Biomedical subjects
H Scott
Publications and source records attributed to H Scott.
Slow rehabilitation of a traumatic lower limb amputee.
A 65-year-old male (GM) was referred to the physiotherapy department of the regional limb fitting centre for outpatient rehabilitation following a right transfemoral amputation five weeks previously. He had been knocked down by a bus and suffered a crush injury to the right leg resulting in a stable fracture to the right pubic ramus, a fractured skull and orbital bone. Immediately following admission to the local district general hospital, his right leg was amputated at the transfemoral level. He was nursed post-operatively in ITU for three days and was ventilated during this time. GM was then transferred to the general orthopaedic ward. He received physiotherapy throughout his hospital stay by ward-based physiotherapists--not experts in amputee management but with access to specialist advice. Early physiotherapy was primarily concerned with respiratory care and maintenance of limb mobility and function in bed. Gentle, active stump exercises were commenced on the first post-operative day. GM sat out of bed on the sixth day and stood with the support of two people on the eighth day. His wound was healing well and treatment in the physiotherapy gym began the same day. Use of the pneumatic post-amputation mobility aid (PPAM aid) (Redhead, 1983; Marks, 1996) was started on day nine. However, progress with this early walking aid (EWA) was slow and GM achieved independent walking using parallel bars on the eighteenth post-operative day.
New tool to predict celiac disease on its way to the clinics.
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Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease.
BACKGROUND & AIMS: Celiac disease appears to be a T cell-mediated enteropathy induced by gluten in genetically predisposed individuals. Duodenal biopsy specimens from patients with celiac disease and histologically normal controls were investigated to see if cytokine expression is related to disease activity. METHODS: Cytokine messenger RNA (mRNA) expression was determined by quantitative reverse-transcription polymerase chain reaction and in situ expression by immunohistochemistry. RESULTS: In normal controls, mRNA levels were usually below the quantitative limit, even after in vitro gluten stimulation. By contrast, interferon (IFN)-gamma mRNA was increased more than 1000-fold in untreated disease. In vitro gluten stimulation of specimens from treated patients (gluten-free diet) increased IFN-gamma mRNA to the levels of untreated patients. In addition, increased mRNA levels for interleukin (IL)-2, IL-4, IL-6, and tumor necrosis factor alpha were found after such stimulation, whereas mRNA for IL-5, IL-10, and IL-12p40 was usually below the quantitative level. Biopsy specimens from untreated patients contained on average 10-fold more lamina propria cells positive for IFN-gamma than normal controls, whereas cells containing IL-4 were rare in both subject groups. CONCLUSIONS: The results show that mucosal gluten exposure in patients with celiac disease rapidly elicits high levels of IFN-gamma expression and lower levels of IL-2, IL-4, IL-6, and tumor necrosis factor alpha even in the virtual absence of IL-12.
CD4+ T cells with specific reactivity against astrovirus isolated from normal human small intestine.
BACKGROUND & AIMS: The gut is the largest immunologic organ in the human body, but little is known about the antigen specificity of mucosal T cells. This study sought to determine whether T cells resident in the duodenal mucosa could recognize astrovirus, a common and clinically important gastroenteritis virus. Serum antibodies against astrovirus are prevalent, indicating frequent viral exposure and postinfectious induction of systemic immune responses. Mucosal immune responses may conceivably mediate protection on astroviral reinfections. METHODS: Small intestinal biopsy specimens with normal histology were obtained from 8 adults and challenged in an organ culture system with inactivated human astrovirus. T cells activated by the viral challenge were isolated either by immunomagnetic positive selection of mucosal resident cells or by collecting cells emigrating into the culture supernatant. RESULTS: Astrovirus-specific, mucosal T-cell lines were isolated from all 8 subjects. Analysis of 29 CD4+ T-cell clones from 3 subjects showed predominant HLA-DR restriction of astrovirus responses. Most of the T-cell clones showed a Th1-like cytokine profile when restimulated with astrovirus. CONCLUSIONS: Helper T cells residing in normal, duodenal mucosa of adult subjects recognize a common enteropathogenic virus. These mucosal CD4+ T cells are presumably important in mucosal defense against recurrent astroviral infections.
APECED: a monogenic autoimmune disease providing new clues to self-tolerance.
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Effects of ischemic tolerance on mRNA levels of IP3R1, beta-actin, and neuron-specific enolase in hippocampal CA1 area of the gerbil brain.
Global cerebral ischemia induced to Mongolian gerbils by ligation of common carotid arteries (CCAs) is known to result in injury to the hippocampal CA1 region. In this study, we examined whether neuronal injury can be depicted by measuring levels of mRNA encoding inositol 1,4,5-trisphosphate receptor type 1 (IP3R1), neuron specific enolase (NSE) and beta-actin and whether these measurements can be use to assess ischemic tolerance. Gerbils were subjected either to cerebral ischemia induced by ligation of both CCAs for 5 min, or to an ischemic tolerance paradigm in which a 2 min ischemic preconditioning was performed 24 hr prior to the 5 min ischemia. At 48 hr after the 5 min ischemic insult, significant decreases in mRNA levels for IP3R1 (26%), NSE (38%) and beta-actin (50%) could be observed in the hippocampal CA1 region. Although levels of mRNA in the preconditioning group were decreased as compared to the sham control, the levels were significantly higher than those in the ischemic group. These results indicate the feasibility of using mRNA measurement as a parameter to assess cerebral ischemic damage. In addition, based on the differences in the decline in mRNA levels between the ischemia group and the preconditioned ischemia group, it can be concluded that this ischemic tolerance paradigm could offer partial protection (around 45%) against the injury due to the 5 min cerebral ischemic insult.
Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease.
The action of tissue Transglutaminase (TGase) on specific protein-bound glutamine residues plays a critical role in numerous biological processes. Here we provide evidence for a new role of this enzyme in the common, HLA-DQ2 (and DQ8) associated enteropathy, celiac disease (CD). The intestinal inflammation in CD is precipitated by exposure to wheat gliadin in the diet and is associated with increased mucosal activity of TGase. This enzyme has also been identified as the main target for CD-associated anti-endomysium autoantibodies, and is known to accept gliadin as one of its few substrates. We have examined the possibility that TGase could be involved in modulating the reactivity of gliadin specific T cells. This could establish a link between previous reports of the role of TGase in CD and the prevailing view of CD as a T-cell mediated disorder. We found a specific effect of TGase on T-cell recognition of gliadin. This effect was limited to gliadin-specific T cells isolated from intestinal CD lesions. We demonstrate that TGase mediates its effect through an ordered and specific deamidation of gliadins. This deamidation creates an epitope that binds efficiently to DQ2 and is recognized by gut-derived T cells. Generation of epitopes by enzymatic modification is a new mechanism that may be relevant for breaking of tolerance and initiation of autoimmune disease.
The use of remifentanil in general anaesthesia for caesarean section in a patient with mitral valve disease.
We report the use of remifentanil as part of a general anaesthetic technique for a patient with mixed mitral valve disease, asthma and pre-eclampsia presenting for an emergency Caesarean section. The use of remifentanil was associated with stable haemodynamic variables during general anaesthesia. No clinically significant respiratory depression was noted in the neonate.
A population-based study of abdominal wall defects in South Australia and Western Australia.
The purpose of this study was to determine the prevalence, clinical characteristics, prenatal diagnosis and occurrence of other birth defects with abdominal wall defects in births and terminations of pregnancy in South Australia (SA) and Western Australia (WA) over the period 1980-90. Cases of gastroschisis, exomphalos, bladder exstrophy, cloacal exstrophy and body stalk anomaly were ascertained from the WA Birth Defects Registry (1980-90) and the SA Birth Defects Register (1986-90). The registers are comparable population-based data collections with information on livebirths and stillbirths of at least 400 g birthweight or 20 weeks' gestation, and terminations of pregnancy for fetal abnormality. The prevalence of gastroschisis was 1.65/10,000 births (59 cases) and of exomphalos 2.90/10,000 births (104 cases). There was no significant difference in prevalence of exomphalos or gastroschisis between SA and WA for the years 1986-90. However, if data from WA for the years 1980-85 were included, SA had a significantly higher prevalence of exomphalos (prevalence ratio 1.71, confidence interval [CI] 1.16-2.55), although not of gastroschisis (prevalence ratio 1.35, CI 0.79-2.32). Exomphalos was significantly more common in mothers < 20 years (odds ratio [OR] 2.45, CI 1.22-4.86) and in mothers of 40 years or older (OR 5.65, CI 1.69-16.77). Gastroschisis was more common in younger mothers (OR 8.76, CI 4.02-19.32). Both exomphalos and gastroschisis were associated with low birthweight, prematurity, intrauterine growth retardation and caesarean section. The reason for the higher prevalence of exomphalos in SA than WA was not clear, but may be related to differences in prenatal diagnosis. The association between maternal age < 20 years and exomphalos raises the possibility of common factors in the aetiology of gastroschisis and exomphalos.
HLA restriction patterns of gliadin- and astrovirus-specific CD4+ T cells isolated in parallel from the small intestine of celiac disease patients.
Celiac disease is a common HLA-DQ2-associated enteropathy caused by an abnormal T-cell-mediated immune response to ingested wheat gliadin proteins. We have previously isolated in situ activated mucosal T cells from celiac disease patients and demonstrated that these T cells were gliadin specific and predominantly DQ2 restricted. In contrast to this, gliadin-specific T cells isolated from peripheral blood display a variable HLA restriction pattern, thereby indicating that the skewed DQ restriction of T cells resident in the celiac lesions could be dictated by a preference for DQ-mediated antigen presentation in the mucosa of CD patients. To address this, we analyzed the HLA restriction of T cells recognizing astrovirus, a common gastroentetitis virus, isolated from intestinal mucosa of six celiac disease patients. As an internal control, gliadin-specific T cells were isolated and analyzed in parallel. The gliadin-specific mucosal T cells were marked in their DQ2 restriction, whereas the parallel astrovirus-specific T cells were predominantly restricted by DR molecules. Our data indicate that the repertoire of T cells present in celiac lesions is determined by the priming antigen(s) and not by a skewing in the expression of functional HLA class II isotypes in the disease affected small intestinal mucosa.
Morphological studies of baseline needle biopsies from living donor kidneys: light microscopic, immunohistochemical and ultrastructural findings.
Fifty-seven consecutive living donors (31 women and 26 men aged 20.7-72.3 years, mean 50.6 years) were subjected to needle biopsy during nephrectomy, immediately before removal of the kidney. By light microscopy, semiquantitative scoring (0-3) was performed for arteriosclerosis, arteriolar hyalinosis (hyalin arteriolosclerosis), glomerulosclerosis, interstitial mononuclear cell infiltration, and interstitial fibrosis/tubular atrophy. Whereas vascular changes were striking in many biopsies (arteriosclerosis grades 2-3: 28/54 cases, arteriolar hyalinosis grades 2-3: 15/55 cases), glomerular and tubulointerstitial changes were mostly low grade. The morphological changes tended to be more pronounced in middle-aged and older individuals, but, in particular, vascular changes were seen also in the younger age group. Immunofluorescence microscopy revealed glomerular granular staining for IgM in 52.7% of the cases, IgA in 9.1%), IgG in 1.8%, and C3 in 12.7%. The main ultrastructural finding was glomerulosclerosis; one case with diffuse glomerular IgA showed distinct dense deposits, and one case showed similar dense deposits without IgA deposition. Arteriolar wall deposition of C3 was found in 58.2% of the cases, and IgM in 10.9%. Especially C3 occurred both with arteriolar hyalinosis and in arterioles without light microscopic alterations. The observation of significant vascular changes in baseline biopsies is relevant especially in the differential diagnosis of chronic rejection and cyclosporine nephropathy. The immunohistochemical findings strongly indicate the occurrence of immunoglobulins and complement factor C3 in both glomeruli and arterioles without clinical or morphological signs of renal disease. The possible pathophysiological significance of such deposits remains, however, uncertain.
Substance misuse and risk of aggression and offending among the severely mentally ill.
BACKGROUND: The aim of this study was to investigate whether 'dual diagnosis' (substance misuse and severe mental illness) is associated with aggression and offending. METHOD: Twenty-seven people meeting the criteria for both psychotic illness and a substance use disorder and 65 people with psychosis only were interviewed. Case notes were also examined and keyworkers asked to rate substance misuse and aggression. RESULTS: The severity of aggression and offending among this community treatment sample was low. Individuals with a dual diagnosis were significantly more likely than those with psychosis only to report any history of committing an offence (P = 0.001), or recent hostile behaviour (P = 0.001). Keyworkers were more likely to report recent aggression among the dually diagnosed (P = 0.01). Significant differences persisted when we used logistic regression to control for potentially confounding demographic and clinical variables. CONCLUSIONS: Dual diagnosis may be an important factor in aggression and offending among severely mentally ill individuals in inner-city areas. Accurate risk assessment requires examination of substance use.
Polymorphonuclear elastase in human colorectal carcinoma.
proteinases are required for invasion through the extracellular matrix (ECM) during tumor invasion and metastasis. Polymorphonuclear (PMN) elastase can degrade ECM components and modulate other proteinases. In the present study PMN elastase activity was found in tissue extracts from 8 of 15 human colorectal carcinomas. Immunoreactive PMN elastase was demonstrated in all carcinoma biopsies with particular enrichment at the tumor-host interface. Immunofluorescence staining localized immunoreactive PMN elastase mainly to neutrophile granulocytes. The human colon carcinoma cell lines Caco-2 and HT-29 did not express PMN elastase. An interaction between tumor cells and elastase producing leukocytes is suggested.
TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis.
The members of the tumor necrosis factor (TNF) family play pivotal roles in the regulation of the immune system. Here we describe a new ligand in this family, designated TWEAK. The mouse and human versions of this protein are unusually conserved with 93% amino acid identity in the receptor binding domain. The protein was efficiently secreted from cells indicating that, like TNF, TWEAK may have the long range effects of a secreted cytokine. TWEAK transcripts were abundant and found in many tissues, suggesting that TWEAK and TRAIL belong to a new group of widely expressed ligands. Like many members of the TNF family, TWEAK was able to induce interleukin-8 synthesis in a number of cell lines. The human adenocarcinoma cell line, HT29, underwent apoptosis in the presence of both TWEAK and interferon-gamma. Thus, TWEAK resembles many other TNF ligands in the capacity to induce cell death; however, the fact that TWEAK-sensitive cells are relatively rare suggests that TWEAK along with lymphotoxins alpha/beta and possibly CD30L trigger death via a weaker, nondeath domain-dependent mechanism.
Guidelines for human gene nomenclature (1997). HUGO Nomenclature Committee.
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Immunochemical characterization of a novel mitochondrially located protein encoded by a nuclear gene within the DFNB8/10 critical region on 21q22.3.
A novel protein encoded by the C210RF2 gene in chromosomal locus 21q22.3 was characterized by immunochemistry. This chromosomal region is known to contain genes for human diseases such as non-syndromic autosomal recessive deafness (DFNB8/10) and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Polyclonal murine antisera were produced against the multivalent peptides deduced from the amino acid sequence of the polypeptide. Immunological reactivity of the obtained antisera was tested with primary cells or established cell lines. On western blotting, the polyclonal sera recognized a single protein product of 25 Kd expressed in cell lines of epithelial and lymphoid origin. Subsequent immunochemistry of several human tissues indicated the ubiquitous expression of the protein. Immunofluorescence studies and co-staining with a mitochondrial-specific dye suggest the subcellular localization of the protein to mitochondria. Mitochondrial localization is also predicted by computer analysis of the polypeptide sequence. As deafness is known to be caused in some instances by defects in mitochondrial function, C210RF2 is a plausible candidate gene for DFNB8/10.
Suspension of nurse who gave drug on consultant's instructions. Engage staff in programmes to raise ethical awareness.
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