Cholesteryl ester storage disease of clinical and genetic characterisation: A case report and review of literature

BACKGROUND Cholesteryl ester storage disease(CESD)is a rare genetic disease.Its symptoms and severity are highly variable.CESD is a systemic disease that can lead to the accumulation of fat and inflammation in the liver,as well as gastrointestinal and cardiovascular disease.The majority of patients require liver transplantation due to decompensated cirrhosis.Enzyme replacement therapy has been approved based on a randomized trial.Our study aims to clinically and genetically evaluate two siblings with CESD who underwent liver transplantation,as well as their first-degree family members.CASE SUMMARY The siblings were compound heterozygous for the missense variant in LIPA exon 8,c.894G>A,(p.Gln298Gln)and a single base pair deletion,c.482del(p.Asn161Ilefs*19).Analyses of single nucleotide polymorphisms showed variants with an increased risk of fatty liver disease and fibrosis for both patients.Clinically,both patients show signs of recurrence of CESD in the liver after transplantation and additional gastrointestinal and cardiovascular signs of CESD.Three family members who were LIPA heterozygous had a lysosomal acid lipase activity below the reference value.One of these carriers,a seven-year-old boy,was found to have severe dyslipidemia and was subsequently treated with statins.CONCLUSION Our study underlines that CESD is a multi-organ disease,the progression of which may occur post-liver transplantation.Our findings underline the need for monitoring of complications and assessment of possible further treatment.     

Calcium-independent phospholipase A(2) influences AMPA-mediated toxicity of hippocampal slices by regulating the GluR1 subunit in synaptic membranes

We have recently documented that phosphorylation of the GluR1 subunit of alpha-amino-3-hydroxy-5-methylisoxazole-propionate (AMPA) glutamate receptors is influenced by calcium-independent forms of phospholipase A(2) (iPLA(2)) activity in the brain. Given the importance of GluR1 subunit phosphorylation in the control of AMPA receptor delivery to synaptic membranes, we tested the influence of iPLA(2) activity on AMPA receptor distribution between neuronal compartments, using organotypic cultured hippocampal slices. In agreement with earlier reports, the iPLA(2) inhibitor bromoenol lactone (BEL) markedly enhanced the phosphorylation of the GluR1 subunit at both Ser831 and Ser845 residues. GluR1 subunit phosphorylation levels were selectively increased by (R)-BEL, an enantio-selective inhibitor of iPLA(2)gamma, but not by (S)-BEL, an iPLA(2)beta inhibitor. The iPLA(2)gamma inhibitor R-BEL also promoted the insertion of new GluR1 subunits into synaptic membranes and exacerbated AMPA-mediated cell death in the CA1 region of the hippocampus. The latter effect was selectively abolished by IEM 1460 and philanthotoxin-433, two antagonists specific for AMPA receptors lacking GluR2 subunits. These results provide evidence that iPLA(2)gamma-related regulation of AMPA receptor GluR1 subunit phosphorylation could represent an important mechanism modulating hippocampal cell death induced by AMPA receptor overstimulation.     

Correction to: Patient perspectives on the therapeutic profile of botulinum neurotoxin type A in cervical dystonia

Journal of Neurology - The article Patient perspectives on the therapeutic profile of botulinum neurotoxin type A in cervical dystonia, written by Cynthia Comella, Joaquim J. Ferreira, Emilie Pain,...     

RF9, a potent and selective neuropeptide FF receptor antagonist, prevents opioid-induced tolerance associated with hyperalgesia

Neuropeptide FF (NPFF) has been proposed to play a role in pain modulation, opioid tolerance, and several other physiological processes. However, pharmacological agents that would help define physiological roles for this peptide are still missing. Here we report the discovery of a potent and selective NPFF receptor antagonist, RF9, that can be administered systemically. This compound does not show any effects by itself but can block efficiently the increase in blood pressure and heart rate evoked by NPFF. When chronically coinjected with heroin, RF9 completely blocks the delayed and long-lasting paradoxical opioid-induced hyperalgesia and prevents the development of associated tolerance. Our data indicate that NPFF receptors are part of a bona fide antiopioid system and that selective antagonists of these receptors could represent useful therapeutic agents for improving the efficacy of opioids in chronic pain treatment.     

Venobronchial fistula: an unusual complication of long-term central venous access

A venobronchial fistula developed between the azygous vein and the upper aspect of the right main bronchus 12 months after completion of the treatment of a stage IIIB non-small-cell lung cancer in a 54-year-old man. The fistula contained the tip of the catheter placed for chemotherapy perfusion. The reported case presented risk factors previously identified for such a complication. In addition, some clinical particularities were present, suggesting new potent risk factors and some preventive means for safe long-term central venous catheterization.     

Streptococcus pneumoniae Resistance to Complement-Mediated Immunity Is Dependent on the Capsular Serotype

Streptococcus pneumoniae strains vary considerably in the ability to cause invasive disease in humans, and this is partially associated with the capsular serotype. The S. pneumoniae capsule inhibits complement- and phagocyte-mediated immunity, and differences between serotypes in these effects on host immunity may cause some of the variation in virulence between strains. However, the considerable genetic differences between S. pneumoniae strains independent of the capsular serotype prevent an unambiguous assessment of the effects of the capsular serotype on immunity using clinical isolates. We have therefore used capsular serotype-switched TIGR4 mutant strains to investigate the effects of the capsular serotype on S. pneumoniae interactions with complement. Flow cytometry assays demonstrated large differences in C3b/iC3b deposition on opaque-phase variants of TIGR4(−)+4, +6A, +7F, and +23F strains even though the thicknesses of the capsule layers were similar. There was increased C3b/iC3b deposition on TIGR4(−)+6A and +23F strains compared to +7F and +4 strains, and these differences persisted even in serum depleted of immunoglobulin G. Neutrophil phagocytosis of the TIGR4(−)+6A and +23F strains was also increased, but only in the presence of complement, showing that the effects of the capsular serotype on C3b/iC3b deposition are functionally significant. In addition, the virulence of the TIGR4(−)+6A and +23F strains was reduced in a mouse model of sepsis. These data demonstrate that resistance to complement-mediated immunity can vary with the capsular serotype independently of antibody and of other genetic differences between strains. This might be one mechanism by which the capsular serotype can affect the relative invasiveness of different S. pneumoniae strains.The important Gram-positive pathogen Streptococcus pneumoniae has an extracellular polysaccharide capsule that inhibits complement activity, neutrophil phagocytosis, and bacterial killing by neutrophil extracellular traps (19, 23, 25, 26, 29, 31), as well as having major effects on bacterial interactions with the epithelium (8, 25, 26, 29, 31, 37). As a consequence, the capsule is essential for virulence (6, 38). Different strains of S. pneumoniae can express capsules with different structures, depending on the type of monosaccharide units and their bonds within the polysaccharide chain, the enzymes for the synthesis of which are encoded by genes within a specific locus in the genome (5, 27, 30). The different types of capsules are divided into 91 capsular serotypes. Although most S. pneumoniae strains can cause disease in humans, the ability to cause invasive infections (septicemia and meningitis) varies up to 60-fold between strains and is closely associated with the capsular serotype (4, 12). Some serotypes (e.g., 1, 4, 5, 7, and 14) are overrepresented among invasive disease isolates compared to the frequency of their isolation as nasopharyngeal commensals, while other capsular serotypes only rarely cause invasive disease despite being common nasopharyngeal commensals (4, 12, 15).The mechanisms causing capsular serotype-dependent variation in virulence are largely unknown but could reflect differences between the abilities of strains of different serotypes to inhibit host immune responses. Potentially, strains expressing capsular serotypes that strongly inhibit immunity could be more likely to establish invasive infection than strains with capsular serotypes that weakly inhibit host immunity, and this hypothesis is partially supported by existing experimental data. The virulence of different capsular serotypes varies markedly in mouse models of infection, but as there is only a weak relationship between virulence in mice and invasive potential in humans, the clinical relevance of these findings is unclear (1, 7, 9, 33). Because of the central role of complement and phagocytosis for systemic immunity to S. pneumoniae (11, 20, 45, 46), differences in the effects of different capsular serotypes on complement activity or phagocytosis are strong candidates for explaining why the serotype can affect virulence. Indeed, existing data show that resistance to complement activity and phagocytosis varies between strains with different capsular serotypes (18, 28, 46). However, in general, these studies have not controlled for strain phase variation or for noncapsular genetic variation between strains. S. pneumoniae has two main phase variants, opaque with an increased capsule thickness and transparent with a thinner capsule but increased expression of some surface proteins, such as PspC, that can affect complement activity (24, 31). Differences in phase variation between strains could therefore affect complement susceptibility. Furthermore, there is considerable genetic variation between S. pneumoniae strains independent of the capsular serotype. Only 60% of gene clusters are common to all S. pneumoniae strains, and the genome content differs by 8 to 10%, on average, between any two strains (10, 13, 16, 17). This genetic variation is partially linked to the capsular serotype (http://www.mlst.net/), and hence, the relationship between the capsular serotype and invasiveness could be due to noncapsular genetic variation rather than direct effects of the capsule.To overcome strain genetic variation confounding the assessment of capsular serotype interactions with the immune system, the capsular loci of one strain can be replaced with the capsular loci from another, creating otherwise isogenic strains expressing different capsular serotypes (29, 35, 43). Data obtained using capsular serotype-switched strains have shown that expression of capsular serotype 3 reduced complement deposition on a previously serotype 2 strain (2), increased the virulence in mice of an originally serotype 6B strain, and conversely decreased the virulence of a serotype 5 strain (22). Furthermore, a recent study demonstrated variations in resistance to neutrophil killing of unopsonized bacteria between capsular serotype-switched strains expressing different capsular serotypes and correlated reduced sensitivity to neutrophil killing with increased prevalence of that capsular serotype as a nasopharyngeal commensal (39). These studies have established the principle that the capsular serotype can affect the complement sensitivity, neutrophil killing, and virulence of S. pneumoniae independently of the strain background. However, as yet, there are only limited data on the effects of different capsular serotypes on complement-dependent immunity to S. pneumoniae and a more detailed assessment is required to help understand why a strain''s capsular serotype is linked to its invasive potential.We have used opaque- and transparent-phase variants of TIGR4 S. pneumoniae strains modified to express different capsular serotypes, two representative of relatively invasive capsular serotypes (4 and 7F) and two representative of less invasive serotypes (6A and 23F), to assess capsular serotype-dependent effects on immunity. We have investigated the effects of the capsular serotype on opsonization of S. pneumoniae with the complement-derived opsonins C3b and iC3b, as well as on neutrophil phagocytosis and virulence in a mouse model of septicemia.     

Poor Stroop performances in 15-year-old dyslexic teenagers

The Stroop test enables interference between color naming and reading to be studied. Protopapas et al. (2007) reported more errors in an interference task and longer reaction times in 12.5-year-old dyslexics; also more Stroop interference with lower reading skills. The present study uses a version of the Stroop with four color cards and aims to test interference and flexibility in older dyslexic teenagers. The four cards are: color naming, reading, interference and flexibility. In the latter, subjects have to name the color of the word inhibiting reading except when the word is inside a box. This flexibility task enables the testing of the capacity for cognitive switching between tasks. Ten dyslexics (15.1 ± 0.7 years old) and fourteen controls (14.3 ± 1.6 years old) participated in the study. All performed the color naming, the reading, the interference and the flexibility tasks in the same order. Subsequently, they performed a sequence of 60 saccades left–right followed by the interference task. Generally, dyslexic teenagers behaved similarly to non-dyslexics as they showed fewer errors in reading and color than in the interference and flexibility tasks. However, they made more errors and needed more time to accomplish each task than non-dyslexics. The results suggest that the inhibitory and attention processes required by the Stroop test are dysfunctioning even in older dyslexics. In contrast, the study shows no evidence for particular difficulty in the flexibility task, which would constitute an argument against problems with mental switching. Following the execution of saccades, errors in the interference test were significantly reduced for dyslexics, while the time was reduced for both groups. The effects are attributed to visual attention training via saccades.     

Follicular dendritic cell tumor of the mediastinum: expression of fractalkine and SDF-1α as mast cell chemoattractants

Follicular dendritic cell tumor (FDCT) is a rare tumor mainly located in laterocervical lymph nodes. We report one case of mediastinal FDCT associated with a history of bullous skin disease and clinically obvious immunosuppression. This tumor was characterized by heavy mast cell infiltration. Mast cells were in close relationship with tumor cells as demonstrated by ultrastructural examination and their presence are probably related with the strong expression of mast cell chemoattractants as fraktalkine and stromal cell-derived factor-1α by tumor cells. The long follow-up period of more than 17 years allowed to us assess the relatively indolent evolution of this tumor characterized by three slowly growing local recurrences without metastasis.