Familial autosomal dominant calcium pyrophosphate dihydrate (CPPD) chondrocalcinosis has previously been mapped to chromosome 5p15. We have identified a mutation in the
ANKH gene that segregates with ...the disease in a family with this condition.
ANKH encodes a putative transmembrane inorganic pyrophosphate (PPi) transport channel. We postulate that loss of function of ANKH causes elevated extracellular PPi levels, predisposing to CPPD crystal deposition.
To investigate the prevalence of ureaplasmas in semen and washed semen and to explore their effect on semen andrology variables.
Prospective study.
In vitro fertilization (IVF) unit of a private ...hospital.
Three hundred forty-three men participating in an assisted reproductive technology (ART) treatment cycle.
The prevalence of ureaplasmas in semen and washed semen tested by culture, polymerase chain reaction assays, and indirect immunofluorescent antibody assays.
Ureaplasmas were detected in 73 of 343 (22%) semen samples and 29 of 343 (8.5%) washed semen samples. Ureaplasmas adherent to the surface of spermatozoa were demonstrated by indirect immunofluorescent antibody testing.
Ureplasma parvum serovar 6 (36.6%) and
U. urealyticum (30%) were the most prevalent isolates in washed semen. A comparison of the semen andrology variables of washed semen ureaplasma positive and negative groups demonstrated a lower proportion of nonmotile sperm in men ureaplasma positive for washed semen.
Ureaplasmas are not always removed from semen by a standard ART washing procedure and can remain adherent to the surface of spermatozoa.
Linkage of chromosome 11q13 to type 1 diabetes (T1D) was first reported from genome scans (Davies et al. 1994; Hashimoto et al. 1994) resulting in P <2.2 x 10(-5) (Luo et al. 1996) and designated ...IDDM4 ( insulin dependent diabetes mellitus 4). Association mapping under the linkage peak using 12 polymorphic microsatellite markers suggested some evidence of association with a two-marker haplotype, D11S1917*03-H0570POLYA*02, which was under-transmitted to affected siblings and over-transmitted to unaffected siblings ( P=1.5 x 10(-6)) (Nakagawa et al. 1998). Others have reported evidence for T1D association of the microsatellite marker D11S987, which is approximately 100 kb proximal to D11S1917 (Eckenrode et al. 2000). We have sequenced a 400-kb interval surrounding these loci and identified four genes, including the low-density lipoprotein receptor related protein (LRP5) gene, which has been considered as a functional candidate gene for T1D (Hey et al. 1998; Twells et al. 2001). Consequently, we have developed a comprehensive SNP map of the LRP5 gene region, and identified 95 SNPs encompassing 269 kb of genomic DNA, characterised the LD in the region and haplotypes (Twells et al. 2003). Here, we present our refined linkage curve of the IDDM4 region, comprising 32 microsatellite markers and 12 SNPs, providing a peak MLS=2.58, P=5 x 10(-4), at LRP5 g.17646G>T. The disease association data, largely focused in the LRP5 region with 1,106 T1D families, provided no further evidence for disease association at LRP5 or at D11S987. A second dataset, comprising 1,569 families from Finland, failed to replicate our previous findings at LRP5. The continued search for the variants of the putative IDDM4 locus will greatly benefit from the future development of a haplotype map of the genome.
Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical ...cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis. PUBLICATION ABSTRACT
Background: Complex Regional Pain Syndrome, CRPS, is recognized to be a common debilitating painful condition. CRPS persisting beyond 12 months is considered a chronic intractable condition which ...profoundly impacts on quality of life, activities of daily living and the ability to sustain employment. Standard treatments include analgesia, education, physiotherapy and desensitization. What happens to such patients in Addenbrooke's CRPS clinic? It is important to know this baseline level of pain and functioning prior to recruiting to n-of-1 cohort studies, as recommended by MRC Guidance. Methods: A service evaluation of 21 patients with CRPS presenting to the Rheumatology Department in 2007–9 with a diagnosis of CRPS (IASP criteria) was performed. Demographic data and clinical outcomes were collected using the Brief Pain Inventory (BPI), Human Activity Profile (HAP, maximal and adjusted scores), Upper and Lower Extremity Functioning Indices (UEFI/LEFI). These were repeated three times over a 12-month period on average. The minimum statistically significant changes are HAP maximum 8, adjusted 7 and 9 for UEFI and LEFI. Only patients with CRPS for over a year were selected. Patients underwent a rehabilitation programme comprising optimal analgesia, education, physiotherapy and desensitization. Results: 21 patients were formally assessed and followed up for 6–18 months. 13 patients fulfilled IASP research criteria for CRPS, 5 fulfilled diagnostic criteria and 3 had persistent unexplained limb pain. 20/21 (95%) were female with an average age of 40.4 years (21–58 years). The average duration of symptoms at the time of assessment was 67.6 months (25–384 months). The average length of time to diagnosis was 12.9 months (2–36 months). Affected sites were upper limb (11), lower limb (6) both upper and lower limb (4); 1 patient had neural damage (CRPS type 2). Maximum pain scores decreased from baseline (8.1) compared with 12–18 month follow-up (7.2) by 11%. Average pain scores reduced by 16% (6.7 to 5.6). Patients reported 47% more pain relief from their analgesia (34 to 50). Average effect of pain on patients' life decreased by 19% (6.9 to 5.6). HAP maximum improved from 59.5 at baseline to 72.8 at 12–18 months and adjusted scores improved from 38.1 to 50.5. UEFI increased from 24.7 to 36.1 and LEFI from 31.9 to 43.1. All these improvements in activity and functioning are greater than the minimal change scores indicating modest, but significant improvements. 2/21 (9.5%) patients returned to employment. Those working continued to do so. Conclusions: Patients with chronic CRPS have only modest benefits from a rehabilitation approach. More innovative treatments are needed. The 12.9 month delay in diagnosis may have contributed to chronicity in this cohort. More awareness of CRPS is needed and this needs to be studied in patients with early disease. Understanding the baseline fluctuations in patients with chronic CRPS allows n-of-1 interventions to be effectively evaluated. Disclosure statement: All authors have declared no conflicts of interest.
Deficiency of iduronate-2-sulphatase (IDS) results in the X linked recessive lysosomal storage disorder Hunter syndrome. Determination of carrier status in families affected by this disorder has been ...performed using a variety of enzymatic tests. None of these tests has proved to be 100% effective at identifying carriers. The aim of this study was to perform carrier testing in a family affected by the disorder, where testing was complicated by the fact that no surviving affected subjects were available for study. Direct dye primer sequencing of PCR products was used to identify mixed bases in an obligate carrier. Two mixed bases were observed within exon VIII. The first base change (T-->A) at nucleotide position 1150 results in a missense mutation (H342Q), while the second base change (G-->T) at nucleotide position 1151 results in a nonsense mutation (G343X). Four additional female family members were screened for the same mutation. Using this approach it is possible to provide unambiguous information about a subject's carrier status and, unlike biochemical testing, this approach will be equally effective when applied to families with the mild form of this disorder.
A series of 2-thioether derivatives of a number of clavine alkaloid (ergoline) ring systems have been synthesized and tested for dopamine antagonist activity. Of the compounds tested ...2-(methylthio)-agroclavine (8,9-didehydro-6,8-dimethyl-2-(methylthio)ergoline) (6) was the most potent and had a profile of activity in animal models indicative of potential antipsychotic activity. The synthesis and biological activity of a number of metabolites of 6, including the 13-hydroxy derivative, are also reported.
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