Biomedical subjects

David Francis

Publications and source records attributed to David Francis.

15 recordsLinked to original sources

PubMed2026

Elucidating the Role of SET as a Key Contributor to Neurodevelopmental Disability Within the 9q34.11 Deletion Syndrome Interval.

The 9q34.11 chromosomal region contains multiple neurodevelopmental genes involved in synaptic transmission, axonal structure and neuronal maturation. Pathogenic microdeletions, duplications and single nucleotide variants in numerous genes were previously linked with neurodevelopmental disorders (NDDs). Amongst them, SET has recently been implicated in a rare NDD with speech delay and facial dysmorphism. This study reports a female with a heterozygous de novo deletion impacting SET but not other NDD-associated genes at 9q34.11. The proband was initially diagnosed with atypical Rett syndrome with overlapping clinical features of SET haploinsufficiency. The deletion was confirmed using microarray and long-read sequencing. Subsequent quantitative proteomic evaluation identified a significant decrease of SET protein in patient-derived fibroblasts compared to control lines. This study provides insights into the proband's clinical course over their 28 year diagnostic odyssey, and emphasises the benefits of early speech therapy interventions. The proband had no functional speech, but regained the capacity to meaningfully communicate and articulate a limited vocabulary in adulthood, concordant with other reported non-paediatric cases of SET-NDD. This study expands current knowledge on the genotypic and phenotypic spectra of SET-NDD, and pinpoints a smaller 9q34.11 critical region excluding upstream NDD-associated genes, STXBP1 and SPTAN1, implicating SET as a significant NDD-associated gene.

Humans↗

PubMed2006

Financial considerations in the conduct of multi-centre randomised controlled trials: evidence from a qualitative study.

BACKGROUND: Securing and managing finances for multicentre randomised controlled trials is a highly complex activity which is rarely considered in the research literature. This paper describes the process of financial negotiation and the impact of financial considerations in four UK multicentre trials. These trials had met, or were on schedule to meet, recruitment targets agreed with their public-sector funders. The trials were considered within a larger study examining factors which might be associated with trial recruitment (STEPS). METHODS: In-depth semi-structured telephone interviews were conducted in 2003-04 with 45 individuals with various responsibilities to one of the four trials. Interviewees were recruited through purposive and then snowball sampling. Interview transcripts were analysed with the assistance of the qualitative package Atlas-ti. RESULTS: The data suggest that the UK system of dividing funds into research, treatment and NHS support costs brought the trial teams into complicated negotiations with multiple funders. The divisions were somewhat malleable and the funding system was used differently in each trial. The fact that all funders had the potential to influence and shape the trials considered here was an important issue as the perspectives of applicants and funders could diverge. The extent and range of industry involvement in non-industry-led trials was striking. Three broad periods of financial work (foundation, maintenance, and resourcing completion) were identified. From development to completion of a trial, the trialists had to be resourceful and flexible, adapting to changing internal and external circumstances. In each period, trialists and collaborators could face changing costs and challenges. Each trial extended the recruitment period; three required funding extensions from MRC or HTA. CONCLUSION: This study highlights complex financial aspects of planning and conducting trials, especially where multiple funders are involved. Recognition of the importance of financial stability and of the need for appropriate training in this area should be paralleled by further similar research with a broader range of trials, aimed at understanding and facilitating the conduct of clinical research.

Journal Article↗

PubMed2006

What influences recruitment to randomised controlled trials? A review of trials funded by two UK funding agencies.

BACKGROUND: A commonly reported problem with the conduct of multicentre randomised controlled trials (RCTs) is that recruitment is often slower or more difficult than expected, with many trials failing to reach their planned sample size within the timescale and funding originally envisaged. The aim of this study was to explore factors that may have been associated with good and poor recruitment in a cohort of multicentre trials funded by two public bodies: the UK Medical Research Council (MRC) and the Health Technology Assessment (HTA) Programme. METHODS: The cohort of trials was identified from the administrative databases held by the two funding bodies. 114 trials that recruited participants between 1994 and 2002 met the inclusion criteria. The full scientific applications and subsequent trial reports submitted by the trial teams to the funders provided the principal data sources. Associations between trial characteristics and recruitment success were tested using the Chi-squared test, or Fisher's exact test where appropriate. RESULTS: Less than a third (31%) of the trials achieved their original recruitment target and half (53%) were awarded an extension. The proportion achieving targets did not appear to improve over time. The overall start to recruitment was delayed in 47 (41%) trials and early recruitment problems were identified in 77 (63%) trials. The inter-relationship between trial features and recruitment success was complex. A variety of strategies were employed to try to increase recruitment, but their success could not be assessed. CONCLUSION: Recruitment problems are complex and challenging. Many of the trials in the cohort experienced recruitment difficulties. Trials often required extended recruitment periods (sometimes supported by additional funds). While this is of continuing concern, success in addressing the trial question may be more important than recruitment alone.

Journal Article↗

PubMed2006

Posttraumatic spinal cord herniation.

We report a 28-year-old woman who presented with a partial Brown-Sequard syndrome 18 months after a fall from a horse. Investigation revealed the cause of her symptoms to be a spinal cord herniation at the level of T6. A review of previously reported cases of posttraumatic spinal cord herniation was undertaken. Six of the cases reported have clear evidence of injury at the site of subsequent herniation; the remaining five cases may be related to trauma or may be spontaneous spinal cord herniation, with an unrelated history of trauma.

Adult↗

PubMed2006

Treatment of idiopathic sudden sensorineural hearing loss.

CONCLUSION: The therapeutic role of corticosteroids and/or corticosteroids with antiviral agents for sudden sensorineural hearing loss (SSNHL) has yet to be fully elucidated; however, in cases where deafness is profound and of recent onset, a therapeutic trial is indicated. OBJECTIVES: To investigate treatment regimens and their efficacies, as well as evaluating the potential prognostic correlates and allowing comparison between local and national standards of care for SSNHL. PATIENTS AND METHODS: A retrospective evidence-based case series of 143 patients seen at the University of Rochester, Department of Otolaryngology between 1999 and 2002 was investigated. Treatment modalities included (1) observation, (2) steroids, and (3) steroids with antivirals. RESULTS: The study demonstrates that steroid treatment, alone or in combination with antivirals, results in a significant improvement rate compared with observation. Results indicate that the more expediently a patient with SSNHL is seen by an otolaryngologist, the better their prognosis.

Adrenal Cortex Hormones↗

PubMed2006

A genetic association study of the functional A118G polymorphism of the human mu-opioid receptor gene in patients with acute and chronic pain.

In this prospective, observational study we explored whether A118G single nucleotide polymorphism in the human mu-opioid receptor (MOR) gene could explain the inter-individual differences in opioid analgesic requirements in patients with acute postoperative pain and chronic pain. The frequency of the wild-type A118 MOR (major) and variant G118 MOR (minor) alleles in the subjects with chronic, noncancer pain (n = 121) and opioid-naïve subjects with acute postoperative pain (n = 101), serving as the control group, were examined. The relationships among the A118G MOR genotype, opioid requirements, and the numerical pain score were analyzed in both groups. The frequency of the minor allele was significantly lower in the subjects with chronic pain when compared with the group with acute postoperative pain (0.079 versus 0.158; P = 0.009 by chi2 test). No statistically significant association was observed between the presence of A118G MOR polymorphism and the average postoperative pain score or the doses of morphine used in the immediate postoperative period. In the high-quartile, opioid utilization, chronic pain patients, the homozygotic carriers of the major allele required significantly higher opioid dose than did the carriers of the minor allele. The results indicate that although the presence of the minor allele does not appear to affect opioid analgesic use in acute postoperative pain, the minor allele is less common in chronic pain patients, especially in those requiring higher doses of opioid analgesics.

Abdomen↗

PubMed2005

Emerging modalities in veterinary rehabilitation.

Many new modalities have been introduced in human and veterinary physical rehabilitation. In many instances, there is sound theory of how they may impact the physiology of various cells, tissues, or organs. This article reviews some of the modalities that have been introduced recently in human and veterinary rehabilitation. Topics include low-level laser, phototherapy, and extracorporeal shock wave treatment.

Animals↗

PubMed2005

Peripersonal spatial attention in children with spina bifida: associations between horizontal and vertical line bisection and congenital malformations of the corpus callosum, midbrain, and posterior cortex.

Horizontal and vertical line bisection was studied in 129 children and adolescents between 8 and 19 years of age, one group (n=32) of typically developing controls and one group (n=97) with spina bifida (SBM), a neurodevelopmental disorder associated with dysmorphology of the corpus callosum, posterior cortex, and midbrain. For each participant, structural brain MRIs were analyzed qualitatively to identify beaking of the midbrain tectum and corpus callosum agenesis and hypoplasia and quantitatively by segmentation and volumetric analyses of regional cortical white and gray matter. Each group showed the line length effect, whereby greater estimation errors are made with longer lines. The group with SBM differed from controls in terms of both accuracy and variability of line bisection. Children with SBM showed pseudoneglect, attending more than controls to left hemispace. The extent of rightward bisection bias was unrelated to right posterior brain volumes, although an intact corpus callosum during development moderated and normalized the exaggerated leftward line bisection bias. More children with SBM than controls attended to inferior hemispace. A normal midbrain and greater posterior cortex volume during development moderated and normalized the downward bias. Children with SBM showed more intra-subject variability than controls. Line bisection in children with SBM reflects three deficits: an exaggerated attentional bias to left hemispace, an abnormal attentional bias to inferior hemispace; and a larger zone of subjective uncertainty in bisection judgments.

Adolescent↗

PubMed2004

Motor learning in children with spina bifida: dissociation between performance level and acquisition rate.

The cerebellum is part of a neural circuit involved in procedural motor learning. We examined how congenital cerebellar malformations affect mirror drawing performance, a procedural learning task that involves learning to trace the outline of a star while looking at the reflection of the star in a mirror. Participants were 88 children with spina bifida myelomeningocele, a neural tube defect that results in lesions of the spinal cord, dysmorphology of the cerebellum, and requires shunt treatment for hydrocephalus, and 35 typically developing controls. Participants completed 10 trials in the morning and 10 trials following a 3-hr delay. Although children with spina bifida myelomeningocele were initially slower at tracing and made more errors than controls, all participants improved their performance of the task, as demonstrated by increased speed and accuracy across trials. Moreover, degree of cerebellar dysmorphology was not correlated with level of performance, rate of acquisition, or retention of mirror drawing. The results suggest that congenital cerebellar dysmorphology in spina bifida does not impair motor skill learning as measured by acquisition and retention of the mirror drawing task.

Adolescent↗

PubMed2004

A prospective study of the use of cryosurgery for the treatment of actinic keratoses.

BACKGROUND: Actinic keratoses are the most common actinic lesions on Caucasian skin. Cryosurgery with liquid nitrogen is commonly used to treat actinic keratoses, but there have been few studies examining the true rate of cure in everyday dermatologic practice. AIM: To determine prospectively the true efficacy of cryosurgery as a treatment for actinic keratoses in everyday dermatologic practice. METHODS: A prospective, multicentered study (a subsidiary study of a photodynamic therapy trial) was performed. Patients with untreated actinic keratoses greater than 5 mm in diameter on the face and scalp were recruited. Eligible lesions received a single freeze-thaw cycle with liquid nitrogen given via a spray device and were reviewed 3 months thereafter. Each center used their preferred freeze time. The only treatment criterion was complete freezing of actinic keratoses and a 1-mm rim of normal skin. Treated lesions were assessed as complete response or noncomplete response. The influence of the duration of freeze, cosmetic outcomes, and adverse events were examined. RESULTS: Ninety adult patients from the community with 421 eligible actinic keratoses were recruited. The overall individual complete response rate was 67.2%[SEM = +/-3.5%; 95% confidence interval (CI) = 60.4-74.1%]. Complete response was 39% for freeze times of less than 5 s, 69% for freeze times greater than 5 s, and 83% for freeze times greater than 20 s. Cosmetic outcomes were good to excellent in 94% of complete response lesions. The main adverse events were pain, stinging, and burning during treatment, and hypopigmentation after healing. CONCLUSIONS: Cryosurgery is an effective treatment for actinic keratoses. The true complete response rate is significantly lower than that previously reported. The freeze duration influences successful treatment. Adverse events are mild and well tolerated.

Adult↗

PubMed2003

Brain mechanisms for reading in children with and without dyslexia: a review of studies of normal development and plasticity.

In this article we review our experience with the application of magnetic source imaging (MSI), the newest of the functional imaging methods, to the study of brain mechanisms for reading among children who read normally and among those with dyslexia. After giving a general description of MSI, we present evidence for reliable and valid maps of the brain mechanism for aural language comprehension as well as for reading. Next, we present data from 39 normal readers, 40 children with dyslexia, and 30 younger children at risk for developing a reading disability. These data show different brain activation maps for individual children with dyslexia and children at risk for dyslexia than for those of normal readers. Such differences most likely reflect aberrant brain organization underlying phonological decoding, rather than variables such as degree of effort. Finally, we present preliminary data demonstrating that the aberrant activation profiles of children with dyslexia may return to normative patterns as a result of a successful reading intervention that enables children to improve phonological decoding skills.

Adolescent↗

PubMed2003

Basal cell carcinoma is associated with high TNF-alpha release but nor with TNF-alpha polymorphism at position--308.

The mechanisms underlying induction of UVB-induced immunosuppression are not fully understood, but tumor necrosis factor alpha (TNF-alpha) is suggested to play a central role. A single base pair polymorphism at position --308 in the promoter region of the TNF-alpha gene associated with an enhanced secretion of TNF-alpha has been identified in humans. We have therefore investigated the association of the --308 polymorphism with the risk of basal cell carcinoma (BCC) in humans. The frequency of TNF G and TNF A alleles among Caucasian patients with a previous BCC (n=191) and health adults (n-107) were compared. For the TNF--308 polymorphism there was significant association between the genotype or allele frequencies and having BCC. To determine whether patients with a previous BCC had an increased capacity to secrete TNF-alpha, mononuclear cells were stimulated with lipopolysaccharide. Mononuclear cells from patients with a previous BCC (n=15) demonstrated a significantly increased release of TNF-alpha upon stimulation with lipopolysaccharide (P<0.03) compared with mononuclear cells age-matched control subjects (n=16). Further studies of other polymorphisms of the TNF-alpha gene associated with increased TNF-alpha production and BCC and necessary.

Adult↗

PubMed2002

Antibody repertoire development in fetal and neonatal piglets. VIII. Colonization is required for newborn piglets to make serum antibodies to T-dependent and type 2 T-independent antigens.

Cesarean-derived piglets were reared for 5 wk under germfree conditions or monoassociated with a benign Escherichia coli (G58-1) or a enterohemorrhagic strain (933D) derived from O157:H7, and immunized i.p. with the T-dependent (TD) Ags fluorescein-labeled (FL) keyhole limpet hemocyanin or trinitrophenylated (TNP) keyhole limpet hemocyanin and the type 2 T-independent Ags TNP-Ficoll or FL-Ficoll. Only colonized piglets showed an increase in serum IgG, IgA, and IgM and had serum Abs to FL, TNP, and colonizing bacteria. While serum Abs to FL or TNP appeared following colonization alone, secondary responses were restricted to piglets immunized using TD carriers. While animals colonized with 933D had significantly higher total serum IgG and IgM levels and specific IgG Abs than those colonized with G58-1, no differences were seen in serum IgA levels, B cell diversification in the ileal Peyer's patches, and specific activity (ELISA activity per micrograms of Ig) of pre-boost serum IgG and IgM anti-TNP and anti-FL Abs. Serum IgA Abs to TNP, FL, or bacteria were not detected. Ag-driven responses, as measured by an increase in specific Ab activity, were only observed in secondary responses to TD Ags and to colonizing, pathogenic E. coli. We propose that germline-encoded, isotype-switched B cells in newborn piglets differentiate to Ab-secreting cells 1) after stimulation by bacteria-activated APCs or 2) through direct stimulation by bacterial products. We further propose that Ag-driven systemic responses require both bacterial colonization and TD Ags translocated to the peritoneum.

Animals↗

PubMed2002

Switch recombination in fetal porcine thymus is uncoupled from somatic mutation.

Since fetal serum Ig isotype profiles suggested that IgG and IgA could be of de novo origin, we studied their transcription and secretion. IgM transcripts were present at 50 days of gestation in major fetal lymphoid tissues, IgG and IgA transcription was pronounced at 60 days in fetal thymus and both transcription and secretion in this organ increased in late fetal life. The CDR3 spectratype of thymic IgG and IgA transcripts was as polyclonal as that of IgM already at 70 days in utero indicating a broad repertoire of switched B-cells. However, VDJs transcribed with the switched isotypes were not hypermutated as were those from immunized fetuses, indicating that switch recombination and somatic mutation are not coupled in utero in piglets. This finding and the fact that the oligoclonal IgA and IgM repertoires in a non-inductive site of the mucosal immune system (parotid gland) becomes polyclonal in piglets reared germ-free, suggest that initial expansion of switched B-cells in fetal and neonatal piglets is not driven by environmental antigen. Our findings collectively suggest that all IgA and IgM may result from de novo synthesis while some IgG probably results from selective transport. The latter is consistent with the gradual decline in serum IgG concentration in germ-free isolator piglets and the expression of FcRn in the porcine placenta.

Animals↗

PubMedDate not supplied

Direct determination of lycopene content in tomatoes (Lycopersicon esculentum) by attenuated total reflectance infrared spectroscopy and multivariate analysis.

Lycopene is a potent antioxidant that has been shown to play critical roles in disease prevention. Efficient assays for detection and quantification of lycopene are desirable as alternatives to time- and labor-intensive methods. Attenuated total reflectance infrared (ATR-IR) spectroscopy was used for quantification of lycopene in tomato varieties. Calibration models were developed by partial least-squares regression (PLSR) using quantitative measures of lycopene concentration from liquid chromatography as reference method. IR spectra showed a distinct marker band at 957 cm(-1) for trans Carbon-Hydrogen (CH) deformation vibration of lycopene. PLSR models predicted the lycopene content accurately and reproducibly with a correlation coefficient (sigma) of 0.96 and standard error of cross-validation <0.80 mg/100 g. ATR-IR spectroscopy allowed for rapid, simple, and accurate determination of lycopene in tomatoes with minimal sample preparation. Results suggest that the ATR-IR method is applicable for high-throughput quantitative analysis and screening for lycopene in tomatoes.

Carotenoids↗