Deletion of LCE3C and LCE3B is a susceptibility factor for psoriatic arthritis: A study in Spanish and Italian populations and meta‐analysis

Objective

The LCE3C_LCE3B‐del variant is associated with psoriasis and rheumatoid arthritis. Its role in psoriatic arthritis (PsA) is unclear, however, as shown by 3 recent studies with contradictory results. In order to investigate whether LCE3C_LCE3B‐del constitutes a risk factor for PsA susceptibility, we first tested this variant in patients with PsA from Spanish and Italian populations and then performed a meta‐analysis including the previous case–control studies.

Methods

We genotyped LCE3C_LCE3B‐del and its tag single‐nucleotide polymorphism (SNP), rs4112788, in an original discovery cohort of 424 Italian patients with PsA and 450 unaffected control subjects. A Spanish replication cohort consisting of 225 patients with PsA and 469 control subjects was also genotyped. A meta‐analysis considering 7,758 control subjects and 2,325 patients with PsA was also performed.

Results

We observed a significant association between PsA and the LCE3C_LCE3B‐del tag SNP in the Italian and Spanish cohorts, with an overall corrected P value of 0.00019 and a corresponding odds ratio of 1.35 (95% confidence interval 1.14–1.59). Stratified analyses by subphenotype indicated a stronger association for patients with oligoarticular disease. Meta‐analysis including data from all previous published studies confirmed an association of PsA with the LCE3C_LCE3B‐del tag SNP.

Conclusion

LCE3C_LCE3B‐del is a susceptibility factor for PsA, confirming the existence of a shared risk factor involving the epidermal skin barrier in autoimmune disorders.

     

Deficient tumor necrosis factor-alpha production in lipoarabinomannan activated macrophages from toll-like receptor-4 deficient mice: implication for mycobacterial susceptibility

Mice with a point mutation of toll-like receptor-4 (TLR-4) (C3H/HeJ) are hypo-responsive to LPS and more susceptible to mycobacterial infections than their control wild type (C3H/OuJ). We have previously shown that TLR-4-deficient mice produced NO in response to the mycobacterial product, ara-lipoarabinomannan (LAM), in the presence of either Interferon-beta (IFN-beta) or Interferon-gamma (IFN-gamma), with a dose response curve that produced levels of NO almost as high as those observed in C3H/OuJ mice at high concentrations of ara-LAM plus either IFN-beta or-gamma. We now report that tumor necrosis factor-alpha (TNF-alpha), an important cytokine for intracellular killing of mycobacteria, remains deficient in these C3H/HeJ mice compared to C3H/OuJ mice even at a high concentration of ara-LAM with either IFN-gamma or IFN-beta. In addition, TNF-alpha was further down regulated by taurine chloramine (Tau-Cl) in C3H/OuJ mice. The low level of TNF-alpha produced in the TLR-4-deficient (C3H/HeJ) mice was also further down regulated by Tau-Cl. These findings implicate the TLR-4 as an additional candidate locus for mycobacterial susceptibility, and provide a pathway for better understanding the molecular basis of this locus in the immunopathogenesis of mycobacterial infection.     

Learning during middle age: a resistance to stress?

Acute stressful experience enhances subsequent learning in males and impairs learning in females. These sex differences emerge soon after puberty in adulthood. Whether these opposite effects of stress on learning extend into older age is unknown. To examine this, young adult (2-3 months) and middle aged (17-18 months) Fischer 344 rats of both sexes were exposed to an acute stressor of brief tailshocks and trained 24 h later with classical eyeblink conditioning using a trace paradigm. Whereas stressful experience enhanced conditioning in adult males and impaired conditioning in adult females, it had no effect whatsoever on conditioning in the aging animals of either sex. There was no effect of aging itself on acquisition of the conditioned response, suggesting that trace conditioning is not necessarily compromised during this period of life. Together, these data indicate that associative learning in the aging animal is resistant to both the negative and positive consequences of stressful experience.     

The impact of maternal- and neonatal-associated factors on human milk's macronutrients and energy

Objectives: To test the impact of specific maternal- and neonatal-associated factors on human milk's macronutrients and energy.

Methods: This study was conducted with the use of a human milk analyzer (HMA, MIRIS, Uppsala, Sweden). Six hundred and thirty samples of raw milk and 95 samples of donor pasteurized milk were delivered from a total of 305 mothers.

Results: A significant inverse correlation of fat, protein and energy content with gestational age and birth weight was established. Fat and energy were lower in colostrum, increased in transitional milk and decreased on the 30th day's mature milk compared to transitional. The rate of protein decline from colostrum to mature milk was lower in premature deliveries compared to that of full-terms, resulting in greater contents of protein in preterm mature milk. The upmost amounts of carbohydrates were found in mature milk of preterm deliveries. A positive correlation was found between maternal age and fat contents. In women with higher post-pregnancy BMI levels greater analogies of fat and energy were presented. In women suffering diet-controlled gestational diabetes (GD), lower protein and higher fat and energy levels were found.

Conclusions: Prematurity, maternal age, diet-controlled GD and high post-pregnancy BMI levels were found to impose statistical significant effect on milk's macronutrients and energy.     

East African immigrant children in Australia have poor immunisation coverage

Aim: To provide data on the immunisation status of recently arrived East African children and adolescents in Australia. Methods: A prospective audit was conducted at a hospital‐based paediatric immigrant health clinic, in Melbourne, Australia, over the time period November 2000–January 2002. Study subjects were consecutive children and adolescents born in East Africa, arriving in Australia after January 1998. Vaccination status was ascertained by parent report and review of patient‐held records where available, and by serological testing for immunity to hepatitis B, tetanus, diphtheria, rubella and measles. Results: Among 136 participants, 132 (97%) had incomplete or unknown immunisation status based on parent report and vaccination records; written records were available for 5/136 (4%) of participants. Only 21/136 (15%) had serological immunity to all five of measles, rubella, tetanus, diphtheria and hepatitis B, despite a total of 395 visits to vaccine providers by participants since migration. A higher proportion of children had serological immunity to measles (90%) compared to the proportion with serological immunity to rubella (77%), tetanus (61%), diphtheria (45%) and hepatitis B (33%). The predictive value of parent‐reported vaccination status for serological immunity was poor. Conclusions: Paediatric East African immigrants in Victoria are very likely to be inadequately immunised and parent‐reported vaccination status does not predict serological immunity. Full catch‐up immunisation is recommended where immunisation status is unknown and written records are unavailable. Consideration should be given to policy and program development to provide timely and complete immunisation coverage in this group after arrival in Australia.     

Acute Tc-99m DMSA scan for identifying dilating vesicoureteral reflux in children: a meta-analysis

Controversy exists regarding the type and/or sequence of imaging studies needed during the first febrile urinary tract infection (UTI) in young children. Several investigators have claimed that because acute-phase Tc-99m dimercaptosuccinic acid (DMSA) renal-scan results are abnormal in the presence of dilating vesicoureteral reflux, a normal DMSA-scan result makes voiding cystourethrography (VCUG) unnecessary in the primary examination of infants with UTI. To evaluate the accuracy of acute-phase DMSA scanning in identifying dilating (grades III through V) vesicoureteral reflux documented by VCUG in children with a first febrile UTI, we performed a meta-analysis of the accuracy of diagnostic tests as reported from relevant studies identified through the PubMed and Scopus databases. Patient-based and renal unit-based analyses were performed. Overall, 13 cohort studies were identified. Nine studies involved patients younger than 2 years, 3 involved children aged 16 years or younger, and 1 involved exclusively neonates. Girls constituted 22% to 85% of the involved children. Pooled (95% confidence intervals) sensitivity and specificity rates of DMSA scanning were 79% and 53%, respectively, for the patient-based analysis (8 studies) and 60% and 65% for the renal unit-based analysis (5 studies). The respective areas under the hierarchical summary receiver operating curves were 0.71 and 0.67. Marked statistical heterogeneity was observed in both analyses, as indicated by I(2) test values of 91% and 87%, respectively. Acute-phase DMSA renal scanning cannot be recommended as replacement for VCUG in the evaluation of young children with a first febrile UTI.     

VEGF-PLCgamma1 pathway controls cardiac contractility in the embryonic heart

The strength of the heart beat can accommodate in seconds to changes in blood pressure or flow. The mechanism for such homeostatic adaptation is unknown. We sought the cause of poor contractility in the heart of the embryonic zebrafish with the mutation dead beat. We find through cloning that this is due to a mutation in the phospholipase C gamma1 (plcgamma1) gene. In mutant embryos, contractile function can be restored by PLCgamma1 expression directed selectively to cardiac myocytes. In other situations, PLCgamma1 is known to transduce the signal from vascular endothelial growth factor (VEGF), and we show here that abrogation of VEGF also interferes with cardiac contractility. Somewhat unexpectedly, FLT-1 is the responsible VEGF receptor. We show that the same system functions in the rat. Blockage of VEGF-PLCgamma1 signaling decreases calcium transients in rat ventricular cardiomyocytes, whereas VEGF imposes a positive inotropic effect on cardiomyocytes by increasing calcium transients. Thus, the muscle of the heart uses the VEGF-PLCgamma1 cascade to control the strength of the heart beat. We speculate that this paracrine system may contribute to normal and pathological regulation of cardiac contractility.     

Responses against complex antigens in various models of CD4 T-cell deficiency

The most common models of CD4 T-cell deficiency are mice exogenously injected with anti-CD4 antibody (Ab), CD4 knockout (CD4^−/−) and major histocompatibility complex (MHC) class II knockout (class II^−/−) mice. We recently described the anti-CD4 Ab transgenic mouse (GK) as an improved CD4 cell-deficient model. This review compares this new GK mouse model with the widely available class II^−/− and CD4^−/− mice, when exposed to complex antigens (foreign grafts and during bacterial or viral infection). We highlight here the cytometric and functional differences (including Ab isotype, viral or bacterial clearance, and graft survival) among these CD4 cell-deficient models. For example, whereas grafts are generally rejected in class II^−/− and CD4^−/− mice as quickly as in wild-type mice, they survive longer in GK mice. Also, CD4^−/− mice produce IgG against both simple model and complex antigens, but class II^−/− and GK mice produce small amounts of IgG2a against complex antigens but not simple model antigens. These differences harbinger the caveats in the use of these various mice.     

Reduction in arthritis severity and modulation of immune function in tissue factor cytoplasmic domain mutant mice

Tissue factor (TF), a transmembrane receptor for plasma factor VII(a), is the main initiator of the coagulation cascade. It has also been implicated in noncoagulant processes, including inflammation. The function of the TF cytoplasmic domain was studied in mice in which 18 of the 20 cytoplasmic amino acids were deleted. This mutation (TF(deltaCT/deltaCT)) is not associated with alterations in blood coagulation. Arthritis was induced by intra-articular injection of methylated bovine serum albumin (mBSA) in mice preimmunized with mBSA. Arthritis severity was significantly reduced in TF(deltaCT/deltaCT) mice compared to wild-type mice, including reductions in synovitis, synovial exudate, cartilage degradation, and bone damage. A marked reduction in synovial interleukin (IL)-1beta and IL-6 mRNA was also observed. Serum anti-mBSA IgG1, but not IgG2a, was increased in mutant mice. Cutaneous delayed-type hypersensitivity and antigen-induced T-cell proliferation were reduced in TF(deltaCT/deltaCT) compared to wild-type mice. A significant down-regulation of lipopolysaccharide-induced IL-1, tumor necrosis factor, IL-6, macrophage migration inhibitory factor, and matrix metalloproteinase-13 mRNA was observed in immunized, but not in naive TF(deltaCT/deltaCT) macrophages ex vivo. These data suggest a significant role for the cytoplasmic domain of TF in the regulation of the immunoinflammatory responses, a murine arthritis model, and macrophage function.     

Surface carbohydrates as recognition determinants in non-opsonic interactions and intracellular viability of group B Streptococcus strains in murine macrophages

Mononuclear cells have been found to play a key role in phagocytosis and eventual killing of group B streptococci (GBS). The rich array of sugars on bacterial surface plus the presence of membrane-associated lectin-receptors on the macrophage suggests that this is a likely means for GBS recognition by these host defense cells. Macrophages have been shown to bind GBS in the absence of serum components. However, participation of carbohydrate moieties in GBS intracellular survival had not been completely elucidated. The aim of this study was to assess the involvement of sugars on adherence and intracellular viability in murine macrophages of GBS serotypes Ia (85147 and 90222 strains), III (80340 and 90356 strains) and V (88641 and 90186 strains) isolated from assymptomatic carriers and patients, respectively. Most isolates showed higher adherence within 2-h incubation. Only 90222-Ia strain exhibited progressive adherence rate until 12-h incubation. All strains showed intracellular viability during first 0.5-h of incubation. Except for 90186-V strain that survived only for 2 h, strains of all serotypes tested were found to survive 24 h into macrophages. Treatments of bacteria by glycosidases inhibited macrophage interaction with GBS strains at varied levels. Neuraminidase inhibited 90-97% adherence and 100% intracellular survival of GBS strains (P<0.0001). Host cell treatments with Rhamnose, N-acetyl-D-glucosaminidase and Fucose (5 mg/ml) inhibited adherence and intracellular viability of GBS strains at varied levels. Removal of GlcNAc residues of invasive GBS isolates enhanced intracellular viability, suggesting that GlcNAc residues may act by intercepting the expression of hidden receptors probably related with invasiveness and survival within macrophages. Lastly, our results demonstrate involvement of sialic acid specific receptors on macrophages and lectinophagocytosis in non-opsonic interaction and survival of GBS invasive isolates.