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Biomedical subjects

H Hodgson

Publications and source records attributed to H Hodgson.

At least 19 recordsLinked to original sources
PubMed2002

IL-10 gene therapy prevents TNBS-induced colitis.

The transfer of genes encoding immunomodulatory proteins to the intestinal mucosa is a promising new approach to the treatment of Crohn's disease (CD). This study investigates the therapeutic efficacy of an adenoviral vector encoding IL-10 (AdvmuIL-10) in experimental colitis. BALB/c mice were treated with a single intravenous injection of AdvmuIL-10, empty cassette virus (Adv0) or PBS prior to the induction of trinitrobenzene sulphonic acid (TNBS) colitis. AdvmuIL-10 treatment prevented the severe loss of body weight associated with TNBS administration. In addition, AdvmuIL-10 therapy led to a significant reduction in both stool markers of inflammation (IL-1beta and TNFR-II) and acute phase response (serum amyloid protein). Finally, the histological scores of mice with TNBS colitis treated with AdvmuIL-10 were significantly lower than Adv0- or PBS-treated controls. The therapeutic efficacy of AdvmuIL-10 was associated with a decrease in the IFN-gamma and IL-6 levels detected in colonic homogenates from mice with TNBS colitis, whereas no effect was observed on cytokine release from stimulated systemic lymphocytes. Thus, AdvmuIL-10 is an effective therapy in the TNBS model of colitis. Gene therapy strategies using adenoviral vectors encoding IL-10 may prove to be a potent therapy for chronic inflammatory conditions such as CD.

Adenoviridae↗
PubMed2002

The relationship between the thyroid gland and the liver.

Thyroxine and tri-iodothyronine are essential for normal organ growth, development and function. These hormones regulate the basal metabolic rate of all cells, including hepatocytes, and thereby modulate hepatic function; the liver in turn metabolizes the thyroid hormones and regulates their systemic endocrine effects. Thyroid dysfunction may perturb liver function, liver disease modulates thyroid hormone metabolism, and a variety of systemic diseases affect both organs. We highlight the intricate relations between the thyroid gland and the liver in health and disease.

Chronic Disease↗
PubMed2001

Clinical management of acute hepatic failure.

Acute hepatic failure is a rare clinical syndrome associated with high mortality. Hepatic failure leads to a well-recognised pattern of clinical signs and symptoms, sometimes with rapid deterioration and progression to multi-organ failure. Early recognition of this syndrome is essential for appropriate treatment; once identified, patients benefit from early interventional support and treatment in the intensive care unit. Aggressive management may allow stabilisation of patients before their transfer to specialist liver units. At present, orthotopic liver transplantation is the only treatment modality that provides significant improvement in outcome. This review examines the aetiology and clinical presentation of acute hepatic failure, providing guidelines regarding patient management. We present a critical appraisal of specific clinical areas, including the management of cardiovascular, cerebral, renal, coagulopathic and infective complications. Liver transplantation is discussed as well as emerging therapies including non-biological and hybrid liver support systems that may provide a "bridge to transplantation".

Brain Edema↗
PubMed2001

Human hepatocyte cell lines proliferating as cohesive spheroid colonies in alginate markedly upregulate both synthetic and detoxificatory liver function.

BACKGROUND/AIMS: Bio-artificial liver support systems for treatment of hepatic failure require maintained expression of hepatocyte function in vitro. We studied cultures of human hepatocyte cell-lines proliferating within alginate beads, investigating the hypothesis that 3-dimensional cohesive colonies of hepatocyte cell-lines would achieve polarity and cell-to-cell contact resulting in upregulation of function. METHODS: HepG2 and HHY41 human cell lines in alginate beads were cultured for >20 days. RESULTS: Proliferation was maintained for 20 days. Production of albumin, prothrombin, fibrinogen, alpha-1-acid glycoprotein and alpha-1-antitrypsin was maintained throughout, maximal at days 8-10, when upregulation was 300-1100% compared with monolayer cultures at similar cell number per unit volume. Detoxificatory functions: ethoxyresorufin deethylase activity, androstenedione metabolism, and urea synthesis from arginine was also increased several-fold. Function returned to pre-freezing levels within 18 h of thawing after cryopreservation of cells in alginate. Electron microscopy revealed spherical colonies of cells of cuboidal shape, with cell-to-cell contact via desmosomes and junctional complexes, abundant microvilli, and cytoplasmic appearances suggesting transcriptionally active hepatocytes. CONCLUSION: Hepatocyte cell-lines, proliferating in alginate express a range of liver-specific functions at levels approaching those found in vivo, relevant to their use in liver support systems.

Alginates↗
PubMed2001

Vascular malformations of the gastrointestinal tract.

Vascular malformations of the gastrointestinal tract may be diagnosed at any age. They may present with bleeding, anaemia, or if they form a mass lesion, with intussusception. Many lesions remain asymptomatic. In a minority of patients there are well-defined genetic conditions present, such as hereditary haemorrhagic telangiectasia. In others, particularly the angiodysplastic lesions that occur in the caecum in elderly patients, the lesions appear to be degenerative. Vascular malformations may affect any section of the gastrointestinal tract, and in some patients there are vascular anomalies elsewhere, particularly in the skin. Diagnosis is usually based on recognition endoscopically, or at angiography. Symptomatic lesions that are discrete and localized respond well to local treatment with laser or heat coagulation or sclerotherapy. Mass lesions, diffuse lesions and severe bleeding may require surgery.

Aged↗
PubMed2000

Three dimensional culture upregulates extracellular matrix protein expression in human liver cell lines--a step towards mimicking the liver in vivo?

Extracellular matrix (ECM) in the liver affects the phenotype of both hepatocytes and non-parenchymal cells. To be able to mimic in vivo liver function for extracorporeal hepatic support using human cell lines, a necessary step is to upregulate the function normally seen in monolayer culture. 3-D spheroid colonies were formed by culturing single HepG2 cells encapsulated in alginate beads. ECM expression in these cultures was compared to monolayer Hep G2 cultures. The following ECM proteins were detected immunohistochemically:- collagens 1, III, V and VI, the glycoproteins fibronectin, tenascin and vitronectin, and the basement membrane protein laminin. In 3-D cultures, all proteins except tenascin were strongly expressed, as compared with weak or undetectable expression in monolayer cultures, even with 10-fold increases in the antibody concentration used. In conclusion, we have demonstrated that the 3-D environment created by alginate encapsulation of cell lines leads to cell behaviour mimicking that in vivo.

Cells, Cultured↗
PubMed1999

Three-dimensional in vitro cell culture leads to a marked upregulation of cell function in human hepatocyte cell lines--an important tool for the development of a bioartificial liver machine.

Upregulating hepatocyte function in proliferating human liver cell lines could provide cells for a bio-artificial liver. Ideally, a means of mimicking the biological extracellular matrix with a relatively inert, bio-compatible matrix is required. Alginate encapsulation of primary hepatocytes is biocompatible. This study aimed to characterize cells grown in a 3D configuration in alginate. A human-derived liver cell line encapsulated in 1% alginate was assessed for synthetic and detoxification functions. Secreted proteins measured (e.g., albumin, fibrinogen, alpha-1-antitrypsin etc.) were increased in alginate compared with monolayers. Cytochrome P450 1A1 activity increased three- to fourfold, whilst urea synthesis, undetectable in monolayer cultures, was synthesized by cells in alginate at levels approaching in vivo production. TEM revealed good ultrastructure reminiscent of normal hepatocytes. Alginate promotes 3D colonies of proliferating cells with upregulated liver functions. Rapid recovery of function of cryopreserved cells (< 18 h) provides added advantages for this system to support the biological component of an artificial liver for patients with fulminant hepatic failure.

Cell Culture Techniques↗
PubMed1999

Behavior of a cell line derived from normal human hepatocytes on non-physiological and physiological-type substrates: evidence for enhancement of secretion of liver-specific proteins by a three-dimensional growth pattern.

The behavior of a recently described cell line, HH25, derived from normal human hepatocytes, has been investigated on several different substrates--tissue-culture plastic, glass, a thin layer of rat-tail collagen I, and thin layers or thick gels of extracellular matrix derived from the Engelbreth-Holm-Swarm murine sarcoma (EHS matrix). Cellular morphology, proliferation, and secretion of three hepatocyte-specific proteins (albumin, alpha1 acid glycoprotein, and alpha1 antitrypsin) have been examined. There were no differences in morphology, proliferation, or differentiated function in the cells on either plastic, glass, collagen, I, or a thin layer of EHS matrix, but on a thick EHS matrix gel the cells altered their morphology (forming three-dimensional colonies with canalicular-like structures) and their production of albumin and alpha1 acid glycoprotein was enhanced. This suggests that the enhanced differentiated function is associated with the morphological change (occurring only on the thick EHS gel) rather than with receptor-mediated cell-matrix interactions (which can also occur on the thin layer of EHS matrix). This cell line is therefore a good in vitro cellular model for the investigation of the roles of morphological changes and of cell-cell and cell-matrix interactions in the control of human hepatocyte behavior without the need for an extensive source of primary tissue.

Albumins↗
PubMed1998

Comparison of three solid phase supports for promoting three-dimensional growth and function of human liver cell lines.

An extracorporeal liver support system will require that liver cells maintain their normal differentiated function. This is more likely to be achieved utilizing a three-dimensional culture configuration rather than a simple monolayer culture. We present data on a human liver cell line attached and maintained on different three-dimensional supports, porous glass (Siran), silicon (Immobasil), and calcium-alginate beads. Albumin, fibrinogen, prothrombin, alpha1-acid glycoprotein and alpha1-antitrypsin secretions were measured. Proliferation was slower on each of the three-dimensional supports than on the monolayer culture. The protein secretion of all 5 proteins was highest in cells encapsulated in alginate; silicon beads supported greater protein secretion than glass. Cells on silicon or within alginate were rounded; those on glass grew in 2 configurations as flattened monolayers and as rounded colonies. Cells in alginate secreted as much protein as the whole liver (e.g., albumin, 14.88 g/10(12) cells/day compared to the whole liver, approximately 12 g/day). Three-dimensional culture of a human liver cell line leads to both proliferation and a high synthetic capacity, an important feature of cells suitable for an extracorporeal liver support system.

Albumins↗
PubMed1997

Nonparenchymal cells from regenerating rat liver generate interleukin-1alpha and -1beta: a mechanism of negative regulation of hepatocyte proliferation.

Following experimental partial hepatectomy of 70% in the rat, there is a semisynchronized surge of hepatocyte proliferation that ceases after 48 to 72 hours. Little is known about the determinants governing the termination of the proliferative phase, although transforming growth factor (TGF) beta has been implicated as an important inhibitor of hepatocyte replication in this model. We previously reported an additional non-TGF-beta inhibitor in medium conditioned by nonparenchymal cells isolated from regenerating liver (CM-NPC-Reg) between 24 and 48 hours after partial hepatectomy, but it was not found in medium conditioned by nonparenchymal cells from unoperated control liver. CM-NPC-Reg suppressed replicative DNA synthesis of primary rat hepatocytes in response to hepatocyte growth factor (HGF), epidermal growth factor (EGF), or TGF-alpha as assessed by 3H-thymidine incorporation. We now present evidence that interleukin (IL)-1 is the major inhibitor of hepatocyte DNA synthesis present in CM-NPC-Reg. IL-1 receptor antagonist abrogated the inhibition, as did antibodies to rat IL-1alpha and -beta; a combination of both antibodies was required, implicating both IL-1alpha and IL-1beta as active constituents in CM-NPC-Reg. To investigate in vivo changes in IL-1 expression, we assessed expression of IL-1alpha messenger RNA (mRNA) in whole rat liver following partial hepatectomy; mRNA was down-regulated at 10 hours in the pre-replicative phase of liver regeneration and up-regulated at 24 hours and 48 hours when proliferation is waning. Rat hepatocytes isolated from liver 24 hours after partial hepatectomy showed increased sensitivity to the inhibitory action of IL-1. Exogenous IL-1beta, administered parenterally to a group of rats at 0 and 12 hours after partial hepatectomy significantly reduced the incorporation of the thymidine analogue, bromodeoxyuridine (BrdU), into hepatocytes at 18 hours. These data indicate that nonparenchymal cells isolated from regenerating rat liver elaborate IL-1, and support the hypothesis that IL-1 plays a role suppressing hepatocyte proliferation and terminating the surge of DNA synthesis induced after partial hepatectomy.

Animals↗
PubMed1997

Pain relief with oral cannabinoids in familial Mediterranean fever.

Cannabinoids have analgesic and, possibly, anti-inflammatory properties but their clinical use has been restricted by legislation. This is the first United Kingdom report of the controlled use of a standardised pharmaceutical preparation of cannabinoids in capsular form. The therapy was assessed in a patient with familial Mediterranean fever, who presented with chronic relapsing pain and inflammation of gastrointestinal origin. After determining a suitable analgesic dosage, a double-blind placebo-controlled cross-over trial was conducted using 50 mg tetrahydrocannabinol daily in five doses in the active weeks and measuring effects on parameters of inflammation and pain. Although no anti-inflammatory effects of tetrahydrocannabinol were detected during the trial, a highly significant reduction (p < 0.001) in additional analgesic requirements was achieved. Future study designs can now incorporate prescribable forms of cannabinoids but the choice of previous cannabis users only as patients has clinical limitations. Cannabis naive patients would tolerate controlled investigations but may generate medicolegal problems.

Administration, Oral↗
PubMed1996

Budesonide prolongs time to relapse in ileal and ileocaecal Crohn's disease. A placebo controlled one year study.

BACKGROUND AND AIMS: To evaluate the efficacy and safety of the topical corticosteroid budesonide, given in an oral controlled release formulation for maintenance of remission in patients with ileal and ileocaecal Crohn's disease (CD). PATIENTS AND METHODS: Out of 176 patients with active CD who had achieved remission (CD activity index score < or = 150) after 10 weeks' treatment with either budesonide or prednisolone, 90 were randomised to continue with once daily treatment of 6 mg budesonide, or 3 mg budesonide or placebo for up to 12 months in a double blind, multicentre trial. Time to symptomatic relapse was calculated using Kaplan-Meier estimates. Morning plasma cortisol was measured at clinic visits and a corticotropin stimulation test was performed after three months of treatment. RESULTS: Thirty two patients were allocated to the 6 mg budesonide group, 31 to the 3 mg group, and 27 to the placebo group. After three months, 19 per cent of the patients in the 6 mg group had relapsed, compared with 45 per cent in the 3 mg group and 44 per cent in the placebo group (p = 0.047). The corresponding results after 12 months was 59 per cent in the 6 mg budesonide group, 74 per cent in the 3 mg group, and 63 per cent in the placebo group (p = 0.44). The median time to relapse or discontinuation was 258 days in the 6 mg group, 139 days in the 3 mg group, and 92 days in the placebo group (p = 0.021). Mean morning plasma cortisol values increased from entry in all three groups with no statistically significant differences at 12 months. All 13 patients remaining in the placebo group after three months had a normal corticotropin stimulation response, compared with 18 of 23 patients in the 6 mg, and 19 of 21 in the 3 mg budesonide groups (p = 0.14). Acne and moon face were slightly more common in the budesonide groups. CONCLUSION: 6 mg budesonide once daily is significantly more efficacious than placebo in prolonging time to relapse in CD, and causes only minor systemic side effects.

Administration, Oral↗
PubMed1994

Carcinoid heart disease: early failure of an allograft valve replacement.

A woman who had carcinoid syndrome and carcinoid heart disease underwent tricuspid and pulmonary valve replacements with a xenograft and a cryopreserved allograft, respectively. Within 3 months of the operation severe pulmonary regurgitation and pulmonary hypertension refractory to medical therapy developed. Autopsy found the biomechanical tricuspid valve to be free of disease but the allograft in the pulmonary position was involved by carcinoid heart disease in a fashion similar to the excised native pulmonary valve.

Carcinoid Heart Disease↗
PubMed1991

Morphometry and cell proliferation in endoscopic biopsies: evaluation of a technique.

A simple method for the quantification of intestinal epithelial cell proliferation in humans was evaluated. Endoscopic biopsy specimens were stained and microdissected, and the number of mitoses per gland or crypt was determined, as was the area of these units. The technique could readily be applied to tissue from the stomach, small intestine colon, and rectum. The number of mitoses and the size of the proliferative compartments increased caudally from the stomach to the cecum in humans. There was a good correlation between area and mitoses per gland or per crypt (r = 0.89; P less than 0.001), confirming the general equivalence between proliferative rate and compartment size. The method was validated by comparing microdissection-derived data with data previously obtained as part of an autoradiography-based study in the dog. This showed that similar differences in proliferation and crypt cell mass could be obtained but in less than one sixth of the time taken to score autoradiographs. It is concluded that this method for the estimation of gastrointestinal epithelial proliferation correlates well with other well-established techniques, confers speed as well as accuracy, has an all encompassing denominator, and can thus avoid many of the problems associated with the quantification of tissue sections.

Animals↗