Hepatocyte transplantation: emerging insights into mechanisms of liver repopulation and their relevance to potential therapies.
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Animals↗
Biomedical subjects
S Gupta
Publications and source records attributed to S Gupta.
Population structure of pathogens: the role of immune selection.
Sunetra Gupta and Roy Anderson discuss how the balance between host immune responses against conserved and variable antigens shapes the population structure of pathogens. At one extreme, immune selection against polymorphic determinants can cause pathogen populations to self-organize spontaneously into discrete antigenic types that may either be maintained over long periods or undergo cyclical or chaotic fluctuations. At the other extreme, diversity may be drastically reduced by competition induced by a strong immune response against a conserved determinant. Where does each pathogen lie along this continuum? How would this knowledge influence our attempts to control an infectious disease?
Alleles↗
Chimeric peptide of Met-enkephalin and FMRFa induces antinociception and attenuates development of tolerance to morphine antinociception.
A synthetic chimeric peptide of Met-enkephalin and FMRFamide (YGGFMKKKFMRFa), based on MERF was synthesized. This peptide was tested for possible antinociceptive effects using the tail flick test in mice. The effect of the chimeric peptide on morphine antinociception and development of tolerance to the antinociceptive action of morphine was also investigated. The chimeric peptide produced significant, dose-dependent antinociception (40, 60 and 90 mg/kg) in the tail flick test. Pretreatment with naloxone (5 mg/kg, IP) significantly attenuated the antinociceptive effect induced by the chimeric peptide (90 mg/kg, IP), indicating involvement of an opioidergic mechanism. In combination experiments with morphine, the antinociceptive dose of the chimeric peptide (60 mg/kg, IP) potentiated morphine (7 mg/kg, IP) antinociception. A low dose of the chimeric peptide (10 mg/kg, IP), that did not produce significant antinociception on its own, also potentiated morphine antinociception. In the tolerance studies, male albino mice received twice daily injections of morphine (20 mg/kg, IP) followed by either saline (0.1 ml) or chimeric peptide (80 mg/kg, IP) for a period of 4 days. A control group received twice daily injections of saline (0.1 ml) for the same period. When tested on Day 5, tolerance to antinociceptive action of morphine (15 mg/kg, IP) was evidenced by decreased response in chronic morphine plus saline treated mice compared to control group. Concurrent administration of chimeric peptide (80 mg/kg, IP) with morphine significantly attenuated the development of tolerance to the antinociceptive action of morphine. The preliminary results of this study demonstrate that peripherally administered chimeric peptide can produce dose dependent, naloxone reversible, antinociception; potentiate morphine antinociception and attenuate morphine tolerance, indicating a possible role of these type of amphiactive sequences in antinociception and its modulation. These chimeric peptides may also prove to be useful tools for further ascertaining the role of FMRFa family of peptides in mechanisms leading to opiate tolerance and dependence.
Analgesics↗
Factors associated with inadequate blood pressure control in hypertensive hemodialysis patients.
Hypertension is common in hemodialysis patients and increases cardiovascular morbidity and mortality. We determined the prevalence of inadequate control of hypertension in 489 patients receiving hemodialysis and identified factors associated with uncontrolled hypertension. We interviewed the patients and abstracted demographic and clinical information from a computerized database. The prevalence of uncontrolled hypertension (average predialysis blood pressure, > or =160/90 mm Hg) was 62%. Ninety-one percent of patients with uncontrolled hypertension were receiving submaximal antihypertensive drug therapy, and 59% withheld their medications before dialysis. Uncontrolled hypertensives had a greater interdialytic weight gain (3.8% v 3.5%, P = 0.07) and a greater excess weight gain (3.1 +/- 1.6 kg v 2.5 +/- 1.4 kg; P < 0.05) compared with controlled hypertensives. Patients with uncontrolled hypertension showed higher interdialytic weight gain (2.7 +/- 0.06 kg v 2.2 +/- 0.13 kg; P < 0.05), were more likely to be black (94% v 81%; P < 0.05), were more likely to have hypertension as the cause of their end-stage renal disease (ESRD) (42% v 24%; P < 0.05), and had been receiving hemodialysis for a shorter time (4.3 +/- 2 yr v 6.1 +/- 0.9 yr; P < 0.05) compared with normotensive patients. There was significant correlation between diastolic blood pressure and both interdialytic weight gain (r = 0.31, P < 0.05) and percent weight gain (r = 0.34, P < 0.05) in the hypertensive but not in the normotensive patients (r = -0.21). Interdialytic weight gain and hypertension as a cause of ESRD were independent predictors of predialysis systolic blood pressure. We conclude that hypertension is uncontrolled in most patients undergoing hemodialysis. Submaximal antihypertensive therapy, excessive interdialytic weight gain, and withholding antihypertensive medication before dialysis are correctable factors potentially contributing to uncontrolled hypertension.
Algorithms↗
Cardiomyocytes from hearts with left ventricular dysfunction after ischemia-reperfusion do not manifest contractile abnormalities.
OBJECTIVES: This study evaluated contractile function in cardiomyocytes isolated from hearts with global left ventricular dysfunction following ischemia-reperfusion. BACKGROUND: Ischemia followed by reperfusion is associated with transient contractile dysfunction, termed "stunning." It is not clear whether this phenomenon is primarily due to intrinsic cardiomyocyte contractile dysfunction. METHODS: Global contractile dysfunction was induced in isolated perfused rat hearts (n = 8) using a model of transient global ischemia (20 min) followed by reperfusion (20 min). Hearts perfused uninterrupted for 40 min were used as controls (n = 8). Cardiomyocytes were isolated using enzymatic digestion and were studied under varying degrees of inotropy (using increasing extracellular calcium [Ca2+]o) and loading conditions (varying extracellular perfusate viscosity). Mechanical function was studied with video edge detection and intracellular calcium ([Ca2+]i) kinetics using fura-2 AM. RESULTS: Global ischemia-reperfusion increased left ventricle (LV) end diastolic pressure (450% vs. 33%, p < 0.01) and reduced LV developed pressure (9% vs. 33%, p < 0.01), LV positive (3% vs. 26%, p < 0.01) and negative (5% vs. 33%, p < 0.01) dP/dt. However, cells isolated from these hearts did not manifest contractile dysfunction. In fact, cell shortening (p < 0.0001) and peak rate of cell shortening (p < 0.05) and increase in [Ca2+]i with each contraction (p < 0.024) were higher in these cells during stimulation with [Ca2+]o of 1 to 10 mmol/liter. The EC50 values for calcium dose response and the slope of the relation between change in [Ca2+]i and change in cell length were no different between the groups. Cell loading (with increasing superfusate viscosity from 1 cp to 300 cp) also did not reveal any abnormalities in cells from the hearts subjected to ischemia-reperfusion. CONCLUSIONS: Cardiomyocytes isolated from hearts with ischemia-reperfusion-induced LV dysfunction or "stunning" have normal contractile function and normal [Ca2+]i transients, when studied both in the unloaded and loaded state. Our data suggest that nonmyocyte factors such as abnormalities in extracellular matrix or abnormal myocyte-interstitial tissue coupling may be important for the genesis of cardiac contractile failure in the stunned heart.
Animals↗
Heparin-surface-modified intraocular lenses in pediatric cataract surgery: prospective randomized study.
PURPOSE: To evaluate the performance of heparin-surface-modified (HSM) intraocular lenses (IOLs) in pediatric eyes after cataract surgery. SETTING: L.V. Prasad Eye Institute, Hyderabad, India. METHODS: This prospective, randomized, double-masked, controlled clinical trial comprised 90 children aged 2 to 14 years with cataract. The patients were consecutively randomized to receive an HSM (Group 1) or an unmodified (Group 2) poly(methyl methacrylate) (PMMA) IOL. Extracapsular cataract extraction (ECCE) with IOL implantation was performed in children 8 years and older and ECCE with primary posterior capsulotomy, anterior vitrectomy, and IOL implantation in children younger than 8 years. Outcome parameters were inflammatory cell deposits on the IOL surface, posterior synechias, and anterior chamber reaction. RESULTS: Follow-up data were available for 73, 70, 60, and 68 patients at 1 week, 1 month, 3 months, and 6 months, respectively. Significantly fewer cell deposits were noted in Group 1 at 1, 3, and 6 months (P < .001). Synechia formation and anterior chamber reaction were comparable in the 2 groups. CONCLUSION: The lower incidence of inflammatory cell deposit formation in eyes with HSM PMMA IOLs indicates that these IOLs have greater bicompatibility than unmodified IOLs in pediatric cataract surgery.
Adolescent↗
Abdominal abscess: late complication after gastroepiploic coronary artery bypass grafting.
The gastroepiploic artery is widely used an arterial conduit during coronary artery revascularisation surgery. We report an unusual complication of a 56-year-old man who developed a late intra-abdominal abscess extending into the mediastinum adjacent to the right ventricle more than 2 years after surgery. This was managed with percutaneous drainage and the patient made a full recovery. The case illustrates the potential problems associated with harvesting of this artery and the need for careful haemostasis.
Abdominal Abscess↗
Involvement of signal transduction pathways in Salmonella typhimurium porin activated gut macrophages.
Many membrane proteins are implicated in the regulation of cell functions by triggering specific signaling pathways. Porins are known potential modulators of cell proliferation and differentiation. We explored the possible involvement of this protein in signal transduction pathways in mouse gut macrophages. In the present work we have shown that porins can trigger signal transduction in mouse macrophages infected with S. typhimurium. Activation of macrophages by porins results in an increase in inositol trisphosphate and intracellular Ca2+ mobilization. There is a translocation of protein kinase C to the membrane which is accompanied by nitric oxide release within the macrophages. This effect is the outcome of the expression of nitric oxide synthase, which is dependent on Protein kinase C. Further, we observed that there is an increased binding of the porins on macrophages infected with S. typhimurium which results in activation of macrophages and triggering of specific signaling pathways. These results indicate that porins induce the production of nitric oxide via a protein kinase C dependent pathway. Nitric oxide plays a fundamental role in macrophage effector function where it has both communication and defensive function.
Animals↗
Trans-acting factors that interact with the proximal promoter sequences of ovalbumin gene are tissue-specific and age-related.
Aging or deterioration of functions of various organs occurs after adulthood due to alterations in the expression of genes that maintain adulthood functions. Molecular changes that occur in regulation of genes in higher organisms after adulthood can be understood by using genes whose timing and rate of expression run parallel with specific functions during the life span. One such function is egg formation in birds which is dependent on the expression of egg protein genes, ovalbumin, lysozyme, vitellogenin, etc. Trans-acting factors are known to play a pivotal role in the regulation of transcription of genes. We show here a decrease in the level/binding of nuclear trans-acting factors with specific cis-acting elements of the promoter of the ovalbumin gene of oviduct of old Japanese quail. This parallels the decrease in the expression of the ovalbumin gene in the oviduct after adulthood. These factors are tissue-specific and bind in a cooperative and sequential manner to the ovalbumin gene promoter.
Age Factors↗
Cartilage-hair hypoplasia syndrome: increased apoptosis of T lymphocytes is associated with altered expression of Fas (CD95), FasL (CD95L), IAP, Bax, and Bcl2.
Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive short-limbed dwarfism associated with thin and sparse hair and cell mediated or combined immunodeficiency. However, the basis of immune deficiency in CHH is unclear. In this study, we investigated a role of apoptosis in immunodeficiency in a patient with CHH. An increased apoptosis of both CD4+ and CD8+ T cells, as determined by TUNEL assay, was observed in CHH compared to an age-matched healthy dwarf control. Increased apoptosis in CHH was associated with increased expression of Fas (CD95), CD95L, and Bax and decreased expression of Bcl-2 and inhibitor of apoptosis protein (IAP) compared to the control. These data suggest that lymphopenia and immunodeficiency in CHH may be, at least in part, due to increased apoptosis of T cells, possibly through the Fas/ FasL signaling pathway.
Apoptosis↗
Tardive dyskinesia: review of treatments past, present, and future.
The aim of this article is to review the theories purported to explain the pathophysiology of tardive dyskinesia (TD) and the various agents investigated for its treatment. The methods used included a review of studies in English, a Medline search, as well as a check of references listed at the end of the articles was conducted to obtain the relevant studies for review. The results show that vitamin E appears to be a promising agent both for the treatment and prophylaxis of TD. Complete remission has been reported with clozapine, but there is a need for further studies. There are cases reported of benefits with numerous miscellaneous agents, including electroconvulsive therapy, but there are no well-designed, substantiating studies. We conclude that there is no universally effective treatment for TD. Vitamin E is promising both for the treatment and possibly prophylaxis of TD. Clozapine therapy should be considered in patients refractory to traditional antipsychotics who develop TD. Judicious use of antipsychotics and periodic monitoring remain the cornerstone of therapy. None of the atypical antipsychotics (risperidone, olanzapine, clozapine, quetiapine) have been used long enough or adequately studied for their effects on TD.
Antioxidants↗
Clinicoimmunologic studies on Phoenix sylvestris Roxb. pollen: an aeroallergen from Calcutta, India.
BACKGROUND: This study highlights the allergenicity and allergenic components of the pollen of Phoenix sylvestris Roxb. (PS), or date sugar palm, which is predominantly airborne in the air of Greater Calcutta. METHODS: A 2-year aerobiologic survey was performed by Burkard sampler. PS pollen extract was used in skin tests of allergic patients, fractionated by (NH4)2SO4 and the Sephacryl S-200 column. The allergenicity of each fraction was checked by skin test and IgE ELISA inhibition. The principal allergenic fraction, Fr.lla, was separated in 11% SDS-PAGE, and its allergenicity was confirmed by IgE ELISA inhibition and immunoblotting. RESULTS: PS pollen grains were found to be prevalent in the air of the suburban zone of Calcutta from January to March with a peak in February. The pollen extract showed high (44.07%) positive skin reaction on 540 respiratory allergic patients. Among the (NH4)2SO4 cut fractions, Fr.II was the most active one, and it was resolved into four subfractions in the Sephacryl S-200 column. Fr.lla was the principal allergenic fraction, showing the presence of two components of 33 and 66 kDa in SDS-PAGE. In IgE immunoblotting, both of the components were found to be allergenic. CONCLUSIONS: The PS pollen grain is an important aeroallergen from Calcutta, India. The 33- and 66-kDa components are the major allergens present in the relevant pollen extract.
Allergens↗
Optic nerve cysticercosis in the optic canal.
The authors present a first case of cysticercosis in the optic canal in a fifteen-year-old female patient. Cysticercosis of the optic nerve is rare. A cyst in the optic canal, beneath the sheath of the optic nerve, has never been reported. The patient presented with rapidly diminishing vision in the left eye, headache and papillitis. A magnetic resonance imaging revealed a cystic lesion at the entrance of the optic canal. Surgery performed was a transcranial orbitotomy which included deroofing of the optic canal and removal of the cyst from under the sheath of the optic nerve. The cyst proved to be cysticercus histopathologically. The outcome was a remarkable visual recovery.
Adolescent↗
Calcium channel activation stabilizes a neuronal calcium channel mRNA.
We have identified a calcium-dependent pathway in neurons that regulates expression levels of the alpha1B subunit and N channel current. When neurons are depolarized and voltage-gated calcium channels activated, the half-life of cellular N channel alpha1B mRNA is prolonged. This stabilizing effect of depolarization is mediated through the 3' untranslated region of a long form of the alpha1B mRNA and may represent a form of modulation of N-channel levels that does not require changes in gene transcription. Increases in N channel expression would affect several key neuronal functions controlled by calcium, including transmitter release and neurite outgrowth.
3' Untranslated Regions↗
Immunity to non-cerebral severe malaria is acquired after one or two infections.
In areas of stable transmission, clinical immunity to mild malaria is acquired slowly, so it is not usually effective until early adolescence. Life-threatening disease is, however, restricted to a much younger age group, indicating that resistance to the severe clinical consequences of infection is acquired more quickly. Understanding how rapidly immunity develops to severe malaria is essential, as severe malaria should be the primary target of intervention strategies, and predicting the result of interventions that reduce host exposure will require consideration of these dynamics. Severe disease in childhood is less frequent in areas where transmission is the greatest. One explanation for this is that infants experience increased exposure to infection while they are protected from disease, possibly by maternal antibody. They therefore emerge from this period of clinical protection with considerably more immunity than those who experience lower transmission intensities. Here we use this data, assuming a period of clinical protection, to estimate the number of prior infections needed to reduce the risk of severe disease to negligible levels. Contrary to expectations, one or two successful infective bites seem to be all that is necessary across a broad range of transmission intensities.
Africa South of the Sahara↗
Rapid clearance of syngeneic transplanted hepatocytes following transduction with E-1-deleted adenovirus indicates early host immune responses and offers novel ways for studying viral vector, target cell and host interactions.
To distinguish between transduced cell clearance and transgene regulation following adenoviral gene transfer, we infected F344 rat hepatocytes with an E-1-deleted adenovirus (Ad beta gal) and studied cell survival in the liver of dipeptidyl peptidase IV-deficient (DPPIV-) F344 rats. Transplanted cells were localized with histochemical staining for DPPIV and transgene expression localized with staining for beta-galactosidase (lacZ). The transgene was expressed in 90-100% hepatocytes without impairment in cell viability in vitro, although transplanted cells were cleared mostly within 1 day by infiltrates containing activated macrophages, CD4+ or CD8+ lymphocytes, and phagocytes. When Ad beta gal-transduced hepatocytes were transplanted repeatedly at 14-day intervals, transplanted cells were cleared rapidly each time. LacZ expression following Ad beta gal administration to intact animals was associated with apoptosis and unscheduled DNA synthesis in the liver. To determine whether adenoviral antigen expression activated consequential MHC-restricted liver injury, we transplanted Ad beta gal-hepatocytes followed subsequently by transplantation of nontransduced hepatocytes. Transplanted cells expressing Ad beta gal were rapidly cleared as before, whereas nontransduced hepatocytes engrafted with progressive liver repopulation. The findings indicated that adenovirally transduced cells are cleared early in the host liver. Use of ex vivo strategies will facilitate analysis of modified adenoviral vectors in the context of immunoregulatory, cellular and viral mechanisms.
Adenoviridae↗
The effect of pre-emptive acupuncture treatment on analgesic requirements after day-case knee arthroscopy.
The role of acupuncture analgesia in the management of postoperative pain is yet to be clearly evaluated. We conducted a prospective, double-blind, randomised controlled study to evaluate the effect of acupuncture pretreatment on the analgesic requirement after knee arthroscopy. Forty-two patients presenting for unilateral knee arthroscopy were randomly allocated to receive a standard anaesthetic with or without acupuncture (given after the induction of anaesthesia). Visual analogue pain scores, time to first postoperative analgesia and total analgesia requirement in the first 24 h were recorded. There was no significant difference between the two groups in any of the outcome measures. We conclude that acupuncture analgesia has no additional effect when given under anaesthesia to patients undergoing knee arthroscopy.
Acupuncture Analgesia↗
Increased activity of caspase 3 and caspase 8 in anti-Fas-induced apoptosis in lymphocytes from ageing humans.
We have previously shown an increased susceptibility of T cell subsets to anti-Fas-induced apoptosis in human ageing [1]. In this study, we have examined the role of downstream mediators, including caspases, in Fas-mediated apoptosis in lymphocytes from ageing humans. The cleavage activity of caspase-8 and caspase-3 was compared between ageing and young subjects at different times following anti-Fas treatment, using colorimetric detection analysis. The expression of Fas-associated death domain (FADD), caspase-8, and caspase-3 in lymphocytes was compared at the protein level using Western blotting, and at the mRNA level by Northern blot analysis. In lymphocytes from ageing subjects, there was an early increase in the cleavage activity of caspase-8 and caspase-3 compared with young controls. Furthermore, increased protein expression of FADD, caspase-8 and caspase-3 at the basal level was observed in lymphocytes from ageing humans. Our results suggest that the altered expression and activity of molecules in the Fas/FasL signalling pathway may play a role in increased Fas-induced apoptosis and T cell deficiency in ageing humans.
Adaptor Proteins, Signal Transducing↗