Severe Asthma in Adults : An Orphan Disease?

Severe asthma affects fewer than 10% of patients with asthma, is associated with a severe risk of death and disability, has a great impact on health and quality of life, and represents a huge cost to patients and society. Given the poor response to treatment and the side effects associated with medications for severe asthma, more efficient, cost-effective, and phenotype-specific medications are needed. Considering severe asthma as an orphan disease could encourage the pharmaceutical industry to stratify studies based on a more detailed characterization of study subjects at baseline, resulting in the development of novel therapeutic approaches.     

Histological diversity in cholangiocellular carcinoma reflects the different cholangiocyte phenotypes

Cholangiocellular carcinoma (CC) originates from topographically heterogeneous cholangiocytes. The cylindrical mucin-producing cholangiocytes are located in large bile ducts and the cuboidal non-mucin-producing cholangiocytes are located in ductules containing bipotential hepatic progenitor cells (HPCs). We investigated the clinicopathological and molecular features of 85 resected CCs (14 hilar CCs [so-called Klatskin tumor], 71 intrahepatic CCs [ICCs] including 20 cholangiolocellular carcinomas [CLCs], which are thought to originate from HPCs]) and compared these with the different cholangiocyte phenotypes, including HPCs. Immunohistochemistry was performed with biliary/HPC and hepatocytic markers. Gene expression profiling was performed in different tumors and compared with nonneoplastic different cholangiocyte phenotypes obtained by laser microdissection. Invasion and cell proliferation assay were assessed using different types of CC cell lines: KMC-1, KMCH-1, and KMCH-2. Among 51 ICCs, 31 (60.8%) contained only mucin-producing CC features (muc-ICCs), whereas 39.2% displayed histological diversity: focal hepatocytic differentiation and ductular areas (mixed-ICCs). Clinicopathologically, muc-ICCs and hilar CCs showed a predominantly (peri-)hilar location, smaller tumor size, and more lymphatic and perineural invasion compared with mixed-ICCs and CLCs (predominantly peripheral location, larger tumor size, and less lymphatic and perineural invasion). Immunoreactivity was similar in muc-ICCs and hilar CCs and in mixed-ICCs and CLCs. S100P and MUC1 were significantly up-regulated in hilar CCs and muc-ICCs compared with mixed-ICCs and CLCs, whereas NCAM1 and ALB tended to be up-regulated in mixed-ICCs and CLCs compared with other tumors. KMC-1 showed significantly higher invasiveness than KMCH-1 and KMCH-2. Conclusion: Muc-ICCs had a clinicopathological, immunohistochemical, and molecular profile similar to that of hilar CCs (from mucin-producing cholangiocytes), whereas mixed-ICCs had a profile similar to that of CLCs (thought to be of HPC origin), possibly reflecting their respective cells of origin.     

MEF2C deletions and mutations versus duplications: A clinical comparison

5q14.3 deletions including the MEF2C gene have been identified to date using genomic arrays in patients with severe developmental delay or intellectual disability, stereotypic behavior, epilepsy, cerebral malformations and a facial gestalt not really distinctive though characterized by broad and/or high, bulging forehead, upslanting palpebral fissures, flat nasal root and bridge, small, upturned nose, hypotonic small mouth resulting in cupid bow/tented upper lip. MEF2C mutations have been also identified in patients with overlapping phenotype so that it is considered the gene responsible for the 5q14.3 deletion syndrome. To date, one single duplication including MEF2C has been reported in a patient with intellectual disability but its clinical significance remains uncertain also because of the large size of the imbalance. Here we present two further patients with 5q14.3 duplications including MEF2C. Their phenotype indeed suggest the pathogenic effect of the MEF2C duplication although other duplicated genes also brain expressed might contribute to the clinical features. In none of them a clear-cut syndrome can be identified. A comparison between MEF2C deleted/mutated and duplicated patients is also presented.     

The effect of He-Ne and Ga-Al-As laser light on the healing of hard palate mucosa of mice

Low-level laser therapy (LLLT) has been used to accelerate wound healing, yet questions remain concerning its therapeutic applications. This study aimed to compare the healing efficacy of helium-neon (He-Ne) red light (laser) and gallium aluminum arsenide (Ga-Al-As) infrared lasers at two different doses on hard palate wounds. In a randomized controlled study, 75 adult male mice were divided into five groups of 15 each, after undergoing identical surgical procedures; a control group, with no laser irradiation; HD1 and HD2 groups, treated with He-Ne laser (wavelengths 632.8 nm, power 5 mW, and spot size 0.02 cm²) at doses of 4 J/cm² and 7.5 J/cm² respectively; and GD1 and GD2 groups, treated with Ga-Al-As laser (wavelengths 830 nm, peak power 25 mW, and spot size 0.10 cm²) at the doses of 4 J/cm² and 7.5 J/cm², respectively. Five animals from each group were killed on the third, seventh, and 14 days after surgery, and biopsies were made for histological analysis. On the 3rd and 7th day after the surgery, the number of polymorphonuclear cells (PMN) in HD1, HD2, GD1, and GD2 groups was significantly lower than that of the control group. On the 7th and 14th day, the fibroblasts and new blood vessels counts and collagen density fibers in HD1, HD2, GD1, and GD2 groups were also significantly higher than that of the control groups, and the fibroblast counts and collagen density fibers in HD1 and HD2 groups were higher than that of the GD1 and GD2 groups. LLLT with He-Ne laser compared to Ga-Al-As laser has a positive healing effect on hard palate gingival wounds in mice regardless of the radiation dose.     

Late brain alterations in sepsis‐survivor rats

Central nervous system (CNS) dysfunction secondary to sepsis is characterized by long‐term cognitive impairment. It was observed that oxidative damage, energetic metabolism impairment, and cytokine level alteration seen in early times in an animal model of sepsis may persist for up to 10 days and might be associated with cognitive damage. In order to understand these mechanisms, at least in part, we evaluated the effects of sepsis on cytokine levels in the cerebrospinal fluid (CSF), oxidative parameters, and energetic metabolism in the brain of rats at both 30 and 60 days after sepsis induction by cecal ligation and perforation (CLP). To this aim, male Wistar rats underwent CLP with “basic support” or were sham‐operated. Both 30 and 60 days after surgery, the CSF was collected and the animals were killed by decapitation. Then, the prefrontal cortex, hippocampus, striatum, and cortex were collected. Thirty days after surgery, an increase of IL‐6 level in the CSF; an increase in the thiobarbituric acid‐reactive species (TBARS) in prefrontal cortex and a decrease in hippocampus, striatum, and cortex; a decrease of carbonyl protein formation only in prefrontal cortex and an increase in striatum; and an increase in the complex IV activity only in hippocampus were observed. Sixty days after sepsis, an increase of TNF‐α level in the CSF; a decrease of TBARS only in hippocampus; an increase of carbonyl protein formation in striatum; and a decrease of complex I activity in prefrontal cortex, hippocampus, and striatum were observed. These findings may contribute to understanding the role of late cognitive impairment. Further studies may address how these findings interact during sepsis development and contribute to CNS dysfunction. Synapse 67:786–793, 2013. © 2013 Wiley Periodicals, Inc.