnic Fijians and Indo-Fijians are revealed substantially during the secondary and tertiary educational institutions

The role and ultrastructure of the liver sinusoidal endothelial cell in fasting, hepatoxicity, and ageing

The majority of liver studies focus on the hepatocyte however the work of this thesis investigates the vital role of the liver sinusoidal endothelial cell (LSEC). LSECs line the liver sinusoids forming a protective barrier between the blood and hepatocytes. The LSEC cytoplasm resembles a sieve, perforated with thousands of transcellular pores of approximately 50-150 nm in diameter called fenestrations, and is underlined by a very sparse extracellular matrix. This facilitates the virtually unimpeded passage of fluid and substances smaller than fenestrations from the blood such as drugs and nutrients, and size-dependent filtration of lipoproteins, to and from hepatocytes. Fenestrations are dynamic structures, in that their size and number can be modulated by hormones, drugs, hepatotoxins, and diseases. Reduction of LSEC fenestration size and number (defenestration) is associated with ageing and pathological states, and is also a cause of hyperlipidemia and reduced drug clearance, thus changes in LSEC morphology can affect the entire organism. This thesis aims to broaden knowledge of the role and ultrastructure of the LSEC in physiological and toxicological states by investigating: whether there is fenestration modulation during fasting that could facilitate increased nutrient exchange between the blood and hepatocytes; whether changes to LSEC ultrastructure during acetaminophen hepatotoxicity are consistent with exacerbation of liver injury and/or with the facilitation of liver regeneration after severe necrosis; whether a substance that targets the LSEC could have a therapeutic benefit in acetaminophen hepatotoxicity by protecting the microvasculature from damage; whether isolation and culture of LSECs from ageing rats maintain the ageing (defenestrated) phenotype, and thus whether it is a valid method to study therapeutic substances in vitro that could reverse defenestration-related ailments associated with normal ageing

Deficiency of the first mannosylation step in the N-glycosylation pathway causes congenital disorder of glycosylation type Ik

Defects of N-linked glycosylation represent diseases with multiple organ involvements that are classified as congenital disorders of glycosylation (CDG). In recent years, several CDG types have been attributed to defects of dolichol-linked oligosaccharide assembly in the endoplasmic reticulum. The profiling of [3H]mannose-labeled lipid-linked oligosaccharides was instrumental in identifying most of these glycosylation disorders. However, this method is poorly suited for the identification of short lipid-linked oligosaccharide biosynthesis defects. To adequately resolve deficiencies affecting the first steps of lipid-linked oligosaccharide formation, we have used a non-radioactive procedure employing the fluorescence detection of 2-aminobenzamide-coupled oligosaccharides after HPLC separation. By applying this method, we have detected the accumulation of dolichylpyrophosphate-GlcNAc2 in a previously untyped CDG patient. The accumulation pattern suggested a deficiency of the ALG1 β1,4 mannosyltransferase, which adds the first mannose residue to lipid-linked oligosaccharides. This was supported by the finding that this CDG patient was compound heterozygous for three mutations in the ALG1 gene, leading to the amino acid substitutions S150R and D429E on one allele and S258L on the other. The detrimental effect of these mutations on ALG1 protein function was demonstrated in a complementation assay using alg1 Saccharomyces cerevisiae yeast mutants. The ALG1 mannosyltransferase defect described here represents a novel type of CDG, which should be referred to as CDG-I

Neuromyelitis optica and pregnancy during therapeutic B cell depletion: infant exposure to anti-AQP4 antibody and prevention of rebound relapses with low-dose rituximab postpartum

Neuromyelitis optica (NMO) predominantly affects women, some in childbearing age, and requires early therapeutic intervention to prevent disabling relapses. We report an anti-AQP4 antibody-seropositive patient who became pregnant seven months after low-dose (100 mg) rituximab application. Pregnancy showed no complications, and low-dose rituximab restarted two days after delivery resulted in neurological stability for 24 months. Remarkably, her otherwise healthy newborn presented with anti-AQP4 antibody and reduced B lymphocyte counts in umbilical cord blood, which normalized three months later. Confirming and extending previous reports, our case suggests that low-dose rituximab might be compatible with pregnancy and prevent rebound NMO disease activity postpartum

Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome

Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS) represent the two ends of a clinical spectrum of disease caused by deficiency of mevalonate kinase (MVK), the first committed enzyme of cholesterol biosynthesis. At least 30 patients with MVA and 180 patients with HIDS have been reported worldwide. MVA is characterized by psychomotor retardation, failure to thrive, progressive cerebellar ataxia, dysmorphic features, progressive visual impairment and recurrent febrile crises. The febrile episodes are commonly accompanied by hepatosplenomegaly, lymphadenopathy, abdominal symptoms, arthralgia and skin rashes. Life expectancy is often compromised. In HIDS, only febrile attacks are present, but a subgroup of patients may also develop neurological abnormalities of varying degree such as mental retardation, ataxia, ocular symptoms and epilepsy. A reduced activity of MVK and pathogenic mutations in the MVK gene have been demonstrated as the common genetic basis in both disorders. In MVA, the diagnosis is established by detection of highly elevated levels of mevalonic acid excreted in urine. Increased levels of immunoglobulin D (IgD) and, in most patients of immunoglobulin A (IgA), in combination with enhanced excretion of mevalonic acid provide strong evidence for HIDS. The diagnosis is confirmed by low activity of mevalonate kinase or by demonstration of disease-causing mutations. Genetic counseling should be offered to families at risk. There is no established successful treatment for MVA. Simvastatin, an inhibitor of HMG-CoA reductase, and anakinra have been shown to have beneficial effect in HIDS

Pathogenesis of peroxisomal deficiency disorders (Zellweger syndrome) may be mediated by misregulation of the GABAergic system via the diazepam binding inhibitor

BACKGROUND: Zellweger syndrome (ZS) is a fatal inherited disease caused by peroxisome biogenesis deficiency. Patients are characterized by multiple disturbances of lipid metabolism, profound hypotonia and neonatal seizures, and distinct craniofacial malformations. Median live expectancy of ZS patients is less than one year. While the molecular basis of peroxisome biogenesis and metabolism is known in considerable detail, it is unclear how peroxisome deficiency leads to the most severe neurological symptoms. Recent analysis of ZS mouse models has all but invalidated previous hypotheses. HYPOTHESIS: We suggest that a regulatory rather than a metabolic defect is responsible for the drastic impairment of brain function in ZS patients. TESTING THE HYPOTHESIS: Using microarray analysis we identify diazepam binding inhibitor/acyl-CoA binding protein (DBI) as a candidate protein that might be involved in the pathogenic mechanism of ZS. DBI has a dual role as a neuropeptide antagonist of GABA(A) receptor signaling in the brain and as a regulator of lipid metabolism. Repression of DBI in ZS patients could result in an overactivation of GABAergic signaling, thus eventually leading to the characteristic hypotonia and seizures. The most important argument for a misregulation of GABA(A) in ZS is, however, provided by the striking similarity between ZS and "benzodiazepine embryofetopathy", a malformation syndrome observed after the abuse of GABA(A) agonists during pregnancy. IMPLICATIONS OF THE HYPOTHESIS: We present a tentative mechanistic model of the effect of DBI misregulation on neuronal function that could explain some of the aspects of the pathology of Zellweger syndrome

Incorporation of a Dietary Omega 3 Fatty Acid Impairs Murine Macrophage Responses to Mycobacterium tuberculosis

by creating an immunosuppressive environment. We hypothesized that incorporation of n-3 PUFA suppresses activation of macrophage antimycobacterial responses and favors bacterial growth, in part, by modulating the IFNγ-mediated signaling pathway.. The fatty acid composition of macrophage membranes was modified significantly by DHA treatment. DHA-treated macrophages were less effective in controlling intracellular mycobacteria and showed impaired oxidative metabolism and reduced phagolysosome maturation. Incorporation of DHA resulted in defective macrophage activation, as characterized by reduced production of pro-inflammatory cytokines (TNFα, IL-6 and MCP-1), and lower expression of co-stimulatory molecules (CD40 and CD86). DHA treatment impaired STAT1 phosphorylation and colocalization of the IFNγ receptor with lipid rafts, without affecting surface expression of IFNγ receptor. in response to activation by IFNγ, by modulation of IFNγ receptor signaling and function, suggesting that n-3 PUFA-enriched diets may have a detrimental effect on host immunity to tuberculosis