Characterization of ARHGEF6, a guanine nucleotide exchange factor for Rho GTPases and a candidate gene for X-linked mental retardation: mutation screening in Börjeson-Forssman-Lehmann syndrome and MRX27

B?rjeson-Forssman-Lehmann syndrome (BFLS) is a syndromic X-linked mental retardation that has been mapped by linkage to Xq26-q27. A nonsyndromic mental retardation family, MRX27, has also been localized to a region of the X chromosome overlapping Xq26-q27. The gene for ARHGEF6 (also known as alphaPIX or Cool-2), a newly identified guanine nucleotide exchange factor, was identified as a potential candidate XLMR gene, due to its location within the BFLS and MRX27 critical regions and its function in the regulation of PAK3 (a known MRX gene). The full coding sequence and genomic structure of the gene for ARHGEF6 was established in silico, based on available genomic, EST, and cDNA sequence information. Mutation analysis in BFLS- and MRX27-affected individuals was carried out. No mutations were found in two BFLS families or MRX27. Although ARHGEF6 is unlikely to be the gene responsible for either BFLS or MRX27, it remains a prime candidate for nonspecific or syndromic mental retardation linked to Xq26.     

A mutation in the type Ⅱ hair keratin KRT86 gene in a Han family with monilethrix

Monilethrix, a congenital disease of hair, is usually associated with mutations in keratin genes, like KRT81, KRT83 and KRT86. We conducted this study to investigate the mutation of type Ⅱ human basic hair keratin hHb/ KRT gene in a Han family with monilethrix and obtain information for potential pathogenic mechanism study of monilethrix. Peripheral blood samples were drawn for genomic DNA detection. Exon 1 and exon 7 of the KRT81, KRT83 and KRT86 genes were amplified by PCR. All PCR products were sequenced directly using an ABI 310 DNA sequencer. These sequences were aligned with the standard sequences in GenBank using the BLAST software. PCR products were digested with restriction endonuclease and restriction fragment length polymorphism (RFLP) analysis was performed. In this study, we identified one novel mutation, which is a heterozygous transitional mutation of G→A at position 1,289 in exon 7 of the KRT86 gene [R430Q (KRT86)]. RFLP assays for the novel mutation excluded the possibility of polymorphism. The R430Q mutation of the KRT86 gene may be pathogenic for monilethrix. Meanwhile, we did not find any novel mutation or recurrent mutation in exons 1 and 7 of KRT81 and KRT83 and exon 1 of KRT86. There is a potential pathogenic gene in the subjects and our results expand the spectrum of mutations in the hHb6 gene.     

Anger in PTSD: Is there a need for a concept of PTSD-related posttraumatic anger?

Despite extensive research on posttraumatic stress disorder (PTSD), anger in PTSD has received little attention. This is surprising, given anger is a key predictor of treatment outcome in PTSD. This paper seeks to build an argument for investigating anger in PTSD as a discrete entity. A key argument is that the capacity to image visual mental phenomena is crucial to the aetiology and maintenance of anger in PTSD. Evidence is reviewed for the influence of visual imagery in anger in PTSD from the perspectives of neuropsychology, psychopathology, anger and PTSD. An argument is advanced for including visual imagery in an integrated (visual-linguistic) cognitive model of anger in PTSD. Directions for research on visual imagery in anger in PTSD and its treatment implications are discussed.     

Is there a role for palmitoylethanolamide in the treatment of depression?

Depression is a common brain disorder affecting about 350 million people worldwide. Although the pharmacological treatment currently available can produce benefits in the majority of cases, residual depressive symptoms, cognitive deficits, functional impairment, and increase in frequency of relapses are frequently present in unipolar and bipolar depressed patients correctly treated. In the last years, numerous evidences have demonstrated the involvement of endocannabinoid system in the pathophysiology of mood disorders. Considering the recent findings about the antidepressant effect of palmitoylethanolamide in animal model, we have hypothesized the potential antidepressant effect of this fatty acid amide in unipolar and bipolar depressed patients.     

Incidental renal neoplasms: is there a need for routine screening? A Danish single‐center epidemiological study

On the basis of associations between tumor size, pathological stage, histological subtype and tumor grade in incidentally detected renal cell carcinoma vs symptomatic renal cell carcinoma, we discussed the need for a screening program of renal cell carcinoma in Denmark. We analyzed a consecutive series of 204 patients with renal tumors in 2011 and 2012. The tumors were classified according to detection mode: symptomatic and incidental and compared to pathological parameters. Eighty‐nine patients (44%) were symptomatic, 113 (55%) were incidental. Information was not available in two patients. In the incidental group, the size (p < 0.05), pathological stage (p < 0.001), Fuhrman grading (p < 0.0001) and Leibovich score (p < 0.0001) were lower than in those causing symptoms. Significantly less in the incidental group had metastasis at follow‐up (p < 0.0001). Incidentally discovered RCC constitute a major part of kidney tumors. They have a more favorable prognosis than symptomatic tumors and seem to be discovered in an earlier phase. Needle core biopsy is an accurate technique for distinguishing between malignant and benign tumors and is recommendable for smaller incidental tumors. Screening may help detect RCC at an earlier stage.     

Identification of a novel 2026G→C mutation of the MRP2 gene in a Japanese patient with Dubin-Johnson syndrome

Dubin-Johnson syndrome is a recessive inherited disorder with conjugated hyperbilirubinemia caused by a dysfunction of multidrug resistance protein 2 (MRP2) on the canalicular membrane of hepatocytes. A mutational analysis of the MRP2 gene was carried out in three Japanese patients and their family members. In two patients, the homozygous mutations c.1901del67 and c,2272del168 were found. In the third patient, a –24CT polymorphism and the two mutations c.1901del67 and 2026GC were detected. The 2026GC mutation was a novel mutation in exon 16 affecting the conversion of Gly⁶⁷⁶ to Arg⁶⁷⁶ (G676R) in the MRP2 protein, and was not detected in fifty healthy volunteers. The G676R mutation was located in the Walker A motif of the first nucleotide binding domain in the MRP2 protein, and it was suggested that the mutation induced the dysfunction of the MRP2 protein. It was concluded that the compound heterozygosity of the two mutations of the MRP2 gene in the third patient contributed to the induction of hyperbilirubinemia in this case.     

Is there a place for intra-articular hyaluronate in osteoarthritis of the knee?

Viscosupplementation refers to the intra-articular injection of hyaluronic acid (HA) as a hyaluronate to relieve pain and improve function, usually in patients with knee OA. HA is the major constituent of a 1-2-micron layer on the surface of articular cartilage as well as a major constituent of synovial fluid (SF). Solutions of HA can act as lubricants when movements are slow and as shock absorbers when movements are fast. In arthritis, the molecular weight of HA is reduced, and so are its properties. Viscosupplementation has been advocated as a way of reversing this, but intra-articular HA has other properties, such as an anti-inflammatory effect, which may also contribute to any therapeutic effect. There is a large placebo effect from intra-articular injections, and the benefits of intra-articular glucocorticoids may be only slightly better than this effect. In only one randomised, placebo-controlled trial was the difference in response significant. Studies of intra-articular HA also show a marked placebo response (where it has been measured), but some have suggested a measurable benefit, which may be more prolonged that that of glucocorticoids. There is only a single study in which the effects of intra-articular therapy with placebo, glucocorticoids and viscosupplementation can be compared. Here, HA may have had a slightly longer period of benefit than triamcinolone hexacetonide or placebo. The very large placebo response after aspiration of the knee may seriously mislead those engaged in uncontrolled therapeutic evaluation of intra-articular therapy. Current evidence suggests that viscosupplements probably provide a similar level of pain relief to glucocorticoids and do so for several months, but the onset is slower, and there is the potential for local adverse reactions.     

Is there today a place for corticosteroids in the treatment of scleroderma?

In systemic sclerosis (SSc), the use of corticosteroids (CS) is controversial due to their association with scleroderma renal crisis (SRC). However, patients with very early and early disease, characterised by main inflammatory component, may benefit from CS therapy.The aim of this review is to discuss pros and cons of CS treatment in SSc, providing current evidence about the use of CS in SSc. Moreover, we discuss also the underlying pathogenetic mechanisms that may be the background for the potential harms and efficacy of CS in SSc.     

Is there a role for fatty acid synthase in the diagnosis of prostatic adenocarcinoma?: A comparison with AMACR

Our aim was to compare the usefulness of fatty acid synthase (FASn) with that of α-methylacyl coenzyme-A racemase (AMACR) in the diagnosis of prostatic adenocarcinoma. The expression of these 2 markers was compared in a tissue microarray containing 62 foci of benign glands and 36 foci of prostatic adenocarcinoma. Similar to AMACR, there was significantly higher FASn expression in adenocarcinoma compared with that in benign glands. The optimal accuracy rate and area under curve (AUC) by receiver operating characteristic analysis for FASn were not significantly different from those for AMACR (accuracy, 80% vs 87%; AUC, 0.942 vs 0.956; P for both, > .05). Moreover, in cases with coexistent malignant and benign glands on the same core, FASn could selectively distinguish a proportion of cases (17/21 [81%]) similar to using AMACR. We conclude that FASn may aid in the diagnosis of prostatic adenocarcinoma, at least to supplement AMACR as another positive marker of carcinoma and potentially increase diagnostic accuracy.     

Identification and molecular characterisation of a homozygous missense mutation in the ADAMTS10 gene in a patient with Weill–Marchesani syndrome

Weill–Marchesani syndrome is a rare disorder of the connective tissue. Functional variants in ADAMTS10 are associated with Weill–Marchesani syndrome-1. We identified a homozygous missense mutation, c.41T>A, of the ADAMTS10 gene in a 19-year-old female with typical symptoms of WMS1: proportionate short stature, brachydactyly, joint stiffness, and microspherophakia. The ADAMTS10 missense mutation was analysed in silico, with conflicting results as to its effects on protein function, but it was predicted to affect the leader sequence. Molecular characterisation in HEK293 Ebna cells revealed an intracellular mis-targeting of the ADAMTS10 protein with a reduced concentration of the polypeptide in the endoplasmic reticulum. A large reduction in glycosylation of the cytoplasmic fraction of the mutant ADAMTS10 protein versus the wild-type protein and a lack of secretion of the mutant protein are also evident in our results.In conclusion, we identified a novel missense mutation of the ADAMTS10 gene and confirmed the functional consequences suggested by the in silico analysis by conducting molecular studies.     

Analysis of IDS gene mutation in a family affected with mucopolysaccharidosis type II北大核心CSCD

Objective To detect potential mutation of iduronate-2-sulfatase (IDS) gene in a family affected withmucopolysaccharidosis type II (MPS II ). Methods For the proband and his unaffected mother, the whole codingsequence of the IDS gene was analyzed with PCR and bidirectional Sanger sequencing. Results A novel splicingmutation, c. 709-1G>A, was detected in the proband, for which his mother was heterozygous. Conclusion The c. 709-1G>A splicing mutation of the IDS gene is probably causative for the MSP II in the proband. Prenataldiagnosis for the mutation may avoid birth of further child affected with this disease.     

Identification of the first deep intronic mutation in the RPS6KA3 gene in a patient with a severe form of Coffin–Lowry syndrome

Coffin–Lowry syndrome (CLS) is an X-linked disorder characterized by growth and psychomotor retardation, hypotonia and progressive skeletal changes. RPS6KA3 is the only gene known to be associated with CLS, and over 150 distinct inactivating mutations in this gene have so far been reported in CLS patients. However, no defect is found in about half of the CLS compatible patients by exon sequencing. We report here the first deep intronic mutation in RPS6KA3, which is associated with the retention of intronic sequences in the mRNAs. Indeed, this finding suggests that all the patients with a highly suggestive CLS clinical diagnosis, but in whom exon screening has failed to detect a mutation, should be reanalyzed at the RNA level.