Association of the Functional Movement Screen™ with match-injury burden in men's community rugby union.

Evidence supporting use of the Functional Movement Screen (FMSTM) to identify athletes' risk of injury is equivocal. Furthermore, few studies account for exposure to risk during analysis. This study investigated the association of FMSTM performance with incidence and burden of match-injuries in adult community rugby players. 277 players performed the FMSTM during pre-season and in-season time-loss injuries and match exposure were recorded. The associations between FMSTM score, pain, and movement-pattern asymmetries with match-injury incidence (≥8-days time-loss/1000hours), severe match-injury incidence (>28-days time-loss/1000hours), and match-injury burden (total time-loss days/1000hours for ≥8-days match-injuries) were analysed using Poisson regression. Multivariate analysis indicated players with pain and movement-pattern asymmetry during pre-season had 2.9 times higher severe match-injury incidence (RR, 90%CI = 2.9, 0.9-9.7) and match-injury burden (RR, 90%CI = 2.9, 1.3-6.6). Players with a typically low FMSTM score (mean - 1SD threshold) were estimated to have a 50% greater match-injury burden compared to players with a typically high FMSTM score (mean + 1SD threshold) as match-injury burden was 10% lower per 1-unit increase in FMSTM score. As the strongest association with injury outcome was found for players with pain and asymmetry, when implementing the FMSTM it is advisable to prioritise these players for further assessment and subsequent treatment.

Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells.

The splicing factor SF3B1 is the most commonly mutated gene in the myelodysplastic syndrome (MDS), particularly in patients with refractory anemia with ring sideroblasts (RARS). We investigated the functional effects of SF3B1 disruption in myeloid cell lines: SF3B1 knockdown resulted in growth inhibition, cell cycle arrest and impaired erythroid differentiation and deregulation of many genes and pathways, including cell cycle regulation and RNA processing. MDS is a disorder of the hematopoietic stem cell and we thus studied the transcriptome of CD34(+) cells from MDS patients with SF3B1 mutations using RNA sequencing. Genes significantly differentially expressed at the transcript and/or exon level in SF3B1 mutant compared with wild-type cases include genes that are involved in MDS pathogenesis (ASXL1 and CBL), iron homeostasis and mitochondrial metabolism (ALAS2, ABCB7 and SLC25A37) and RNA splicing/processing (PRPF8 and HNRNPD). Many genes regulated by a DNA damage-induced BRCA1-BCLAF1-SF3B1 protein complex showed differential expression/splicing in SF3B1 mutant cases. This is the first study to determine the target genes of SF3B1 mutation in MDS CD34(+) cells. Our data indicate that SF3B1 has a critical role in MDS by affecting the expression and splicing of genes involved in specific cellular processes/pathways, many of which are relevant to the known RARS pathophysiology, suggesting a causal link.

The design and synthesis of potent inhibitors of hepatitis C virus NS3-4A proteinase.

Hepatitis C virus (HCV) is the cause of the majority of transfusion-associated hepatitis and a significant proportion of community-acquired hepatitis worldwide. Infection by HCV frequently leads to persistent infections that result in a range of clinical conditions including an asymptomatic carrier state, severe chronic active hepatitis, cirrhosis and, in some cases, hepatocellular carcinoma. The HCV genome consists of a single-stranded, positive sense RNA containing an open reading frame of approximately 9060 nucleotides. This is translated into a single polyprotein of approximately 3020 amino acids (C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B), which in turn is processed by a series of host and viral proteinases into at least 10 cleavage products. The N-terminal portion of the NS3 protein encodes a serine proteinase that is responsible for the cleavage at the NS3-4A, NS4A-4B, NS4B-5A and NS5A-5B junctions. The 54 amino acid NS4A protein is a cofactor that binds to the NS3 protein and enhances its proteolytic activity. This report describes the expression of a recombinant NS3-4A proteinase fusion protein in Escherichia coli and the in vitro characterization of the enzyme activity using synthetic peptide substrates. It then demonstrates how these results were employed to guide the design of potent inhibitors of this enzyme.

Purification and characterization of an NAD(+)-linked formaldehyde dehydrogenase from the facultative RuMP cycle methylotroph Arthrobacter P1.

When Arthrobacter P1 is grown on choline, betaine, dimethylglycine or sarcosine, an NAD(+)-dependent formaldehyde dehydrogenase is induced. This formaldehyde dehydrogenase has been purified using ammonium sulphate fractionation, anion exchange- and hydrophobic interaction chromatography. The molecular mass of the native enzyme was 115 kDa +/- 10 kDa. Gel electrophoresis in the presence of sodium dodecyl sulphate indicated that the molecular mass of the subunit was 56 kDa +/- 3 kDa, which is consistent with a dimeric enzyme structure. After ammonium sulphate fractionation the partially purified enzyme required the addition of a reducing reagent in the assay mixture for maximum activity. The enzyme was highly specific for its substrates and the Km values were 0.10 and 0.80 mM for formaldehyde and NAD+, respectively. The enzyme was heat-stable at 50 degrees C for at least 10 min and showed a broad pH optimum of 8.1 to 8.5. The addition of some metal-binding compounds and thiol reagents inhibited the enzyme activity.

Previous cytology in patients with invasive carcinoma of the cervix.

The cytologic history of 346 patients presenting with invasive carcinoma of the cervix was reviewed. A total of 74 patients (21%) reported that cervical cytology had been performed in the five years prior to presentation; confirmation of the cytologic history was obtained in 65 cases. Smears were available for review in 34 cases; of 28 smears originally reported as negative, 20 were found to be abnormal on review. The possible reasons for the failure of cytologic detection in these patients are discussed.

Treatment of preinvasive disease of the cervix by cone biopsy.

During the years 1952--1977, 646 patients with abnormal cervical cytology underwent one biopsy (595) or ring biopsy of the cervix. The histological diagnoses were invasive carcinoma 20 (3%) microinvasive carcinoma 16 (2%), carcinoma in situ and severe dysplasia 418 (65%), other dysplasias 149 (23%). The remainder, 43 (7%) had no demonstrable abnormality. Following biopsy 41 (7%) patients with non-invasive disease had abnormal cytology within a year of biopsy. A further 12 (2%) developed abnormal cytology after one year. These recurrences occurred up to 12 years after the initial treatment, and in one patient invasive squamous carcinoma has developed.

Acceptability of the cytopipette in a general hospital.

Altogether 2,798 cytopipette smears have been taken by patients entering the general medical and surgical wards of a hospital. Twelve unsuspected positive smears were found, a rate of 4 per 1,000. Biopsy of these patients has shown five pre-malignant lesions, one invasive carcinoma of cervix, and one carcinoma of corpus uteri. Five patients await biopsy.The cytopipette is both acceptable to the patient (62% acceptance) and a feasible laboratory technique and can produce good cytological smears. Only 30% of patients entering the hospital had already had the opportunity to obtain a smear before, and most of them welcomed the opportunity for the test.Though the self-pipette may be criticized for its inaccuracy we feel that any test, if it can detect cervical abnormality at the rate of 4 women per 1,000, is better than no test at all. It should have a place in routine cytological testing of women second only to the use of Ayre's spatula.