A study of the drop-outs in psychopharmacological research with bulimics

Given the high drop-out rates frequently noted in drug trials with bulimic subjects, we have attempted to correlate drop-out status with a greater level of psychopathology as measured by a thorough standardized psychological assessment battery (NIMH-DIS, EDI, POMS and SCL-90). Despite a trend toward higher scores on the Paranoid Ideation Subscale of the SCL-90 among drop-outs compared to completers, there were no significant differences found between the two groups participating in a fifteen week double blind crossover study on the effectiveness of desipramine in bulimia.     

Immunohistochemical null-phenotype for mismatch repair proteins in colonic carcinoma associated with concurrent <Emphasis Type="Italic">MLH1</Emphasis> hypermethylation and <Emphasis Type="Italic">MSH2</Emphasis> somatic mutations

Microsatellite instability, a well-established driver pathway in colorectal carcinogenesis, can develop in both sporadic and hereditary conditions via different molecular alterations in the DNA mismatch repair (MMR) genes. MMR protein immunohistochemistry (IHC) is currently widely used for the detection of MMR deficiency in solid tumors. The IHC test, however, can show varied staining patterns, posing challenges in the interpretation of the staining results in some cases. Here we report a case of an 80-year-old female with a colonic adenocarcinoma that exhibited an unusual “null” IHC staining pattern with complete loss of all four MMR proteins (MLH1, MSH2, MSH6, and PMS2). This led to subsequent MLH1 methylation testing and next generation sequencing which demonstrated that the loss of all MMR proteins was associated with concurrent promoter hypermethylation of MLH1 and double somatic truncating mutations in MSH2. These molecular findings, in conjunction with the patient’s age being 80 years and the fact that the patient had no personal or family cancer history, indicated that the MMR deficiency was highly likely sporadic in nature. Thus, the stringent Lynch syndrome type surveillance programs were not recommended to the patient and her family members. This case illustrates a rare but important scenario where a null IHC phenotype signifies complex underlying molecular alternations that bear clinical management implications, highlighting the need for recognition and awareness of such unusual IHC staining patterns.     

Clinical Sequencing Defines the Genomic Landscape of Metastatic Colorectal Cancer

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Multiplex ligation‐dependent probe amplification and fluorescence in situ hybridization are complementary techniques to detect cytogenetic abnormalities in multiple myeloma

Multiple myeloma (MM) is a genetically heterogeneous disease with diverse clinical outcomes. Interphase fluorescence in situ hybridization (i‐FISH) is the most commonly used approach to detect recurrent cytogenetic abnormalities in this malignancy. We aimed to assess the performance of multiplex ligation‐dependent probe amplification (MLPA) to reveal copy number abnormalities (CNAs) in MM. Diagnostic bone marrow samples from 81 patients were analyzed using 42 MLPA probes for the following regions: 1p32‐31, 1p21, 1q21.3, 1q23.3, 5q31.3, 12p13.31, 13q14, 16q12, 16q23, and 17p13. All samples were also screened by i‐FISH for the presence of hyperdiploidy, deletion/monosomy of chromosome 13, deletion of TP53, disruption of the immunoglobulin heavy‐chain gene, t(4;14), t(11;14), t(14;16), t(8;14), gain of 5q and abnormalities of chromosome 1. A total of 245 alterations were detected in 79 cases (98%). Investigating the same aberrations, the two methods showed a congruency of higher than 90%. A low proportion of cells with the relevant abnormality, focal CNAs and unmatched probes were responsible for the discrepancies. MLPA revealed 95 CNAs not detected by i‐FISH providing additional information in 53 cases (65%). Scrutiny of CNAs on chromosome 1, using more than 20 probes, revealed significant heterogeneity in size and location, and variable intra‐chromosomal and intra‐clonal rates of loss or gain. Our results suggest that MLPA is a reliable high‐throughput technique to detect CNAs in MM. Since balanced aberrations are key to prognostic classification of this disease, MLPA and i‐FISH should be applied as complementary techniques in diagnostic pathology. © 2013 Wiley Periodicals, Inc.     

Dopaminergic candidate genes in Tourette syndrome: association between tic severity and 3' UTR polymorphism of the dopamine transporter gene.

Multiple evidence suggests an involvement of the dopamine neurotransmitter system in Tourette syndrome (TS). Therefore, dopaminergic candidate genes are in the center of genetic association analyses of TS. In this study, 103 TS patients and their parents have been characterized for different dopamine-related polymorphisms including the 48 bp variable number of tandem repeats (VNTR) of the dopamine D4 receptor (DRD4) gene, the 40 bp VNTR of the dopamine transporter (DAT1, SLC6A3) gene and the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene. In addition, the 120 bp duplication and three single nucleotide polymorphisms (SNPs) were assessed in the promoter region of the DRD4 gene. The -616G allele and the 2-G-A-C haplotype (i.e., the 2-repeat form of the 120 bp sequence approximately -616G approximately -615A approximately -521C combination) were preferentially transmitted, however, these results did not remain significant after correction for multiple testing. Case-control analyses have also been carried out, resulting in negative findings. On the other hand, using a dimensional approach, the DAT1 40 bp VNTR showed an association with the peak tic-severity as measured by the Yale Global Tic Severity Scale. Patients with at least one copy of the 9-repeat allele had significantly more severe symptoms than individuals with the homozygous 10/10 genotype (P = 0.002). In summary, allele frequencies did not differ between cases and controls, but DAT1 genotype accounted for variations of tic severity within the TS group.