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Biomedical subjects

A King

Publications and source records attributed to A King.

At least 19 recordsLinked to original sources
PubMed2006

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer.

The phenomenon of enhanced glycolysis in tumours has been acknowledged for decades, but biochemical evidence to explain it is only just beginning to emerge. A significant hint as to the triggers and advantages of enhanced glycolysis in tumours was supplied by the recent discovery that succinate dehydrogenase (SDH) and fumarate hydratase (FH) are tumour suppressors and which associated, for the first time, mitochondrial enzymes and their dysfunction with tumorigenesis. Further steps forward showed that the substrates of SDH and FH, succinate and fumarate, respectively, can mediate a 'metabolic signalling' pathway. Succinate or fumarate, which accumulate in mitochondria owing to the inactivation of SDH or FH, leak out to the cytosol, where they inhibit a family of prolyl hydroxylase enzymes (PHDs). Depending on the PHD inhibited, two newly recognized pathways that support tumour maintenance may ensue: affected cells become resistant to certain apoptotic signals and/or activate a pseudohypoxic response that enhances glycolysis and is conveyed by hypoxia-inducible factor.

Fumarate Hydratase↗
PubMed2006

The DNA sequence and biological annotation of human chromosome 1.

The reference sequence for each human chromosome provides the framework for understanding genome function, variation and evolution. Here we report the finished sequence and biological annotation of human chromosome 1. Chromosome 1 is gene-dense, with 3,141 genes and 991 pseudogenes, and many coding sequences overlap. Rearrangements and mutations of chromosome 1 are prevalent in cancer and many other diseases. Patterns of sequence variation reveal signals of recent selection in specific genes that may contribute to human fitness, and also in regions where no function is evident. Fine-scale recombination occurs in hotspots of varying intensity along the sequence, and is enriched near genes. These and other studies of human biology and disease encoded within chromosome 1 are made possible with the highly accurate annotated sequence, as part of the completed set of chromosome sequences that comprise the reference human genome.

Base Sequence↗
PubMed2006

Entamoeba histolytica: comparison of the role of receptors and filamentous actin among various endocytic processes.

Entamoeba histolytica is the causative agent of amoebic dysentery. Uptake of iron is critical for E. histolytica growth and iron-bound human transferrin (holo-transferrin) has been shown to serve as an iron source in vitro. Although a transferrin-binding protein has been identified in E. histolytica, the mechanism by which this iron source is taken up by this pathogen is not well understood. To gain insight into this process, the uptake of fluorescent-dextran, -holo-transferrin, and human red blood cells (hRBCs) was compared. Both dextran and transferrin were taken up in an apparent receptor-independent fashion as compared to hRBCs, which were taken up in a receptor-mediated fashion. Interestingly, the uptake of FITC-dextran and FITC-holo-transferrin differentially relied on an intact actin cytoskeleton suggesting that their internalization routes may be regulated independently.

Actins↗
PubMed2006

Desensitized renal transplant recipients show reduced cellular responses to in vitro challenge.

Intravenous immunoglobulin (IVIG) desensitization protocols permit transplantation of sensitized renal recipients against alloantibody incompatibility barriers. It appears that IVIG induces a sustained down-regulation of alloantibody that facilitates crossmatch compatibility. However, the consequence of desensitization upon cellular immunity has not been addressed. We compared in vitro proliferative responses and cytokine expression between desensitized transplant recipients (IVIG) and non-IVIG-treated patients (controls). Eleven patients who were crossmatch-incompatible with living donors underwent treatment with IVIG and plasmapheresis. Nine patients converted to negative crossmatches and were transplanted. With a mean follow-up time of 17.6 +/- 6.7 months, graft survival is 100%. Peripheral mononuclear cells were collected 12.5 +/- 9 months after transplantation and tested for proliferative response and cytokine elaboration following challenge with staphylococcal enterotoxin b (SEB) and donor-specific mixed lymphocyte reaction (dMLR). Proliferative reactions were 90% lower (P < .05) among IVIG versus controls in response to SEB and dMLR challenge. Cytokine response to SEB challenge was equivalent (P = NS) between IVIG and controls. In contrast, cytokine elaboration was 60% lower (P < .05) for IVIG versus controls in response to dMLR. One year after renal transplantation, desensitized patients showed in vitro hyporesponsiveness to superantigen and donor-specific challenge. This suggests that IVIG promotes a down-regulation in cellular immunity that may facilitate good graft outcome.

Cytotoxicity, Immunologic↗
PubMed2005

An origin for short gamma-ray bursts unassociated with current star formation.

Two short (< 2 s) gamma-ray bursts (GRBs) have recently been localized and fading afterglow counterparts detected. The combination of these two results left unclear the nature of the host galaxies of the bursts, because one was a star-forming dwarf, while the other was probably an elliptical galaxy. Here we report the X-ray localization of a short burst (GRB 050724) with unusual gamma-ray and X-ray properties. The X-ray afterglow lies off the centre of an elliptical galaxy at a redshift of z = 0.258 (ref. 5), coincident with the position determined by ground-based optical and radio observations. The low level of star formation typical for elliptical galaxies makes it unlikely that the burst originated in a supernova explosion. A supernova origin was also ruled out for GRB 050709 (refs 3, 31), even though that burst took place in a galaxy with current star formation. The isotropic energy for the short bursts is 2-3 orders of magnitude lower than that for the long bursts. Our results therefore suggest that an alternative source of bursts--the coalescence of binary systems of neutron stars or a neutron star-black hole pair--are the progenitors of short bursts.

Journal Article↗
PubMed2005

Islet transplantation outcomes in mice are better with fresh islets and exendin-4 treatment.

AIMS/HYPOTHESIS: Although islet transplantation in diabetes holds great promise, two or three donor pancreases are usually required to achieve normoglycaemia in human or rodent recipients. We investigated whether there were differences between fresh and cultured islets in terms of transplantation outcome. We also investigated the effects of normoglycaemia during engraftment and the effects of exendin-4, a glucagon-like peptide-1 receptor agonist, on islet transplantation. MATERIALS AND METHODS: Seventy-five fresh islets were transplanted to the right kidney of diabetic mice and 425 fresh islets were transplanted to the left kidney. The mice were treated with exendin-4 or vehicle for 14 days, after which the large graft was removed by left nephrectomy. In a separate set of experiments, islets cultured in the presence or absence of exendin-4 for 72 h, or fresh islets, were transplanted to diabetic mice. In both sets of experiments, blood glucose levels were monitored. RESULTS: Compared with cultured islets, fresh islets were more effective at reversing hyperglycaemia in mice. The treatment of the recipient mice with exendin-4 did not have beneficial effects on glucose homeostasis. However, when islets are cultured, exendin-4 treatment increases the rate of reversal of hyperglycaemia, but not to the degree of fresh islets. CONCLUSIONS/INTERPRETATION: Fresh islets are more effective than cultured islets at reversing hyperglycaemia. Exendin-4 has beneficial effects on islet transplantation.

Animals↗
PubMed2005

Distraction techniques for schizophrenia.

BACKGROUND: Distraction techniques are a form of coping strategies used in cognitive behavioural techniques. They may be of value as an adjunctive treatment for people with schizophrenia or schizophrenia-like illnesses. OBJECTIVES: To review the effects of distraction techniques for people with schizophrenia. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group's Register (October 2003), manually searched reference lists and contacted relevant authors. SELECTION CRITERIA: We included all randomised controlled trials comparing distraction techniques with other treatments for schizophrenia. DATA COLLECTION AND ANALYSIS: We reliably selected, quality assessed and data extracted studies. We excluded data where more than 50% of participants in any group were lost to follow up. For binary outcomes, we calculated a fixed effects risk ratio (RR) and its 95% confidence interval (CI), along with the number needed to treat/harm (NNT/H). For continuous data we calculated the weighted mean difference (WMD). MAIN RESULTS: In terms of mental state, distraction techniques did not have a clear effect (n=60, 1 RCT, MD endpoint BPRS 1.60 CI -0.49 to 3.69). Distraction does not obviously engage people in the studies (n=159, 5 RCTs, RR leaving the study before completion 1.08 CI 0.72 to 1.63). AUTHORS' CONCLUSIONS: Clinicians, researchers, policy makers and recipients of care cannot be confident of the effects of distraction techniques from the findings of this review. The few pioneering studies are small, short and poorly reported. Further data from already completed trials might help inform practice, but more trials do seem to be justified as some of these potentially simple techniques, even if their effect is negligible, could be widely implemented and prove more acceptable than other more intrusive treatments.

Adaptation, Psychological↗
PubMed2005

Anxiety and depression in the acute porphyrias.

A previous study of self-rated psychosocial aspects in patients with acute porphyria found that depression, and particularly anxiety, is more common in porphyria patients than in the general population or general medical outpatient attenders. Nearly half of the sample (46%) reported at least some problem with anxiety and/or depression: anxiety caseness was 26% and depression caseness was 13%. This paper extends our previous observations and investigates further the associations between porphyria and anxiety, depression and general mental health in 90 patients (58 acute intermittent porphyria, 32 variegate porphyria). The findings of this study confirm that anxiety is raised in patients with acute intermittent porphyria and with variegate porphyria, in both males and females, compared to the normative population and, using a series of questionnaires exploring the physical and psychosocial features of anxiety, that this anxiety is experienced as a 'relatively stable personality trait', rather than a 'transitory emotional state' (i.e. intrinsic rather than secondary to the porphyria).

Anxiety↗
PubMed2005

Management of the patient and family with neurofibromatosis 2: a consensus conference statement.

A consensus conference on neurofibromatosis 2 (NF2) was held in 2002 at the request of the United Kingdom (UK) Neurofibromatosis Association, with particular emphasis on vestibular schwannoma (VS) surgery. NF2 patients should be managed at specialty treatment centres, whose staff has extensive experience with the disease. All NF2 patients and their families should have access to genetic testing because presymptomatic diagnosis improves the clinical management of the disease. Some clinical manifestations of NF2, such as ocular abnormalities, can be detected in infancy; therefore, clinical screening for at-risk members of NF2 families can start at birth, with the first magnetic resonance (MRI) scan at 10-12 years of age. Minimal interference, maintenance of quality of life, and conservation of function or auditory rehabilitation are the cornerstones of NF2 management, and the decision points to achieve these goals for patients with different clinical presentations are discussed.

Adult↗
PubMed2005

The hip trial: psychosocial consequences for mothers of using ultrasound to manage infants with developmental hip dysplasia.

BACKGROUND: The hip trial aimed to assess clinical effectiveness, economic and psychosocial costs, and benefits of ultrasound imaging (US) compared with conventional clinical assessment alone to guide the management of infants with neonatal hip instability. OBJECTIVE: To report on psychosocial consequences for mothers and the developing mother-child relationship of US, and associations between abduction splinting and maternal psychosocial distress. DESIGN: Multicentre randomised controlled trial. SETTING: Thirty three hospitals in the United Kingdom and Ireland. PARTICIPANTS, INTERVENTIONS: A total of 629 infants with neonatal hip instability randomised to US examination or clinical assessment alone before treatment decision. Questionnaires were completed by 561 (89%) mothers at 8 weeks and 494 (79%) at 1 year. MAIN OUTCOME MEASURES: Anxiety, postnatal depression, parenting stress assessed by standardised questionnaires. Maternal concerns about hip problems were assessed using the Infant hip worries inventory. RESULTS: At 8 weeks, there were no differences between US and non-US groups of the trial in maternal anxiety (mean difference (MD) -1.2, 95% confidence interval (CI) -3.2 to 0.8), depression (MD 0.0, 95% CI -0.7 to 0.8), parenting stress (MD -1.2, 95% CI -2.8 to 0.4), or other measures. The same pattern was evident at 1 year. In an explanatory analysis, early splinting was associated with increased anxiety at 8 weeks (MD 3.8, 95% CI 1.7 to 5.9) and increased level of hip worries at 8 weeks (MD 6.8, 95% CI 5.6 to 7.9) and 1 year (MD 1.3, 95% CI 0.3 to 2.4). CONCLUSIONS: Although early splinting is associated with maternal anxieties, US is not associated with any increase or reduction in psychosocial effects on mothers. Together with the clinical findings, this suggests that the use of US allows reduction in splinting rates without increased risk of adverse clinical or psychosocial outcomes.

Adult↗
PubMed2005

Gastric ciliated metaplasia. A study of 3406 gastrectomy specimens from dwellers of the Atlantic and the Pacific basins.

BACKGROUND: Ciliated cells in gastrectomies from patients dwelling in the Pacific and Atlantic basins have been reported previously. AIM: To compare all the results in an attempt to explain the findings. METHODS: Sections from 3406 gastrectomies were reviewed: 1966 and 1440 from the Atlantic and Pacific basins, respectively. Ciliated cells and intestinal metaplasia (IM) were recorded; IM was classified into focal or extensive IM. The total number of sections/gastrectomy was noted. RESULTS: In the Atlantic basin, 5% of specimens had ciliated metaplasia (CM); it was more frequent in intestinal carcinoma (IC; 9%) than diffuse carcinoma (DC; 3%) or miscellaneous gastric diseases (MGD; 3%). In the Pacific basin, the frequency of specimens with CM was 29%: it was more frequent in IC (43%) than in DC (16%) or MGD (10%). The difference between the frequency of CM in specimens with IC or with DC/MGD in the Atlantic and the Pacific basins was significant (p < or = 0.05). The presence of CM was influenced by age and the extent of IM in both basins, but not by sex or the number of sections investigated. CONCLUSIONS: CM-apparently an independent microscopic marker-was significantly higher in the Pacific than in the Atlantic basin. Environmental carcinogens involved in the evolution of IM and IC seem to be implicated in gastric ciliogenesis. Carcinogens that differ in nature and/or in strength in both basins might activate the latent natural genes encoding ciliated processes in gastric cells in patients subsequently developing gastric carcinoma, more notably of intestinal type.

Adult↗
PubMed2005

Extensive intestinal metaplasia in gastric carcinoma and in other lesions requiring surgery: a study of 3,421 gastrectomy specimens from dwellers of the Atlantic and Pacific basins.

BACKGROUND: Extensive intestinal metaplasia (EIM) has been reported in gastrectomies from patients dwelling in the Pacific and Atlantic basins. AIMS: To compare all the results in an attempt to explain the findings. METHOD: All sections from 3,421 gastrectomies were reviewed at various hospitals: 1946 in the Atlantic and 1475 in the Pacific basin. Sections with EIM showed IM encompassing one or more entire low power field (>or=5 mm in length/section) in one or more section. RESULTS: In the Atlantic basin, EIM was present in 18.8% (153 of 814) of specimens with intestinal carcinoma (IC) and in 10.3% (65 of 630) of those with diffuse carcinoma (DC). In the Pacific basin, EIM was found in 62.9% (412 of 655) of gastrectomies with IC and in 33.3% (160 of 481) of those with DC. The numbers of specimens with EIM were significantly higher in the Pacific than in the Atlantic basin for both carcinoma phenotypes, particularly among elderly patients (>or=60 years). CONCLUSIONS: The proportion of gastrectomies with EIM was higher among populations at a higher gastric cancer risk than in those with a lower cancer risk. EIM was mostly associated with IC rather than DC or with miscellaneous gastric diseases (841 control gastrectomies) in both basins. The proportion of gastrectomies with EIM was significantly higher in Vancouver than in New York and in Santiago de Chile than in Buenos Aires, even though these populations reside at approximately the same geographical latitude, but in different basins. Environmental factors seem to accelerate the evolution of EIM.

Age Factors↗
PubMed2005

Multiple meningiomas: differential involvement of the NF2 gene in children and adults.

OBJECTIVE: To screen for NF2 mutations in people with meningiomas. METHODS: Lymphocyte or tumour DNA was analysed from 46 individuals from 36 families who presented with a meningioma at age < or =15 years without vestibular schwannoma (VS), or who had multiple meningiomas in adulthood before the diagnosis of VS. RESULTS: Eight of 13 people with meningioma and other features of neurofibromatosis 2 (NF2) had an identified constitutional NF2 mutation in blood DNA, but none of the other subjects had identified constitutional NF2 mutations. CONCLUSIONS: Constitutional NF2 mutations are the most likely cause of meningioma in children and in people with a meningioma plus other non-VS features of NF2. Mosaic NF2 may be the cause of about 8% of multiple meningiomas in sporadic adult cases, but there are other causes in the majority of other such patients and in multiple meningioma in families.

Adolescent↗
PubMed2005

Gastric glassy cells: a study of 3202 gastrectomy specimens from dwellers of the Atlantic and Pacific basins.

Fifteen years ago we detected gastric cells with glassy cytoplasm (GCs) in the human pyloric antrum. The frequency of these cells was subsequently investigated in sections from gastrectomies carried on in populations dwelling on the rim of the Atlantic and Pacific basins. In this work we compared the results obtained in these disparate geographic regions. We reviewed sections from 3203 gastrectomies (1942 in the Atlantic basin and 1261 in the Pacific basin). In the Atlantic basin 12/1942 (0.6%) of the gastrectomies had GCs, whereas in the Pacific basin 26/1261 (2.1%) of the gastrectomies had GCs. The difference was significant (p<0.05). The proportion of gastrectomies with GCs was higher in patients in Vancouver, Canada, than in New York, and higher in Santiago de Chile than in Buenos Aires, despite the fact that these populations reside at approximately the same geographic latitude. Previous studies with the same material indicated that both the extension of intestinal metaplasia and the frequency of ciliated metaplasia were significantly higher in the Pacific than in the Atlantic basin. Hence, the difference in the frequencies of GCs appears to be a new indication that dissimilar environmental exposures in the two basins might have influenced the histological make-up of the gastric mucosa.

Aged↗
PubMed2004

DNA sequence and analysis of human chromosome 9.

Chromosome 9 is highly structurally polymorphic. It contains the largest autosomal block of heterochromatin, which is heteromorphic in 6-8% of humans, whereas pericentric inversions occur in more than 1% of the population. The finished euchromatic sequence of chromosome 9 comprises 109,044,351 base pairs and represents >99.6% of the region. Analysis of the sequence reveals many intra- and interchromosomal duplications, including segmental duplications adjacent to both the centromere and the large heterochromatic block. We have annotated 1,149 genes, including genes implicated in male-to-female sex reversal, cancer and neurodegenerative disease, and 426 pseudogenes. The chromosome contains the largest interferon gene cluster in the human genome. There is also a region of exceptionally high gene and G + C content including genes paralogous to those in the major histocompatibility complex. We have also detected recently duplicated genes that exhibit different rates of sequence divergence, presumably reflecting natural selection.

Base Composition↗
PubMed2004

Melanoma cell migration is upregulated by tumour necrosis factor-alpha and suppressed by alpha-melanocyte-stimulating hormone.

We reported recently that the inflammatory cytokine tumour necrosis factor alpha (TNF-alpha) can upregulate integrin expression, cell attachment and invasion of cells through fibronectin in a human melanoma cell line (HBL). Furthermore, the actions of TNF-alpha were suppressed by the addition of an anti-inflammatory peptide alpha-melanocyte-stimulating hormone (alpha-MSH). In the current study, we extend this work investigating to what extent TNF-alpha might stimulate melanoma invasion by promoting cell migration and whether alpha-MSH is also inhibitory. Two human melanoma cell lines were examined in vitro (HBL and C8161) using a scratch migration assay. Analysis using either time-lapse video microscopy or imaging software analysis of migrating 'fronts' of cells revealed that C8161 cells migrated more rapidly than HBL cells. However, when cells were stimulated with TNF-alpha both cell types responded with a significant increase in migration distance over a 16-26 h incubation time. alpha-Melanocyte-stimulating hormone had an inhibitory effect on TNF-alpha-stimulated migration for HBL cells, completely blocking migration at 10(-9) M. In contrast, C8161 cells did not respond to alpha-MSH (as these cells have a loss-of-function melanocortin-1 receptor). However, stable transfection of C8161 cells with the wild-type melanocortin-1 receptor produced cells whose migration was significantly inhibited by alpha-MSH. In addition, the use of a neutralising antibody to the beta(1)-integrin subunit significantly reduced migration in both cell types. This data therefore supports an inflammatory environment promoting melanoma cell migration, and in addition shows that alpha-MSH can inhibit inflammatory stimulated migration. The data also support a fundamental role of the beta(1)-integrin receptor in melanoma cell migration.

Cell Movement↗
PubMed2004

The DNA sequence and analysis of human chromosome 13.

Chromosome 13 is the largest acrocentric human chromosome. It carries genes involved in cancer including the breast cancer type 2 (BRCA2) and retinoblastoma (RB1) genes, is frequently rearranged in B-cell chronic lymphocytic leukaemia, and contains the DAOA locus associated with bipolar disorder and schizophrenia. We describe completion and analysis of 95.5 megabases (Mb) of sequence from chromosome 13, which contains 633 genes and 296 pseudogenes. We estimate that more than 95.4% of the protein-coding genes of this chromosome have been identified, on the basis of comparison with other vertebrate genome sequences. Additionally, 105 putative non-coding RNA genes were found. Chromosome 13 has one of the lowest gene densities (6.5 genes per Mb) among human chromosomes, and contains a central region of 38 Mb where the gene density drops to only 3.1 genes per Mb.

Chromosome Mapping↗