The 17-year single-center experience with the use of azathioprine to maintain remission in ulcerative colitis

Despite the accumulation of positive data, the role of azathioprine (AZA) in the maintenance of remission of ulcerative colitis is still controversial. We looked at the follow-up of the ulcerative colitis patients who, after responding to either steroids or cyclosporin (CsA), received AZA at our referral center for over a decade. The 39 patients (29 m/10f) were treated between 1991 and 2007. Twenty-five of them had responded to CsA, the remaining 14 to corticosteroids. AZA was usually overlapped with either of the two agents at the initial dose of 2 mg/kg/day. The definitions of remission, relapse, and AZA toxicity followed commonly agreed criteria. The median duration of the AZA treatment was 14 months (<1–201). Fifty-two percent and 14%, respectively, of the CsA and the steroid responders needed surgery (overall rate = 38%). The figures were 32 and 15 at the first year. The majority of the patients had 1–2 relapses often in connection with withdrawal of AZA; only 3 of these relapsers needed hospitalization. AZA caused toxicity in 16/39 (41%) patients, requiring withdrawal in 23% of the cases; leukopenia (17%) and hepatitis/cholestasis (10%) ranked first and second for frequency. All of the patients in whom AZA was stopped (or reduced) relapsed. In conclusion, the 1-year colectomy rates compare favorably with the figures reported by the literature. By contrast, the toxicity rates were higher than expected. Failure to genotype or to use escalating AZA doses can only be hypothesized as causes.     

Identification of a commonly amplified 4.3 Mb region with overexpression of C8FW, but not MYC in MYC-containing double minutes in myeloid malignancies

Double minutes (dmin), the cytogenetic hallmark of genomic amplification, are found in approximately 1% of karyotypically abnormal acute myeloid leukemias (AML) and myelodysplastic syndromes (MDS). The MYC gene at 8q24 has been reported to be amplified in the majority of the cases, and generally it has been assumed that MYC is the target gene. However, only a few studies have focused on the extent of the amplicon or on the expression patterns of the amplified genes. We have studied six cases (five AML and one MDS) with MYC-containing dmin. Detailed fluorescence in situ hybridization analyses identified a common 4.3 Mb amplicon, with clustered proximal and distal breakpoints, harboring eight known genes (C8FW, NSE2, POU5FLC20, MYC, PVT1, AK093424, MGC27434 and MLZE). The corresponding region was deleted in one of the chromosome 8 homologues in five of the six cases, suggesting that the dmin originated through extra replication (or loop-formation)--excision--amplification. Northern blot analysis revealed that MYC was not overexpressed. Instead, the C8FW gene, encoding a phosphoprotein regulated by mitogenic pathways, displayed increased expression. These results exclude MYC as the target gene and indicate that overexpression of C8FW may be the functionally important consequence of 8q24 amplicons in AML and MDS.     

Arginine metabolism in tumor-associated macrophages in cutaneous malignant melanoma: evidence from human and experimental tumors

Tumor-associated macrophages (TAMs) may elicit contrasting effects on tumor growth, depending on their biological activities. Macrophages use arginine either to synthesize nitric oxide (NO) through the inducible NO synthase (iNOS) or to produce ornithine through arginase activity. Although the effects of NO are primarily cytotoxic, production of ornithine may promote tumor cell proliferation. Thus, iNOS/arginase balance in TAMs may be crucial in tumor progression. The aim of this study was (a) to explore iNOS and arginase expression in TAMs associated with human melanoma at different stages of tumor progression and (b) to explore whether melanoma cells influence iNOS and/or arginase expression in TAMs under basal condition and in the presence of interferon gamma and/or lipopolysaccharide. Immunohistochemical analyses performed on tissue sections from in situ melanoma, invasive melanoma of different pT categories, and metastatic melanoma revealed that (a) the percentage of iNOS-positive TAMs was significantly higher in in situ and thin melanomas in comparison with more advanced, thicker tumors; (b) the percentage of arginase-positive TAMs did not change among the pT categories analyzed; and (c) the percentage of iNOS-positive TAMs was greater than that of arginase-positive TAMs in peritumoral and intratumoral locations of thin melanomas (pT1). Moreover, by the use of an in vitro experimental protocol represented by B16 murine melanoma cells cocultivated with inflammatory macrophages, we found that melanoma cells stimulate iNOS expression and NO production in macrophages. In conclusion, our in vivo and in vitro results suggest that, mainly in early melanoma lesions, iNOS prevails over arginase in TAMs, a phenomenon possibly stimulated by contact with tumor cells. However, macrophages stimulated by murine melanoma cells secreted a level of NO compatible with an antitumor activity only in the presence of interferon gamma.     

Characterization of a hotspot region on chromosome 12 for amplification in ring chromosomes in atypical lipomatous tumors

Ring chromosomes are cytogenetic hallmarks of genomic amplification in several bone and soft tissue tumors, in particular atypical lipomatous tumors (ALT). In ALT, the ring chromosomes invariably contain amplified material from the central part of the long arm of chromosome 12, mainly 12q12→15, but often also segments from other chromosomes are involved. Previous studies have shown that one of the recurrent amplicons in ALT, located in 12q13.3‐14.1 and harboring the candidate target genes TSPAN31 and CDK4, often has a sharp centromeric border. To characterize this breakpoint region in more detail, 12 cases of ALT with ring chromosomes were analyzed by array comparative genomic hybridization and fluorescence in situ hybridization. In the seven cases showing a sharply delineated amplicon in 12q13.3‐14.1, the breakpoint region was further investigated by real time quantitative polymerase chain reaction and Vectorette PCR. The breakpoints clustered to a 146‐kb region containing 11 genes. Whereas there was no indication that the breakpoints gave rise to fusion genes, in silico analysis revealed that the breakpoint region was enriched for repeated elements that could be important for ring chromosome formation in ALT. © 2009 Wiley‐Liss, Inc.     

Molecular cytogenetic characterization of a complex rearrangement involving chromosomes 9 and 22 in a case of Ph-negative chronic myeloid leukemia

The "golden path", produced by the Human Genome Project effort, is composed of a collection of overlapping and fully sequenced BAC/PAC clones covering almost completely the human genome. These clones can be advantageously exploited as fluorescence in situ hybridization (FISH) probes for the characterization of rearrangements frequently found in tumors. Breakpoint characterization can be further refined by generating additional smaller FISH probes through LONG-PCR amplification of specific DNA segments, 5-10 kb in size, using appropriate BAC/PAC probes as template. We report here an example of this approach that has been used to characterize a complex Ph-negative chronic myeloid leukemia (CML Ph-) case in which the BCR/ABL fusion gene was found located on chromosome 9.     

Flight muscles in falcons (Falconiformes,Falconinae): A quantitative approach

The family Falconidae has contrasting behaviors on its flight within the subfamilies. Falcons are primarily aerial predators requiring accuracy, high speed, and controlled movements during flight. Caracaras are generalists that seek food while walking and their flight is characterized as slow and erratic. We aimed to explore the muscle mass of the primary wing muscles in several species of Falconinae and to identify possible differences related to the role that these muscles perform during flight. We studied 34 wing muscles in 11 specimens of five species of falcons. The percentage of each muscle with respect to body mass was calculated as well as the total wing muscle mass. The search for differences between muscles of falcons and caracaras was analyzed using Bayesian statistical inference. Published data from Polyborinae were used for comparison. Five muscles were significantly different between both subfamilies mm. latissimus dorsi pars caudalis, biceps brachii, extensor carpi radialis, flexor digitorum superficialis, and extensor digitorum communis. The first two muscles were larger in Polyborinae, which could be useful to achieve more strength and stabilization. In falcons the last three muscles listed were larger, which might be associated with their fast and acrobatic flight. Variations in certain muscles generate, in turn, differences in function, which is reflected in their type of flight and its use. These findings reinforce the modular character of the locomotor system of birds whereby the regions involved in locomotion can have morphological peculiarities according to their lifestyle.     

Own or dam’s genotype? Classical colony breeding may bias spontaneous and stress-challenged activity in DAT-mutant rats

There is considerable interest in understanding what makes an individual vulnerable or resilient to the deleterious effects of stressful events. From candidate genes, dopamine (DA) and dopamine transporter (DAT) have been linked to anxiety, depression, and post-traumatic stress disorder. We investigated role of DAT using the new DAT heterozygous (DAT-HET) and homozygous mutant (DAT-KO) rat models of hyperdopaminergia. We studied the impact of two breeding conditions in spontaneous locomotor behavior of female rats. The classical colony, through mating DAT-HET males × DAT-HET females (breeding HET–HET), was used. A second WT colony was derived and maintained (breeding WT–WT). Additionally, a subgroup of rats was bred through mating DAT-KO males × WT females (atypical HET, breeding KO–WT). We studied the effects of genotype and its interaction with maternal care (depending by breeding condition). HET–HET breeding led to reduced activity in HET females compared to WT rats (from WT–WT breeding). However, HET females from KO–WT breeding did not differ so much from WT rats (WT–WT breeding). The maternal-care impact was then confirmed: HET mothers (breeding HET–HET) showed reduced liking/grooming of pups and increased digging away from nest, compared to WT mothers (breeding WT–WT). In their female offspring (HET, breeding HET–HET vs. WT, breeding WT–WT), isolation plus wet bedding induced higher and more persistent impact on activity of HET rats, even when the stressor was removed. Our results highlight the importance of epigenetic factors (e.g., maternal care) in responses to stress expressed by offspring at adulthood, quite independently of genotype. DAT hypofunction could determinate vulnerability to stressful agents via altered maternal care.     

Brief Report: Coherent Motion Processing in Autism: Is Dot Lifetime an Important Parameter?

Journal of Autism and Developmental Disorders - Contrasting reports of reduced and intact sensitivity to coherent motion in autistic individuals may be attributable to stimulus parameters. Here, we...     

What is semantic in semantic dementia? The decay of knowledge of physical entities but not of verbs,numbers and body parts

Background: Conceptual knowledge does not decay randomly in patients with cerebral damage, suggesting that dedicated neural substrates may support different categories of knowledge. Semantic dementia is an optimal natural model for studying the organization of semantic memory. Nevertheless, in a pathology primarily characterized by a semantic memory disorder categorical- and modality- specific effects are not obvious findings. In fact, there is no clear evidence of categorical effects, at least concerning two broad categories of knowledge, that is, natural items and artifacts. Furthermore, transmodal deficits do not seem to be the rule in SD. Also quite robust is the observation that some conceptual domains are relatively spared in this pathology, that is, numerical knowledge, abstract words, and action verbs.

Aims: To explore category specific and modality specific deficit in SD and to support the evidence that semantic degradation in SD primarily involves knowledge of the objects in the real world, whereas categories of knowledge whose items can be less easily identified by surface attributes, such as verbs, numbers and body parts, are more preserved.

Methods and Procedures: We investigated the semantic impairment in 8 patients with Semantic Dementia (SD). Voxel-based morphometry (VBM) in each patient was also obtained

Outcomes and Results: In some patients manmade objects were significantly more preserved than natural items, verbs more preserved than nouns and the number system entirely preserved; the body parts category was the least impaired in all subjects; finally, in three patients visual semantic knowledge was significantly more preserved than verbal semantic knowledge. VBM showed that atrophy of the anterior inferior temporal regions was insufficient to impair knowledge about verbs, numbers and body parts, whose impairment was associated with more widespread atrophy. In subjects whose verbal semantic knowledge was significantly more impaired than visual semantic knowledge, atrophy was principally distributed in the left hemisphere. In patients with significant impairment for natural items compared to manmade objects, atrophy was not confine in the temporal lobes.

Conclusion: We conclude that in SD semantic decay primarily involves the real-world items whose knowledge is processed by surface sensorifunctional features and that this is the type of knowledge stored in the temporal lobes. Our data support a model that associates a semantic hub with modality/category specific neural substrates.