Mutations in the SPINK1 gene in idiopathic pancreatitis Italian patients

Idiopathic chronic and acute recurrent pancreatitis (IP) have been associated with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Mutations in the serine protease inhibitor Kazal 1 (SPINK1) have been described in some idiopathic chronic patients and it has been suggested that mutations in this gene could be responsible for a loss of trypsin inhibitor function. In this study, the 5'UTR region, and the four exons and exon-intron boundaries of the SPINK1 gene in 32 IP patients have been analyzed. Three IP patients (9.3%) and one control/100 carried the N34S mutation of the SPINK1 gene (Fisher's exact test, P=0.044). No other mutation that could be associated with an altered function of the SPINK1 protein was observed. The N34S mutation was present in two patients who carried the CFTR-IVS8 5T variant and in one who carried the L997F variant in the CFTR gene. The association of SPINK1 with CFTR gene mutations in IP patients is statistically significant (3/32 IP cases and 0/100 control individuals carrying mutations in both genes; Fisher's exact test P=0.01).     

Discordance between IgA Switching at the DNA Level and IgA Expression at the mRNA Level in IgA-Deficient Patients

IgA deficiency is a common immune disorder in Caucasians and is associated with certain MHC conserved extended haplotypes, such as [HLA-B8, SC01, DR3], which presumably carry a susceptibility gene(s). We applied a competitive digestion-circularization PCR method to quantitate the number of switch (S)mu to S alpha rearrangements in peripheral B cells from IgA-deficient subjects homozygous for this haplotype and compared their number with the productive C alpha mRNA level to determine C alpha gene expression in IgA-switched B cells. Two types of defects, low expression of both secreted and membrane forms of productive C alpha mRNA in IgA-switched B cells and impaired IgA switching, were characterized in IgA-deficient subjects homozygous for [HLA-B8, SC01, DR3]. The former defect was also found in another noncarrier subject. It may directly cause low IgA secretion and reflects a blockade in post-IgA switch differentiation of B cells. These results suggest that the heterogeneity of defects in IgA deficiency is not simply ascribable to MHC susceptibility genes.     

MRI fused with prone FDG PET/CT improves the primary tumour staging of patients with breast cancer

Objective

Our aim was to evaluate the diagnostic accuracy of magnetic resonance imaging (MRI) fused with prone 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) in primary tumour staging of patients with breast cancer.

Methods

This retrospective study evaluated 45 women with 49 pathologically proven breast carcinomas. MRI and prone PET-CT scans with time-of-flight and point-spread-function reconstruction were performed with the same dedicated breast coil. The studies were assessed by a radiologist and a nuclear medicine physician, and evaluation of fused images was made by consensus. The final diagnosis was based on pathology (90 lesions) or follow-up?≥?24 months (17 lesions).

Results

The study assessed 72 malignant and 35 benign lesions with a median size of 1.8 cm (range 0.3–8.4 cm): 31 focal, nine multifocal and nine multicentric cases. In lesion-by-lesion analysis, sensitivity, specificity, positive and negative predictive values were 97%, 80%, 91% and 93% for MRI, 96%, 71%, 87%, and 89% for prone PET, and 97%. 94%, 97% and 94% for MRI fused with PET. Areas under the curve (AUC) were 0.953, 0.850, and 0.983, respectively (p?<?0.01).

Conclusions

MRI fused with FDG-PET is more accurate than FDG-PET in primary tumour staging of breast cancer patients and increases the specificity of MRI.

Key points

? FDG PET-CT may improve the specificity of MRI in breast cancer staging.? MRI fused with prone 2-[fluorine-18]-fluoro-2-deoxy-D-glucose PET-CT has better overall diagnostic performance than MRI.? The clinical role of fused PET-MRI has not yet been established.

     

Wnt7a signaling promotes dendritic spine growth and synaptic strength through Ca²⁺/Calmodulin-dependent protein kinase II

The balance between excitatory and inhibitory synapses is crucial for normal brain function. Wnt proteins stimulate synapse formation by increasing synaptic assembly. However, it is unclear whether Wnt signaling differentially regulates the formation of excitatory and inhibitory synapses. Here, we demonstrate that Wnt7a preferentially stimulates excitatory synapse formation and function. In hippocampal neurons, Wnt7a increases the number of excitatory synapses, whereas inhibitory synapses are unaffected. Wnt7a or postsynaptic expression of Dishevelled-1 (Dvl1), a core Wnt signaling component, increases the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs), but not miniature inhibitory postsynaptic currents (mIPSCs). Wnt7a increases the density and maturity of dendritic spines, whereas Wnt7a-Dvl1-deficient mice exhibit defects in spine morphogenesis and mossy fiber-CA3 synaptic transmission in the hippocampus. Using a postsynaptic reporter for Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII) activity, we demonstrate that Wnt7a rapidly activates CaMKII in spines. Importantly, CaMKII inhibition abolishes the effects of Wnt7a on spine growth and excitatory synaptic strength. These data indicate that Wnt7a signaling is critical to regulate spine growth and synaptic strength through the local activation of CaMKII at dendritic spines. Therefore, aberrant Wnt7a signaling may contribute to neurological disorders in which excitatory signaling is disrupted.     

Infection of human fallopian tube epithelial cells with Neisseria gonorrhoeae protects cells from tumor necrosis factor alpha-induced apoptosis

Following infection with Neisseria gonorrhoeae, bacteria may ascend into the Fallopian tubes (FT) and induce salpingitis, a major cause of infertility. In the FT, interactions between mucosal epithelial cells and gonococci are pivotal events in the pathogen's infection cycle and the inflammatory response. In the current study, primary FT epithelial cells were infected in vitro with different multiplicities of infection (MOI) of Pil+ Opa+ gonococci. Bacteria showed a dose-dependent association with cells and induced the secretion of tumor necrosis factor alpha (TNF-alpha). A significant finding was that gonococcal infection (MOI = 1) induced apoptosis in approximately 30% of cells, whereas increasing numbers of bacteria (MOI = 10 to 100) did not induce apoptosis. Apoptosis was observed in only 11% of cells with associated bacteria, whereas >84% of cells with no adherent bacteria were apoptotic. TNF-alpha was a key contributor to apoptosis, since (i) culture supernatants from cells infected with gonococci (MOI = 1) induced apoptosis in na?ve cultures, suggesting that a soluble factor was responsible; (ii) gonococcal infection-induced apoptosis was inhibited with anti-TNF-alpha antibodies; and (iii) the addition of exogenous TNF-alpha induced apoptosis, which was inhibited by the presence of increasing numbers of bacteria (MOI = 10 to 100). These data suggest that TNF-alpha-mediated apoptosis of FT epithelial cells is likely a primary host defense mechanism to prevent pathogen colonization. However, epithelial cell-associated gonococci have evolved a mechanism to protect the cells from undergoing TNF-alpha-mediated apoptosis, and this modulation of the host innate response may contribute to establishment of infection. Understanding the antiapoptotic mechanisms used by Neisseria gonorrhoeae will inform the pathogenesis of salpingitis and could suggest new intervention strategies for prevention and treatment of the disease.     

Liver radioembolization using 90 y resin microspheres in elderly patients: tolerance and outcome

Purpose Yttrium 90 (90 Y) microsphere radioembolization (90 Y-RE) is an emerging locoregional treatment for liver cancer. The most common complications of 90 Y-RE arise from excessive irradiation of nontarget organs (eg, gastrointestinal tract, lung, and nontumoral liver). Patients with advanced age may have substantial comorbidities that can affect their life expectancy, and tolerance to radiation in elderly patients may be altered. The purpose of this study is to evaluate the safety and survival of elderly patients treated with 90 Y-RE. Materials and Methods We analyzed 255 patients with liver tumors (primary or metastatic) who were treated with 90 Y-RE in our institution from September 2003 to February 2010. We categorized patients as "elderly" if aged ≥ 70 years and "younger" if aged < 70 years. Results Seventy-three patients (29%) were aged ≥ 70 years. The most frequent liver tumor among elderly patients was hepatocellular carcinoma. Complication rates were similar in both groups: 10.4% of elderly patients and 9.9% of younger patients developed radioembolization-induced liver disease (P = 1.000). Only 1.5% of elderly patients developed gastrointestinal ulceration and no patient in the elderly group developed pneumonitis. The median overall survival of patients with hepatocellular carcinoma was similar in elderly and younger groups (13 months, 95% confidence interval [CI], 10.4-15.5 and 12 months, 95% CI, 4.2-15.7; P = 0.4). In patients with colorectal carcinoma metastatic to the liver, the median overall survival was 10 months (95% CI, 5.2-14.7) for elderly patients and 13 months (95% CI, 7.0-18.9) for younger patients (P = 0.3). The median overall survival of patients with other histologies was 9 months (95% CI, 3.5-14.4) for younger patients and 4 months (95% CI, 2.7-5.2) for elderly patients (P = 0.9). Conclusion Elderly patients did not have more toxicity than younger patients treated with 90 Y-RE, and survival was similar for each histology. Elderly patients should be considered for 90 Y-RE if they otherwise meet the inclusion criteria applicable to younger patients.