Lockdown in a specialised rehabilitation unit: the best of times.

Specialised rehabilitation units offer inpatient multi-disciplinary rehabilitation for individuals with severe and enduring mental illness. A cornerstone of therapy is the work in the community through further education and community organisations. However, coronavirus restrictions have meant that such external supports are no longer available for the duration of the crisis. This has led to opportunities for developing new ways of offering rehabilitation within hospital environments. This article describes some of the new initiatives developed. The benefits of the lockdown for service users are also discussed. Many found the cessation of visits from family members with whom they had an ambivalent relationship helpful. The lockdown improved relationships between patients on the unit and encouraged a greater feeling of community. The lockdown has also emphasised the importance of team self-awareness and an awareness of the nature of the treatments offered.

Paediatric intensive care and neonatal intensive care airway management in the United Kingdom: the PIC-NIC survey.

In 2011, the Fourth National Audit Project (NAP4) reported high rates of airway complications in adult intensive care units (ICUs), including death or brain injury, and recommended preparation for airway difficulty, immediately available difficult airway equipment and routine use of waveform capnography monitoring. More than 80% of UK adult intensive care units have subsequently changed practice. Undetected oesophageal intubation has recently been listed as a 'Never Event' in UK practice, with capnography mandated. We investigated whether the NAP4 recommendations have been embedded into paediatric and neonatal intensive care practice by conducting a telephone survey of senior medical or nursing staff in UK paediatric intensive care units (PICUs) and neonatal intensive care units (NICUs). Response rates were 100% for paediatric intensive care units and 90% for neonatal intensive care units. A difficult airway policy existed in 67% of paediatric intensive care units and in 40% of neonatal intensive care units; a pre-intubation checklist was used in 70% of paediatric intensive care units and in 42% of neonatal intensive care units; a difficult intubation trolley was present in 96% of paediatric intensive care units and in 50% of neonatal intensive care units; a videolaryngoscope was available in 55% of paediatric intensive care units and in 29% of neonatal intensive care units; capnography was 'available' in 100% of paediatric intensive care units and in 46% of neonatal intensive care units, and 'always available' in 100% of paediatric intensive care units and in 18% of neonatal intensive care units. Death or serious harm occurring secondary to complications of airway management in the last 5 years was reported in 19% of paediatric intensive care units and in 26% of neonatal intensive care units. We conclude that major gaps in optimal airway management provision exist in UK paediatric intensive care units and especially in UK neonatal intensive care units. Wider implementation of waveform capnography is necessary to ensure compliance with the new 'Never Event' and has the potential to improve airway management.

The use of intrathecal analgesia and contrast radiography as preoperative diagnostic methods for digital flexor tendon sheath pathology.

REASONS FOR PERFORMING STUDY: The sensitivity of ultrasonography for the diagnosis of manica flexoria (MF) tears within the digital flexor tendon sheath (DFTS) is lower than for diagnosis of marginal tears of the deep digital flexor tendon (DDFT). Additional diagnostic tools would assist in appropriate decision making for either conservative or surgical management. OBJECTIVES: To evaluate the improvement in lameness of horses with MF or DDFT tears following intrathecal analgesia and to assess the sensitivity and specificity of contrast radiography for the diagnosis of these tears. METHODS: The case records of horses presented to a referral clinic over a 7-year period that underwent intrathecal diagnostic analgesia, or intrathecal analgesia and contrast radiography, of the DFTS with subsequent tenoscopy were examined. RESULTS: Fifty-three limbs had intrathecal diagnostic analgesia performed and 23 contrast tenograms were assessed in horses undergoing DFTS tenoscopy. Horses with DDFT tears were significantly more likely to respond positively to intrathecal diagnostic analgesia than those with MF tears (P = 0.02). Using contrast radiography, tears of the MF were predicted with an overall sensitivity of 96% and specificity of 80%; marginal tears of the DDFT were predicted with an overall sensitivity of 57% and specificity of 84%. CONCLUSIONS: The results of intrathecal analgesia of the DFTS in combination with contrast radiography have a high sensitivity for predicting MF tears. The sensitivity of contrast radiography for predicting tears of the DDFT is lower but the specificity remains high. POTENTIAL RELEVANCE: Contrast radiography performed at the same time as intrathecal analgesia provides useful information regarding the presence of MF tears and DDFT tears, which can assist in the decision of whether to manage the lameness conservatively or with tenoscopic evaluation.

The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer. The Cancer Research Campaign/British Prostate Group United Kingdom Familial Prostate Cancer Study Collaborators.

Predisposition to prostate cancer has a genetic component, and there are reports of familial clustering of breast and prostate cancer. Two highly penetrant genes that predispose individuals to breast cancer (BRCA1 and BRCA2) are known to confer an increased risk of prostate cancer of about 3-fold and 7-fold, respectively, in breast cancer families. Blood DNA from affected individuals in 38 prostate cancer clusters was analyzed for germ-line mutations in BRCA1 and BRCA2 to assess the contribution of each of these genes to familial prostate cancer. Seventeen DNA samples were each from an affected individual in families with three or more cases of prostate cancer at any age; 20 samples were from one of affected sibling pairs where one was < or = 67 years at diagnosis. No germ-line mutations were found in BRCA1. Two germ-line mutations in BRCA2 were found, and both were seen in individuals whose age at diagnosis was very young (< or = 56 years) and who were members of an affected sibling pair. One is a 4-bp deletion at base 6710 (exon 11) in a man who had prostate cancer at 54 years, and the other is a 2-bp deletion at base 5531 (exon 11) in a man who had prostate cancer at 56 years. In both cases, the wild-type allele was lost in the patient's prostate tumor at the BRCA2 locus. However, intriguingly, in neither case did the affected brother also carry the mutation. Germ-line mutations in BRCA2 may therefore account for about 5% of prostate cancer in familial clusters.

Frequent loss of BRCA1 mRNA and protein expression in sporadic ovarian cancers.

Germline mutations in the BRCA1 gene cause inherited susceptibility to breast and ovarian cancers. However, somatic mutations of BRCA1 are rare in sporadic breast and ovarian tumours. To establish whether BRCA1 is altered during the development of sporadic ovarian cancer by mechanisms other than somatic mutation, we have analysed 57 sporadic epithelial ovarian tumours for BRCA1 protein and RNA expression. Reduced or absent protein expression was observed in 90% of tumours. Decreased protein expression was significantly associated with a reduction in the levels of RNA expression. Somatic mutations of BRCA1 and LOH at the BRCA1 locus were detected in 3.5% and 44% of informative tumours, respectively; there was no significant correlation between the levels of protein and RNA expression and the DNA mutation and/or LOH status. Together, these data suggest that expression of BRCA1 is down-regulated at the level of transcription during the development of sporadic ovarian cancers.

Mutation analysis of the c-mos proto-oncogene in human ovarian teratomas.

Female transgenic mice lacking a functional c-mos proto-oncogene develop ovarian teratomas, indicating that c-mos may behave as a tumour-suppressor gene for this type of tumour. We have analysed the entire coding region of the c-MOS gene in a series of human ovarian teratomas to determine whether there are any cancer-causing alterations. DNA from twenty teratomas was analysed by single-strand conformational analysis (SSCA) and heteroduplex analysis (HA) to screen for somatic and germline mutations. In nine of these tumours the entire gene was also sequenced. A previously reported polymorphism and a single new sequence variant were identified, neither of which we would predict to be disease-causing alterations. These results suggest that mutations in the coding region of the c-MOS gene do not play a significant role in the genesis of human ovarian teratomas.

Aberrant splicing of the TSG101 and FHIT genes occurs frequently in multiple malignancies and in normal tissues and mimics alterations previously described in tumours.

Intragenic deletions of TSG101, the human homolog of a mouse gene (tsg101) that acts to suppress malignant cell growth, were reported in human breast tumours. We screened TSG101 for somatic mutations in DNA and RNA samples isolated from a variety of common human malignancies, EBV-immortalised B-cells, and normal lung parenchyma. Intragenic TSG101 deletions in RNA transcripts were frequently found in all types of samples. Analysis of DNA failed to show genomic rearrangements corresponding to transcripts containing deletions in the same samples. The breakpoints of most transcript deletions coincide with genuine or cryptic splice site sequences, suggesting that they result from alternative or aberrant splicing. A similar spectrum of transcript deletions has previously been described in the putative tumour suppressor gene FHIT. We analysed FHIT in the same series of RNA samples and detected truncated FHIT transcripts frequently in both tumour and normal tissues. In addition, transcripts from TSG101, FHIT and seven other genes were analysed in RNA isolated from normal peripheral blood lymphocytes. Large TSG101 and FHIT intragenic transcript deletions were detected and these appeared to be the predominant transcript in 'aged' lymphocytes. Similar alterations were not detected in transcripts of the other genes which were analysed. Our findings demonstrate that truncated TSG101 and FHIT transcripts are commonly detected in both normal and malignant tissues and that a significant fraction of these are likely to be the result of aberrant splicing. While we cannot exclude that alterations in TSG101 and FHIT occur during cancer development, our data indicate that in this context the commonly observed transcript abnormalities are misleading.

Viral and cellular gene expression in CD4+ human lymphoid cell lines infected by the simian immunodeficiency virus, SIV/Mne.

Our laboratory has undertaken an analysis of cellular and viral gene expression in CD4+ human lymphoid cell lines infected by the human and simian immunodeficiency viruses, HIV-1 and SIV/Mne, respectively. The purpose of the current study was to: (i) examine the effects of SIV/Mne infection on host macromolecular synthesis and compare the results to those in the HIV-1 system; and (ii) investigate the mechanisms responsible for the restriction of SIV/Mne infection in CD4 positive lymphoid cells which are readily infected by HIV-1. First we determined that SIV does not impose selective blocks on host macromolecular synthesis, unlike HIV-1, which induces both the selective inhibition of cellular protein synthesis and the degradation of cellular mRNAs (Agy, M., Wambach, M., Foy, K., and Katze, M. G., 1990, Virology 177, 251-258). No such selective reduction in cellular mRNA stability or protein synthesis was observed in cells infected by SIV/Mne. Additional differences between SIV and HIV-1 were observed using a panel of CD4+ human cell lines. While HIV-1-infected all cell lines. SIV/Mne efficiently infected only the MT-4, C8166, and 174 x CEM cell lines. Repeated efforts to infect CEM or Jurkat cells were unsuccessful as determined by PCR analysis of viral DNA. HUT 78 cells supported a limited infection detectable only by PCR analysis. These data suggest the block in viral replication in the nonsusceptible cell lines is at an early step. Interestingly, all the SIV susceptible cells were virally transformed, C8166 and MT-4 by HTLV-1, and 174 x CEM by Epstein-Barr virus. Furthermore FACS analysis revealed that all susceptible cells expressed two B cell associated markers, B7/BB1 and CD40. These observations taken together highlight differences between the HIV and SIV viruses, and suggest that for efficient replication, SIV/Mne may require an additional cell surface molecule, cofactors provided by transforming viruses, or a complex interplay between the two.

Expression of cellular genes in CD4 positive lymphoid cells infected by the human immunodeficiency virus, HIV-1: evidence for a host protein synthesis shut-off induced by cellular mRNA degradation.

We have investigated the effects of HIV-1 infection on cellular gene expression in two different human CD4 positive lymphoid cell lines: CEM and C8166 cells. As a prerequisite for this study it was necessary to develop virus-cell culture systems in which greater than 90% of the cells could be near synchronously infected by HIV-1. Further, since HIV-1 is a cytopathic virus, it was essential that cellular gene expression be examined in virus-infected cells which remained viable. After meeting these requirements, we measured cellular RNA and protein levels in virus-infected lymphocytes. In the cell lines examined the levels of cellular protein synthesis markedly decreased at times when viral-specific protein synthesis was increasing. Both Northern and slot blot analysis revealed that the declines in host protein synthesis were due, at least in part, to declines in steady state levels of cellular mRNAs. Runoff assays with nuclei isolated from infected cells demonstrated that the decreases in cellular mRNA levels were not due to declines in cellular RNA polymerase II transcription rates. To determine if the decreases in cellular protein synthesis also might be due to specific translational controls exerted by HIV-1, we compared the polysome association of cellular RNAs in infected and uninfected C8166 cells. The polysome distribution of cellular mRNAs was virtually identical in mock- and HIV-1-infected cells although, as expected, the total amount of cellular mRNAs were significantly lower in virus-infected cells. Taken together, these results suggest that HIV-1 may encode mechanisms to inhibit cellular protein synthesis, likely as a result of cellular mRNA degradation, rather than specific blocks in cellular mRNA translation.