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Biomedical subjects

K Jacobson

Publications and source records attributed to K Jacobson.

At least 19 recordsLinked to original sources
PubMed2003

Cholinergic pathways modulate experimental dinitrobenzene sulfonic acid colitis in rats.

Recent studies have suggested that neuroimmune interactions modulate intestinal mucosal immune responses. In the current study, we examined the role of cholinergic pathways in modulating the severity of acute dinitrobenzene sulfonic acid colitis, using pharmacological agents to suppress acetylcholinesterase in Sprague-Dawley rats, and evaluating the colitis in the cholinergic hyperresponsive Flinder's sensitive line rats and their control counterparts, the Flinder's resistant line. Colitis was induced by intrarectal dinitrobenzene sulfonic acid (80 mg x ml(-1) in 50% ethanol); controls received intrarectal saline. Sprague-Dawley rats received an acetylcholinesterase inhibitor, physostigmine (50 microg x kg(-1) s.c.) or neostigmine (50 microg x kg(-1) s.c.), 30 min prior to intrarectal dinitrobenzene sulfonic acid; controls received saline vehicle. On day 5, the macroscopic damage score, myeloperoxidase activity (an estimate of granulocyte infiltration) and smooth muscle thickness were evaluated in the inflamed colonic segment. Significant increases in macroscopic damage score and colonic smooth muscle thickness were observed in Sprague-Dawley and Flinder's Resistant Line rats on day 5 following intrarectal dinitrobenzene sulfonic acid compared to saline controls. Increased myeloperoxidase activity was also observed in dinitrobenzene sulfonic acid-treated Sprague-Dawley rats and Flinder's Resistant Line rats. In contrast, Flinder's Sensitive Line rats failed to demonstrate a significant rise in macroscopic damage, smooth muscle layer thickness, or myeloperoxidase activity on day 5 following intrarectal dinitrobenzene sulfonic acid when compared to saline-treated Flinder's Sensitive Line controls. Neostigmine and physostigmine treatment prior to intrarectal dinitrobenzene sulfonic acid significantly attenuated macroscopic damage score, myeloperoxidase activity and smooth muscle thickness on day 5 compared to colitic Sprague-Dawley controls. Significantly greater reductions in myeloperoxidase activity were observed with physostigmine vs. neostigmine pretreatment. These data suggest that cholinergic pathways modulate the acute colonic inflammatory response associated with the dinitrobenzene sulfonic acid model, with central pathways exerting a greater protective effect relative to peripheral pathways. Further studies are required to determine the contributions of sites in the nervous system and neuro-effector junctions.

Animals↗
PubMed2003

Curcumin attenuates DNB-induced murine colitis.

Numerous therapies used for inflammatory bowel disease (IBD) target the transcription factor NF-kappaB, which is involved in the production of cytokines and chemokines integral for inflammation. Here we show that curcumin, a component of the spice turmeric, is able to attenuate colitis in the dinitrobenzene sulfonic acid (DNB)-induced murine model of colitis. When given before the induction of colitis it reduced macroscopic damage scores and NF-kappaB activation. This was accompanied by a reduction in myeloperoxidase activity, and using semiquantitative RT-PCR, an attenuation of the DNB-induced message for IL-1beta was detected. Western blotting analysis revealed that there was a reproducible DNB-induced activation of p38 MAPK detected in intestinal lysates by using a phosphospecific antibody. This signal was significantly attenuated by curcumin. Furthermore, we show that the immunohistochemical signal is dramatically attenuated at the level of the mucosa by curcumin. We conclude that the widely used food additive curcumin is able to attenuate experimental colitis through a mechanism correlated with the inhibition of the activation of NF-kappaB and effects a reduction in the activity of p38 MAPK. We propose that this agent may have therapeutic implications for human IBD.

Animals↗
PubMed2003

How should laboratories communicate with primary care? Obtaining general practitioners' views.

AIMS: Recognising the importance of communication with our primary care colleagues, focus groups were held with GPs to determine how they perceived the current lines of communication with their local microbiology laboratory and the PHLS, and how they could be improved. METHODS: Focus groups were held in Plymouth, Gloucester, Bristol and Hereford. Between four and 10 GPs and/or PCG Board members attended each workshop. The modes of communication i.e. websites, face-to-face contact, laboratory reporting, telephone advice, newsletters, guidance and surveillance were discussed. RESULTS: Microbiology websites should be user friendly, with clear labelling as to whom the page is directed. They should contain locally relevant data, antibiotic guidance and information leaflets. Despite great variation in laboratory reporting protocols GPs were mostly happy with reports received. Results, especially serology, should contain a clear conclusion and could refer to a website for further information. Electronic reporting was enthusiastically awaited. All GPs felt they had excellent access to telephone advice. GPs would value data and guidance on their use of diagnostic tests. CONCLUSION: These workshops highlight the variation in laboratory reporting protocols that should be addressed. Website development for GPs should include locally relevant data. GPs would value details of their laboratory use and costs.

England↗
PubMed2003

High resolution sequence-based DPB1 typing identified two novel DPB1 alleles, DPB1*9401 and DPB1*9501, from a Kenyan population.

Two novel DPB1 alleles, DPB1*9401 and DPB1*9501, were identified from a Kenyan population during sequence-based HLA-DPB1 typing. Molecular cloning and sequencing of multiple clones confirmed that one of the new DPB1 alleles is identical to DPB1*0402 at exon 2 except for a single nucleotide substitution (CGG -->TGG), changing codon 70 from Arg to Trp. The new allele has been named DPB1*9401. This is the first report of polymorphism at codon 70 of HLA-DPB1 alleles. New codon combinations have been identified in another novel DPB1 allele named DPB1*9501. The extensive diversity at DPB1 locus of this East African population is being revealed by high resolution sequence-based DPB1 typing.

Amino Acid Sequence↗
PubMed2002

Oxidation of orthopaedic UHMWPE.

Retrieved EtO sterilised acetabular cups usually show much less degradation than gamma-ray sterilised cups. Some of our retrieved EtO sterilised cups did, however, reveal unexpected bulk oxidation. It was observed that this oxidation was always accompanied by whitening of the material. This whitening was found to be due to a break-up of the compression moulded material into its original particles. It was noticed that there was no oxidation in all parts, where the break-up and whitening appeared. The oxidation did, however, occur exclusively in the parts where there was a badly consolidated material. Upon examining shelf aged, unsterilised samples, it was found that the degradation was also present here. This shows that the observed phenomenon is not due to the service in vivo and that it must originate from the processing step. Just as for the retrieved samples, the shelf aged cups only showed oxidation in the bulk and not at the surface. It was concluded that the material used for the cups had been badly fused together during the compression moulding and that the machining had created a bad stress situation in the cups leading to a break-up of the particles. The mechanism that initiates the oxidation is not known, but it is believed that the distribution depends on how the internal stresses have acted to break up the structure. In the areas where the particles have been separated, there is probably a higher availability of oxygen than what is normally observed in UHMWPE.

Biocompatible Materials↗
PubMed2002

The joint analysis of personal interview and family history diagnoses: evidence for validity of diagnosis and increased heritability estimates.

BACKGROUND: Psychiatric diagnoses obtained at personal interview are only moderately reliable and depend critically on accurate self-observation. Reports by family members provide additional information but may be biased. It is unclear how best to combine these two sources of diagnostic data. METHODS: Using complete data on lifetime prevalence for six disorders in approximately 1200 male-male twin pairs from a population based registry, we first applied a standard bivariate twin model--which treats self-diagnoses and informant-diagnoses as separate phenotypes--and then examined a 'multiple-rater' model--which assumes that self-report and co-twin-report are fallible indices of one underlying disease liability. Best-fit models were chosen using Akaike's information criterion. RESULTS: Standard bivariate analyses indicated that the same genetic factors accounted for variation in self-reported and co-twin-reported diagnoses. The multiple-rater model produced a substantial decrease in variance attributed to individual-specific environment and a proportional increase in heritability of liability for major depression, generalized anxiety disorder, alcohol dependence and adult antisocial behaviour, but not for drug abuse/dependence or regular tobacco use. The best-fit model consistently included either a 'bias' or a 'correlated error' path. No evidence for family environmental risk factors was found for any disorder. CONCLUSION: The genetic factors that influence self-report psychiatric illness also influence psychiatric illness as described by relatives. For many psychiatric disorders, incorporation of self-report and family history data in a single model may reduce measurement error and increase estimates of heritability. However, account must be taken of the fact that family history reports are systematically biased. While promising, these results are preliminary and require replication.

Adult↗
PubMed2001

Drop attacks in older patients secondary to an otologic cause.

The clinical features and treatment of seven patients with drop attacks attributable to inner ear disease presenting after age 65 are described. A neurologic or cardiovascular cause of drop attacks was initially suspected. Audiovestibular testing documented a unilateral inner ear disorder. The salient clinical features of these cases are discussed. The patients underwent ablative vestibular surgery, and all compensated well and were free of vertigo and falls up to 10 years postoperatively.

Aged↗
PubMed2001

Partitioning of Thy-1, GM1, and cross-linked phospholipid analogs into lipid rafts reconstituted in supported model membrane monolayers.

As shown earlier, raft-like domains resembling those thought to be present in natural cell membranes can be formed in supported planar lipid monolayers. These liquid-ordered domains coexist with a liquid-disordered phase and form in monolayers prepared both from synthetic lipid mixtures and lipid extracts of the brush border membrane of mouse kidney cells. The domains are detergent-resistant and are highly enriched in the glycosphingolipid GM1. In this work, the properties of these raft-like domains are further explored and compared with properties thought to be central to raft function in plasma membranes. First, it is shown that domain formation and disruption critically depends on the cholesterol density and can be controlled reversibly by treating the monolayers with the cholesterol-sequestering reagent methyl-beta-cyclodextrin. Second, the glycosylphosphatidylinositol-anchored cell-surface protein Thy-1 significantly partitions into the raft-like domains. The extent of this partitioning is reduced when the monolayers contain GM1, indicating that different molecules can compete for domain occupation. Third, the partitioning of a saturated phospholipid analog into the raft phase is dramatically increased (15% to 65%) after cross-linking with antibodies, whereas the distribution of a doubly unsaturated phospholipid analog is not significantly affected by cross-linking (approximately 10%). This result demonstrates that cross-linking, a process known to be important for certain cell-signaling processes, can selectively translocate molecules to liquid-ordered domains.

Antibodies↗
PubMed2001

Local photorelease of caged thymosin beta4 in locomoting keratocytes causes cell turning.

The broad aim of this work was to explore the feasibility of using light-directed perturbation techniques to study cell locomotion. Specifically, a caged form of thymosin beta4 (Tbeta4) was photoactivated in a defined local region of locomoting fish scale keratocytes and the resulting perturbation of locomotion was studied. Purified Tbeta4 was produced in an inactive form by "caging" with ([n-nitroveratryl]oxy)chlorocarbamate. In vitro spectrophotofluorometric assays indicated that caged Tbeta4 did not change the normal actin polymerization kinetics, whereas photoactivated Tbeta4 significantly inhibited actin polymerization. With an a priori knowledge of the cytoplasmic diffusion coefficient of Tbeta4 as measured by fluorescence recovery after photobleaching experiments, the rapid sequestration of actin monomers by uncaged Tbeta4 and the consequent reduction in the diffusional spread of the Tbeta4-actin complex were predicted using Virtual Cell software (developed at the Center for Biomedical Imaging Technology, University of Connecticut Health Center). These simulations demonstrated that locally photoactivating Tbeta4 in keratocytes could potentially elicit a regional locomotory response. Indeed, when caged Tbeta4 was locally photoactivated at the wings of locomoting keratocytes, specific turning about the irradiated region was observed, whereas various controls were negative. Additionally, loading of exogenous Tbeta4 into both keratocytes and fibroblasts caused very rapid disassembly of actin filaments and reduction of cellular contractility. Based on these results, a mechanical model is proposed for the turning behavior of keratocytes in response to photoreleased Tbeta4.

3T3 Cells↗
PubMed2001

Adenovirus infections in adult recipients of blood and marrow transplants.

Adenoviruses are increasingly recognized pathogens that affect blood and marrow transplant (BMT) recipients. Experiences with 2889 adult BMT recipients were reviewed to study the incidence, clinical spectrum, risk factors for dissemination, response to therapy, and outcome of adenovirus infections. Eight-five patients (3%) were diagnosed by means of culture (n=85) or culture and histopathological examination (n=6). Nine patients had asymptomatic viruria, and 76 had symptomatic infections, which included upper respiratory tract infection (n=20), enteritis (n=18), hemorrhagic cystitis (n=10), pneumonia (n=15), and disseminated disease (n=13). The overall mortality rate was 26%. A higher mortality rate was observed among patients with pneumonia (73%) and disseminated disease (61%). Risk factors for dissemination included receipt of an allogeneic transplant, presence of graft-versus-host disease (GVHD), and receipt of concurrent immunosuppressive therapy. Intravenous ribavirin was not associated with an appreciable benefit among 12 patients who received this treatment. In conclusion, adenovirus infections are an important cause of morbidity and mortality in adult BMT recipients, particularly allogeneic transplant recipients with GVHD who are receiving immunosuppressive therapy. The need for an effective, nontoxic antiviral therapy is apparent.

Adenoviridae Infections↗
PubMed2001

Cytomegalovirus pneumonia in adults with leukemia: an emerging problem.

Cytomegalovirus (CMV) pneumonia is reportedly unusual among adults with leukemia who have not undergone transplantation. To assess the frequency of CMV pneumonia and its outcome during the present time, we reviewed the experience of 2136 hospitalized adults with leukemia. Sixty-one patients (2.9%) had CMV pneumonia diagnosed. The frequency doubled from 1.4% in 1992--1994 to 2.8% in 1995--1997 (P<.05). Fifty-four patients (89%) had received treatment with an immunosuppressive chemotherapeutic regimen that contained fludarabine (n=37), high-dose cytoxan (n=17), or both (n=10), and 15 patients (25%) had received granulocyte transfusions that were stimulated with hematopoietic growth factors from unscreened donors. The overall CMV pneumonia--associated mortality rate was 57%. Among autopsied patients who had leukemia, the frequency of CMV pneumonia increased from 0%, 2.3%, and 0% in 1992, 1993, and 1994, respectively, to 4.6%, 6.5%, and 16% in 1995, 1996, and 1997, respectively (P<.05). CMV has emerged as an important cause of life-threatening pneumonia in adults with leukemia who have received potent immunosuppressive therapies and stimulated granulocyte transfusions from unscreened donors.

Adult↗
PubMed2001

Activation of A(3)adenosine receptor protects against doxorubicin-induced cardiotoxicity.

Adenosine exerts a marked protective effect on the heart during cardiac ischemia. This protection is mediated by binding to the A(1)and A(3)subtypes of adenosine receptor (A(1)R and A(3)R, respectively). The objective of the present study was to investigate whether activation of A(1)and A(3)adenosine receptors may reduce doxorubicin-induced damage to cardiomyocytes in culture. Cultured cardiomyocytes from newborn rats were treated with 0.5--5 microm doxorubicin (DOX) for 18 h and then incubated in drug-free medium for an additional 24 h. This treatment resulted in cell damage and lactate dehydrogenase release, even after low (0.5 microm) doses of the drug, and increased in a concentration-dependent manner. Activation of A(3)-subtype but not A(1)-subtype receptors attenuated doxorubicin-cardiotoxicity after drug treatment for 18 h followed by 24 h incubation in drug-free medium. Modulation of intracellular calcium mediated by activation of A(3)R, but not by A(1)R, in cultured myocytes suggested an important pathophysiological significance of this subtype of adenosine receptors. Protection by A(3)R agonist Cl-IB-MECA (2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide) following DOX treatment is evident in: (1) decreases in intracellular calcium overloading and abnormalities in Ca(2+)transients; (2) reduction of free-radical generation and lipid peroxidation; (3) attenuation of mitochondrial damage by protection of the terminal link (COX-complex) of respiratory chain; (4) attenuation of the decrease in ATP production and irreversible cardiomyocyte damage. Cardioprotection caused by Cl-IB-MECA was antagonized considerably by the selective A(3)adenosine receptor antagonist MRS1523.

Adenosine↗
PubMed2001

Lipid rafts reconstituted in model membranes.

One key tenet of the raft hypothesis is that the formation of glycosphingolipid- and cholesterol-rich lipid domains can be driven solely by characteristic lipid-lipid interactions, suggesting that rafts ought to form in model membranes composed of appropriate lipids. In fact, domains with raft-like properties were found to coexist with fluid lipid regions in both planar supported lipid layers and in giant unilamellar vesicles (GUVs) formed from 1) equimolar mixtures of phospholipid-cholesterol-sphingomyelin or 2) natural lipids extracted from brush border membranes that are rich in sphingomyelin and cholesterol. Employing headgroup-labeled fluorescent phospholipid analogs in planar supported lipid layers, domains typically several microns in diameter were observed by fluorescence microscopy at room temperature (24 degrees C) whereas non-raft mixtures (PC-cholesterol) appeared homogeneous. Both raft and non-raft domains were fluid-like, although diffusion was slower in raft domains, and the probe could exchange between the two phases. Consistent with the raft hypothesis, GM1, a glycosphingolipid (GSL), was highly enriched in the more ordered domains and resistant to detergent extraction, which disrupted the GSL-depleted phase. To exclude the possibility that the domain structure was an artifact caused by the lipid layer support, GUVs were formed from the synthetic and natural lipid mixtures, in which the probe, LAURDAN, was incorporated. The emission spectrum of LAURDAN was examined by two-photon fluorescence microscopy, which allowed identification of regions with high or low order of lipid acyl chain alignment. In GUVs formed from the raft lipid mixture or from brush border membrane lipids an array of more ordered and less ordered domains that were in register in both monolayers could reversibly be formed and disrupted upon cooling and heating. Overall, the notion that in biomembranes selected lipids could laterally aggregate to form more ordered, detergent-resistant lipid rafts into which glycosphingolipids partition is strongly supported by this study.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2001

A chemical analysis of the clogging process of polymeric biliary endoprostheses.

Insertion of polymeric biliary endoprostheses is widely used as a method of palliation of malignant strictures of the biliary tree. Despite the success of this technique, clogging of the stent in a few months is still an existing problem. The aim of the present study has been to investigate the causes of the obstruction, considering both the stent material and the composition of the obstructing deposit. 16 ready-to-implant and 33 occluded retrieved prostheses were analysed by ATR-FTIR spectroscopy. The clogging sludge was recovered and studied by FTIR spectroscopy and pyrolysis derivatisation/gas chromatography/mass spectrometry (Py/GC/MS). The results of the analyses showed that the deposit was mainly formed by proteins, bilirubin, calcium palmitate and bilirubinate, cholesterol and its fatty acids salts. It was found that approximately 50% of the examined ready-to-implant samples were made of ethylene-vinylacetate copolymer (EVA) instead of polyethylene (PE), as was stated in the producer declaration. Moreover, 94% of the retrieved samples were found to be made of EVA indicating that this material is less suitable than PE for this application. All retrieved PE and EVA stents showed a protein-like black layer strongly absorbed on the surface.

Biliary Tract↗
PubMed2001

EGF-stimulated lamellipod extension in adenocarcinoma cells.

The extension of lamellipodia has been triggered by the application of epidermal growth factor (EGF). We have used an atomic force microscope (AFM) to investigate this lamellipodial extension. During extension we could detect an increase in height from about 500 nm for the stable lamellipodium to typical values of 600-800 nm for the extending lamellipodium. The AFM was also used to determine the mechanical properties of the lamellipodium where we found a decrease of the elastic modulus by a factor of 1.4 at the same location within the same cell. Both findings are consistent with the cortical expansion hypothesis, suggesting that severing of actin filaments, leading to a swelling of the cytoskeleton, generates the protrusive force during lamellipodial extension.

Adenocarcinoma↗
PubMed2001

Infectious diarrhea in children.

Infectious diarrhea in children remains an important cause of morbidity in North America with rotavirus, nontyphoidal salmonella, Campylobacter and Giardia being the predominant pathogens in children younger than 5 years. Knowledge of the epidemiology of the diarrheal illness in a community together with the clinical information are necessary when determining the extent of investigation. Oral rehydration remains the mainstay of therapy and antibiotics are reserved for specific clinical situations and infections.

Adolescent↗
PubMed2001

Direct, high-resolution measurement of furrow stiffening during division of adherent cells.

It is unclear whether cell division is driven by cortical relaxation outside the equatorial region or cortical contractility within the developing furrow alone. To approach this question, a technique is required that can monitor spatially-resolved changes in cortical stiffness with good time resolution. We employed atomic force microscopy (AFM), in force-mapping mode, to track dynamic changes in the stiffness of the cortex of adherent cultured cells along a single scan-line during M phase, from metaphase to cytokinesis. Video microscopy, which we used to correlate the AFM data with mitotic events identified by light microscopy, indicated that the AFM force-mapping technique does not perturb dividing cells. Here we show that cortical stiffening occurs over the equatorial region about 160 seconds before any furrow appears, and that this stiffening markedly increases as the furrow starts. By contrast, polar relaxation of cells does not seem to be an obligatory event for cell division to occur.

Animals↗