Positron emission tomography of murine liver metastases and the effects of treatment by combretastatin A-4

. There are major potential advantages in non-invasive measurement of preclinical tumour biology and therapeutic response in clinically relevant, internal body sites, notably the ability to follow outcome in individual animals rather than averaging results from groups. We have exploited positron emission tomography (PET) to determine the feasibility of detecting liver metastases in B6D2F₁ mice using fluorine-18 fluorodeoxyglucose ([¹⁸F]FDG) both before and after treatment by the novel cytotoxic agent, combretastatin A-4. The normal distribution of [¹⁸F]FDG in the absence of disease was characterised, with the clear delineation of the brain, the heart and the urinary bladder in all studies. In untreated mice with liver metastases, a strong correlation (r ² = 0.98) was found between the quantitative estimates of [¹⁸F]FDG uptake obtained by analysis of PET images, and those obtained from ex vivo assay of liver plus metastases excised immediately after imaging. In this first series, the effective limit of resolution was in livers containing a number of small metastases (range 8–14) with a single volume equivalent of approximately 200 mm³. PET image analysis was concordant with histological measurements in showing that single intraperitoneal doses of combretastatin A-4 resulted in an average 30% volume destruction of metastatic mass by 24 h following administration. Received 1 August and in revised form 26 October 1998     

Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma [published erratum appears in Hum Mol Genet 1999 May;8(5):943]

Desmosomes are highly organized intercellular adhesive junctions that are particularly prominent in epidermis and other tissues experiencing mechanical stress. Desmoplakin, a constitutive component of the desmosomal plaque, is the most abundant protein present in such junctions and plays a critical role in linking the intermediate filament network to the plasma membrane in these tissues. Here we report the first mutation in the gene encoding desmoplakin. The identified mutation, resulting in a null allele and haploinsufficiency, was observed in genomic DNA from a kindred with the dominantly inherited skin disorder, striate palmoplantar keratoderma. Affected individuals had a linear pattern of skin thickening on the fingers and palms and circumscribed areas of skin thickening on the soles. Affected skin demonstrated loosening of intercellular connections, disruption of desmosome-keratin intermediate filament interactions and a proportion of rudimentary desmosomal structures. The disorder mapped to chromosome 6p21 with a maximum lod score of 10.67. The mutation was a heterozygous C-->T transition in exon 4 of the desmoplakin gene and predicted a premature termination codon in the N-terminal region of the peptide. This is the first reported mutation of desmo-plakin and also the first inherited skin disorder in which haploinsufficiency of a structural component has been implicated. It identifies dosage of desmoplakin as critical in maintaining epidermal integrity.      

Extravasation of phenytoin in the hand

A case of subcutaneous phenytoin extravasation in the hand is reported. Treatment consisting of compressive dressing, elevation, and splinting was successful in restoring hand function.     

Foreign epitopes in immunodominant regions of hepatitis B core particles are highly immunogenic and conformationally restricted.

The presentation of heterologous amino acid sequences on the surface of hepatitis B core antigen (HBcAg) particles has been studied using a defined linear neutralization site from human rhinovirus (HRV). Previous work has shown that fusion particles, in which the HRV peptide sequence is linked to the amino terminus of the HBcAg protein, induce excellent immune responses in experimental animals. Using predictive models of HBcAg particulate structure and the approximate location of the major immunogenic regions we have designed and constructed bacterial expression vectors which direct synthesis of chimeric particles in which heterologous sequences are presented within an immunodominant area on the particle. Immunological responses to the heterologous peptide sequence are improved by at least tenfold when compared with amino terminal fusions of the same peptide sequence to HBcAg. Moreover, the restriction placed on the heterologous peptide by its linkage at both ends within the HBcAg protein results in a more constrained structure. In the case of the rhinovirus peptide sequence this results in an antigenic conformation more closely resembling that on the native virus particle. Such a system lends itself well as a general approach to the induction of high titre antibodies against defined epitopes.     

Antigen processing and presentation of human rhinovirus to CD4 T cells is facilitated by binding to cellular receptors for virus

Human rhinovirus serotypes (HRV) fall into two distinct groups, major and minor, by virtue of their cell receptor-binding ability. In this study minor receptor-binding group viruses are demonstrated to bind directly to cells of the murine immune system, including lymphoid dendritic cells which act as antigen-presenting cells, although they do not produce a productive infection in murine cells. This binding is specific and can be blocked by other serotypes of minor-group HRV Pre-treatment of HRV 1A, a minor-group virus, with HRV 1A-specific antibodies inhibited the cellular proliferation of murine virus primed T helper cells, whereas antibody treatment of HRV 15, a non-binding major serotype, gave no inhibition. The cell binding ability of minor-group HRV played a role in the overall immunogenicity of this virus group, which was shown to be enhanced compared to the immunogenicity of major-group viruses in mice.     

Orthopaedic assessment unit: a service model for the delivery of orthopaedic trauma care in a major trauma centre during the global pandemic (COVID-19)

IntroductionWe describe a new service model, the Orthopaedic Assessment Unit (OAU), designed to provide care for trauma patients during the COVID-19 pandemic. Patients without COVID-19 symptoms and isolated musculoskeletal injuries were redirected to the OAU.MethodsWe prospectively reviewed patients throughput during the peak of the global pandemic (7 May 2020 to 7 June 2020) and compared with our historic service provision (7 May 2019 to 7 June 2019). The Mann–Whitney and Fisher Exact tests were used to test the statistical significance of data.ResultsA total of 1,147 patients were seen, with peak attendances between 11am and 2pm; 96% of all referrals were seen within 4h. The majority of patients were seen by orthopaedic registrars (52%) and nurse practitioners (44%). The majority of patients suffered from sprains and strains (39%), followed by fractures (22%) and wounds (20%); 73% of patients were discharged on the same day, 15% given follow up, 8% underwent surgery and 3% were admitted but did not undergo surgery. Our volume of trauma admissions and theatre cases decreased by 22% and 17%, respectively (p=0.058; 0.139). There was a significant reduction of virtual fracture clinic referrals after reconfiguration of services (p<0.001).ConclusionsRapid implementation of a specialist OAU during a pandemic can provide early definitive trauma care while exceeding national waiting time standards. The fall in trauma attendances was lower than anticipated. The retention of orthopaedic staff in the department to staff the unit and maintain a high standard of care is imperative.     

Relationships between bulimia,childhood sexual abuse,and family environment

Prior studies investigating the relationship between childhood sexual abuse and bulimia have yielded mixed to weak empirical support for such an association. The current research, utilizing relatively restrictive definitions of abuse and bulimia, obtained significant associations between bulimia, sexual abuse, and a chaotic family environment in female college students. Among abuse victims, severity of abuse was also associated with bulimia. Although some analyses suggested that a chaotic family environment moderated the abuse—bulimia association, sexual abuse, and family environment appeared to combine in an additive manner to increase the probability of bulimia. © 1994 by John Wiley & Sons, Inc.     

Cell-free DNA analysis in current cancer clinical trials: a review

Cell-free DNA (cfDNA) analysis represents a promising method for the diagnosis, treatment selection and clinical follow-up of cancer patients. Although its general methodological feasibility and usefulness has been demonstrated, several issues related to standardisation and technical validation must be addressed for its routine clinical application in cancer. In this regard, most cfDNA clinical applications are still limited to clinical trials, proving its value in several settings. In this paper, we review the current clinical trials involving cfDNA/ctDNA analysis and highlight those where it has been useful for patient stratification, treatment follow-up or development of novel approaches for early diagnosis. Our query included clinical trials, including the terms ‘cfDNA’, ‘ctDNA’, ‘liquid biopsy’ AND ‘cancer OR neoplasm’ in the FDA and EMA public databases. We identified 1370 clinical trials (FDA = 1129, EMA = 241) involving liquid-biopsy analysis in cancer. These clinical trials show promising results for the early detection of cancer and confirm cfDNA as a tool for real-time monitoring of acquired therapy resistance, accurate disease-progression surveillance and improvement of treatment, situations that result in a better quality of life and extended overall survival for cancer patients.Subject terms: Cancer, Tumour biomarkers, Predictive markers     

Behavioural and emotional difficulties in students attending schools for children and adolescents with severe intellectual disability

Background   For several decades, researchers and clinicians have been aware of an increased prevalence of psychiatric disorder in children with intellectual disability. However, there are few research studies exploring this issue.
Methods   The parents of 123 children attending schools for children with 'severe learning difficulties' completed the Developmental Behaviour Checklist (DBC) in order to identify those children with clinically significant behavioural and emotional problems. Comparisons were made with norms for the DBC and a range of child variables were investigated as possible correlates of disorder.
Results   Some 50.4% of the children scored above the cut-off on the DBC for psychiatric disorder. The child's severity of physical disability was related most strongly to parental ratings of behavioural and emotional problems. There were also effects for the child's age and the absence of Down's syndrome.
Conclusions   The present study confirms previous research findings of a high prevalence of behavioural and emotional difficulties amongst children with intellectual disability, and identifies a number of correlates of disorder which require further investigation.