Maternally-derived Antibodies to Schizont Egress Antigen-1 and Protection of Infants From Severe Malaria.

BACKGROUND: In holoendemic areas, children suffer the most from Plasmodium falciparum malaria, yet newborns and young infants express a relative resistance to both infection and severe malarial disease (SM). This relative resistance has been ascribed to maternally-derived anti-parasite immunoglobulin G; however, the targets of these protective antibodies remain elusive. METHODS: We enrolled 647 newborns at birth from a malaria-holoendemic region of Tanzania. We collected cord blood, measured antibodies to Plasmodium falciparum Schizont Egress Antigen-1 (PfSEA-1), and related these antibodies to the risk of severe malaria in the first year of life. In addition, we vaccinated female mice with PbSEA-1, mated them, and challenged their pups with P. berghei ANKA parasites to assess the impact of maternal PbSEA-1 vaccination on newborns' resistance to malaria. RESULTS: Children with high cord-blood anti-PfSEA-1 antibody levels had 51.4% fewer cases of SM compared to individuals with lower anti-PfSEA-1 levels over 12 months of follow-up (P = .03). In 3 trials, pups born to PbSEA-1-vaccinated dams had significantly lower parasitemia and longer survival following a P. berghei challenge compared to pups born to control dams. CONCLUSIONS: We demonstrate that maternally-derived, cord-blood anti-PfSEA-1 antibodies predict decreased risk of SM in infants and vaccination of mice with PbSEA-1 prior to pregnancy protects their offspring from lethal P. berghei challenge. These results identify, for the first time, a parasite-specific target of maternal antibodies that protect infants from SM and suggest that vaccination of pregnant women with PfSEA-1 may afford a survival advantage to their offspring.

A pilot study estimating liver fibrosis with ultrasound shear-wave elastography: does the cause of liver disease or location of measurement affect performance?

OBJECTIVE: The purpose of this study was to evaluate the diagnostic accuracy of real-time shear-wave elastography for assessment of liver fibrosis in an unselected patient population, comparing shear-wave elastography measurements obtained at and remote from the site of random liver biopsy. SUBJECTS AND METHODS: In a prospective study of 50 patients (21 with and 29 without hepatitis C) referred for clinically indicated random liver biopsy for diffuse liver disease, shear-wave elastography measurements were taken from four locations before biopsy: one at the left lobe, two at the right lobe, and one at the biopsy location. The mean, minimum, maximum, and SD of shear-wave elastography were compared with pathologic grading. Steatosis and serum markers were analyzed using multiple logistic regression. Optimized shear-wave elastography thresholds were calculated using AUC analysis. RESULTS: The AUC (95% CI) at the biopsy site, ipsilateral lobe, and contralateral lobe were 0.82 (0.63-1.0), 0.84 (0.67-1.0), and 0.59 (0.19-0.99) in hepatitis C patients; 0.89 (0.75-1.0), 0.88 (0.73-1.0), and 0.93 (0.80-1.0) in nonhepatitis C patients; and 0.85 (0.74-0.96), 0.89 (0.79-0.99), and 0.80 (0.67-0.93) in all patients, respectively. Optimized biopsy site shear-wave elastography values for detecting Metavir score F2 or greater were 1.87 m/s (75% sensitivity and specificity), 2.00 m/s (80% sensitivity and specificity), and 1.89 m/s (76% sensitivity and specificity) in hepatitis C, nonhepatitis C, and all patients, respectively. Steatosis and serum markers were not significant. CONCLUSION: Real-time shear-wave elastography accurately predicted significant fibrosis (stage ≥ 2) in an unselected patient population with diffuse disease, including patients with and without hepatitis C. Shear-wave elastography best predicts pathologic grading when taken at the biopsy site or ipsilateral lobe in hepatitis C patients. Percentage steatosis was not predictive of shear-wave elastography results.

Hypertrophy of the Anterior External Arcuate Fasciculus: A Rare Variant With Implications for the Development of the Arcuate Nucleus.

A rare anatomic variant of a markedly enlarged anterior external arcuate fasciculus (AEAF) on the ventral medullary surface is reported and compared to two controls. The hypertrophic AEAF was nine times larger in diameter than normal, whereas the arcuate nucleus (AN) and inferior olivary nucleus (ION) appeared histologically normal in size and neuronal distribution, and morphometric analysis of the AN confirmed that it was within the normal range. Calbindin-2 (calretinin, CALB2) expression was identified in the AN and in the fibers of the normal AEAF. The hypertrophic AEAF did not contain calbindin-2-expressing fibers. CALB2 expression was also present in the ventrolateral portion of the ION, both in the index case and in one of the control cases. The origin of the additional fibers was not identified; however, the potential origin of these fibers and its implications for the development of the AEAF are discussed.

Calretinin expression in high-grade invasive ductal carcinoma of the breast is associated with basal-like subtype and unfavorable prognosis.

Calretinin, a calcium-binding protein, is a widely used marker for mesothelial differentiation. There is accumulating evidence of calretinin expression in epithelial and mesenchymal malignancies, as well. The objectives of this study were to (1) further delineate the expression of calretinin in grade 3 breast carcinomas in the context of molecular subtypes and (2) identify the impact of calretinin expression on overall and disease-free survival. On the basis of immunohistochemical expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor-2 (HER2), cytokeratin 5/6, and epidermal growth factor receptor, 214 grade 3 invasive ductal carcinomas were stratified into 36 luminal A, 63 luminal B, 24 HER2 positive, 81 basal-like (including 13 metaplastic carcinomas), and 10 unclassified. Tissue microarrays were analyzed for immunohistochemical expression of calretinin. High-level calretinin expression was identified in a significant proportion of basal-like (54.3%), HER2 (33.3%), and unclassified (30%) tumors. In contrast, luminal A and B subtypes demonstrated high-level calretinin expression in only 11.1% and 12.7%, respectively (P < .0001). Within the basal-like group, 38.5% of the metaplastic carcinomas demonstrated high-level expression, associated predominantly with the epithelial component and squamous metaplasia. High-level calretinin expression was strongly associated with decreased overall survival in the entire cohort of grade 3 cancer (P = .0096) and in the basal-like group (P = .039). Multivariate analysis revealed that both tumor stage and high-level calretinin expression were independent predictors of overall survival (P = .0002 and P = .0023, respectively). In conclusion, high-level calretinin expression is most common in grade 3 tumors with a basal-like phenotype and is associated with poor overall survival.

Application of molecular techniques in the diagnosis, prognosis and management of patients with colorectal cancer: a practical approach.

There has been an increasing role for molecular diagnostics in the diagnosis and management of cancer, and colorectal carcinoma is no exception. Recent molecular advances have elucidated 3 broad molecular subtypes of colorectal cancer, including chromosomal instability, microsatellite instability, and cytosine-phosphoguanine island methylator phenotype, which will be discussed. Also, the common syndromes associated with colorectal carcinoma will be reviewed with a focus on the differentiation between Lynch syndrome and microsatellite unstable tumors. Molecular biomarkers for predictive and prognostic markers are also becoming widely used, and due to the clinical use of monoclonal antibodies to the epidermal growth factor receptor, an emphasis is placed on that pathway.