Plasma C3a-des-Arg Levels in Women with and without Endometriosis

Problem  The lack of a reliable method for early non-invasive detection of endometriosis often results in delayed diagnosis. The aim of this study was to test the hypothesis that the plasma concentration of complement factor C3a (anaphylatoxin) can be used as a non-invasive test in the diagnosis of endometriosis.
Method of study  The C3a concentration was analyzed using ELISA in 160 patients with ( n  = 109) or without ( n  = 51) endometriosis during menstruation ( n  = 49), follicular phase ( n  = 55), and luteal ( n  = 56) phase.
Results  Plasma C3a concentration was comparable between patients with [102 (27–2213) ng/mL] and without [105 (32–2340) ng/mL] ( P  = 0.84) endometriosis, also when assessed separately during menstruation, follicular phase, and luteal phase.
Conclusion  We found no difference in C3a levels between women with and without endometriosis and did not confirm our hypothesis that plasma C3a levels can be used as diagnostic test for endometriosis.     

A newborn with spinal muscular atrophy type 0 presenting with a clinicopathological picture suggestive of myotubular myopathy

We report a male term newborn with genetically confirmed spinal muscular atrophy type 0, presenting with arthrogryposis and severe generalized weakness and requiring ventilatory support. Muscle biopsy revealed fibers with central nuclei resembling myotubes and negative myotubularin immunohistochemical staining compared with a control muscle biopsy. The absence of myotubularin associated with survival motor neuron protein deficiency suggests that survival motor neuron protein may have a role in muscle fiber maturation and myotubularin expression. Studying the pathology of this rare and lethal neonatal form of spinal muscular atrophy may further our understanding of spinal muscular atrophy pathogenesis.     

Differential regulation of constitutive androstane receptor expression by hepatocyte nuclear factor4alpha isoforms

Constitutive androstane receptor (CAR; NR1I3) controls the metabolism and elimination of endogenous and exogenous toxic compounds by up-regulating a battery of genes. In this work, we analyzed the expression of human CAR (hCAR) in normal liver during development and in hepatocellular carcinoma (HCC) and investigated the effect of hepatocyte nuclear factor 4alpha isoforms (HNF4alpha1 and HNF4alpha7) on the hCAR gene promoter. By performing functional analysis of hCAR 5'-deletions including mutants, chromatin immunoprecipitation in human hepatocytes, electromobility shift and cotransfection assays, we identified a functional and species-conserved HNF4alpha response element (DR1: ccAGGCCTtTGCCCTga) at nucleotide -144. Both HNF4alpha isoforms bind to this element with similar affinity. However, HNF4alpha1 strongly enhanced hCAR promoter activity whereas HNF4alpha7 was a poor activator and acted as a repressor of HNF4alpha1-mediated transactivation of the hCAR promoter. PGC1alpha stimulated both HNF4alpha1-mediated and HNF4alpha7-mediated hCAR transactivation to the same extent, whereas SRC1 exhibited a marked specificity for HNF4alpha1. Transduction of human hepatocytes by HNF4alpha7-expressing lentivirus confirmed this finding. In addition, we observed a positive correlation between CAR and HNF4alpha1 mRNA levels in human liver samples during development, and an inverse correlation between CAR and HNF4alpha7 mRNA levels in HCC. These observations suggest that HNF4alpha1 positively regulates hCAR expression in normal developing and adult livers, whereas HNF4alpha7 represses hCAR gene expression in HCC.     

<Superscript>99m</Superscript>Tc-chelator engineering to improve tumour targeting properties of a HER2-specific Affibody molecule

Purpose Monitoring HER2 expression is crucial for selection of breast cancer patients amenable to HER2-targeting therapy. The Affibody molecule Z_HER2:342 binds to HER2 with picomolar affinity and enables specific imaging of HER2 expression. Previously, Z_HER2:342 with the additional N-terminal mercaptoacetyl-glycyl-glycyl-glycyl (maGGG) sequence was labelled with ^99mTc and demonstrated specific targeting of HER2-expressing xenografts. However, hepatobiliary excretion caused high radioactivity accumulation in the abdomen. We investigated whether the biodistribution of Z_HER2:342 can be improved by substituting glycyl residues in the chelating sequence with more hydrophilic seryl residues. Methods The Affibody molecule Z_HER2:342, carrying the chelators mercaptoacetyl-glycyl-seryl-glycyl (maGSG), mercaptoacetyl-glycyl-D-seryl-glycyl [maG(D-S)G] and mercaptoacetyl-seryl-seryl-seryl (maSSS), were prepared by peptide synthesis and labelled with ^99mTc. The differences in the excretion pathways were evaluated in normal mice. The tumour targeting capacity of ^99mTc-maSSS-Z_HER2:342 was studied in nude mice bearing SKOV-3 xenografts and compared with the capacity of radioiodinated Z_HER2:342. Results A shift towards renal excretion was obtained when glycine was substituted with serine in the chelating sequence. The radioactivity in the gastrointestinal tract was reduced threefold for the maSSS conjugate in comparison with the maGGG conjugate 4 h post injection (p.i.). The tumour uptake of ^99mTc-maSSS-Z_HER2:342 was 11.5 ± 0.5% IA/g 4 h p.i., and the tumour-to-blood ratio was 76. The pharmacokinetics and uptake characteristics of technetium-labelled Z_HER2:342 were better than those of radioiodinated Z_HER2:342. Conclusion The introduction of serine residues in the chelator results in better tumour imaging properties of the Affibody molecule Z_HER2:342 compared with glycyl-containing chelators and is favourable for imaging of tumours and metastases in the abdominal area.     

Ten-year follow up after laparoscopic Nissen fundoplication for gastroesophageal reflux disease

Laparoscopic Nissen fundoplication was first undertaken in the early 1990s. Appreciable numbers of patients with 10-year follow up are only now available. This study assesses long-term outcome and durability of outcome after laparoscopic Nissen fundoplication for treatment of gastro-esophageal reflux disease. Since 1991, 829 patients have undergone laparoscopic fundoplications and are prospectively followed. Two hundred thirty-nine patients, 44 per cent male, with a median age of 53 years (+/- 15 standard deviation) underwent laparoscopic Nissen fundoplications at least 10 years ago; 28 (12%) patients were "redo" fundoplications. Before and after fundoplication, among many symptoms, patients scored the frequency and severity of dysphagia, chest pain, vomiting, regurgitation, choking, and heartburn using a Likert scale (0 = never/not bothersome to 10 = always/very bothersome). Symptom scores before versus after fundoplication were compared using a Wilcoxon matched-pairs test. Data are reported as median, mean +/- standard deviation, when appropriate. After fundoplication, length of stay was 2 days, 3 days +/- 4.8. Intra-operative inadvertent events were uncommon and without sequela: 1 esophagotomy, 1 gastrotomy, 3 cardiac dysrhythmias, and 3 CO2 pneumothoraces. Complications after fundoplication included: 1 postpneumonic empyema, 3 urinary retentions, 2 superficial wound infections, 1 urinary tract infection, 1 ileus, and 1 intraabdominal abscess. There were two perioperative deaths; 88 per cent of the patients are still alive. After laparoscopic Nissen fundoplication, frequency and severity scores dramatically improved for all symptoms queried (P < 0.001), especially for heartburn frequency (8, 8 +/- 3.2 versus 2, 3 +/- 2.8, P < 0.001) and severity (10, 8 +/- 2.9 versus 1, 2 +/- 2.5, P < 0.001). Eighty per cent of patients rate their symptoms as almost completely resolved or greatly improved, and 85 per cent note they would again have the laparoscopic fundoplication as a result of analysis of our initial experience, thereby promoting superior outcomes in the future. Nonetheless, follow up at 10 years and beyond of our initial experience documents that laparoscopic fundoplication durably provides high patient satisfaction resulting from long-term amelioration of the frequency and severity of symptoms of gastroesophageal reflux disease. These results promote further application of laparoscopic Nissen fundoplication.     

English and French Taste Words Used Metaphorically

This paper compares the lexical, semantic, and syntactic structures involved when talking about taste in English and in French. We look for equivalents of expressions such as have tasted blood, have a sweet tooth, faire des yeux doux, la lutte est âpre and define taste using a written corpus of literary and non-literary quotations. Taste is approached more directly in English, where it is one of the prisms through which reality can be apprehended and knowledge achieved via direct perception of the world. It is also a subjective experience, the transitive verb taste linking the taster and the tastant, whereas the property of the food is described objectively in French, often avoiding using goût(er) and without a direct reference to a taster. Taste is used to refer not only to food but also—and, in a literary context, mainly—to nonfood, and adverbs in -ly (sweetly, bitterly, etc.) are directly derived from taste adjectives and more closely linked to them than the corresponding analytical expressions in French, which mark a greater distance from the central concept <goût>. Inductive as opposed to deductive thought filters the perception of reality, just as the language spoken frames the mind: taste draws from experience, goût is based on analysis. The concept <taste/goût> might be universal because of a supposed common biological substrate in humans, but its conceptualization emphasizes different semantic traits: pragmatic experience leading to knowledge through senses and emotions in English vs. intellectual analysis and judgement leading to hedonic appreciation in French.     

Comparison of prognostic usefulness (three years) of computed tomographic angiography versus 64-slice computed tomographic calcium scanner in subjects without significant coronary artery disease

Coronary computerized tomographic angiography (CTA) has been used as a noninvasive method for ruling out high-grade stenoses. Even in the absence of such stenoses, analysis of coronary atherosclerosis may provide for important prognostic information, and this may be superior to exclusive coronary artery calcium scoring. We tested this hypothesis in patients undergoing CTA for clinical indications who had no stenoses requiring revascularization. From December 2004 to December 2006, 706 consecutive patients who underwent CTA but had no high-grade stenoses were included (58% men, mean age 59 ± 11 years). CTA and coronary artery calcium scoring (Agatston method) were performed using a 64-slice CT scanner with a gantry rotation time of 330 ms. CT angiograms were categorized as completely normal (group 1), showing minor plaque (group 2), or showing intermediate stenoses (group 3). Follow-up information was obtained in 670 patients (95%) over a mean of 3.2 years. There were 31 major adverse events (5%), namely 9 deaths (all noncoronary), 2 myocardial infarctions, 5 strokes, 13 coronary revascularization procedures (percutaneous or surgical > 6 months after CTA), and 2 peripheral percutaneous interventions. Coronary status as defined by CTA was predictive of major events after adjustment for age and gender. In group 1, the probability of event-free survival at 3 years was 100%; in group 2, it was 96%; and in group 3, it was 91%. Compared to group 1, the risk in group 2 was increased 2.3-fold, and in group 3, it was increased 5.6-fold after adjusting for age and gender. However, after addition of the coronary artery calcium score to the regression analysis, CT angiographic status no longer appeared to be predictive. In conclusion, the risk of a major adverse cardiovascular event or death increased in a graded manner with degree of coronary atherosclerosis as defined by CTA even in the absence of high-grade coronary stenoses. However, in the absence of high-grade stenoses, we were unable to demonstrate a superior prognostic value of CTA compared to coronary artery calcium.     

Convergence of body mass index of immigrants to the Canadian-born population: evidence from the National Population Health Survey (1994–2006)

Recent immigrants typically have better physical health than the native born population. However, this ‘healthy immigrant effect’ tends to gradually wane over time, with increasing length of residence in the host country. To assess whether the body mass index (BMI) of different immigrant groups converged to the Canadian population’s levels, we estimated 12-year trajectories of changes in BMI (accounting for socio-demographic changes). Using data from seven longitudinal waves of the National Population Health Survey (1994 through 2006), we compared the changes in BMI (kg/m²) among three groups: white immigrants, non-white immigrants and Canadian born, aged 18–54 at baseline. We applied linear random effects models to evaluate these BMI separately in 2,504 males and 2,960 females. BMI increased in Canadian born, white immigrants, and non-white immigrants over the 12-year period. However, non-white immigrants (males and females) had a lower mean BMI than Canadian born individuals during this period [Males: −2.27, 95% Confidence interval (CI) −3.02 to −1.53; Females: −1.84, 95% CI −2.79 to −0.90]. In contrast, the mean BMI in white male immigrants and Canadian born individuals were similar (−0.32, 95% CI −0.91 to 0.27). Even after adjusting for time since immigration, non-white immigrants had lower BMI than white immigrants. White male immigrants were the only sub-group to converge to the BMI of the Canadian born population. These results indicate that the loss of ‘healthy immigrant effect’ with regard to convergence of BMI to Canadian levels may not be experienced equally by all immigrants in Canada.     

Structural neural correlates of impairments in social cognition in first episode psychosis

Several studies have demonstrated that patients with schizophrenia show impairments in social cognition and current evidence indicate that this deficit is associated with abnormal activity in specific brain regions. In addition to functional imaging studies, we believe that the identification of structural correlates of social cognitive processes may help to better understand the neural underpinnings of these specific skills. The main objective of this study was to investigate the relationship between gray matter density and social cognitive deficits in first episode of schizophrenia spectrum psychosis, using a comprehensive assessment that we previously demonstrated to be a highly sensitive measure of social cognitive deficits in this population. Thirty-eight patients with a first episode of psychosis participated in this study, and the Four Factor Test of Social Intelligence was used as a measure of social cognition. Social cognitive impairments in first episode psychosis were significantly correlated with reduced gray-matter density in the left middle frontal gyrus other regions within the mirror neuron system network (MSN), namely the right supplementary motor cortex, the left superior temporal gyrus and the left inferior parietal lobule. We concluded that structural abnormalities within the MSN may account for the social cognitive deficits present in some psychiatric disorders, such as schizophrenia.