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Biomedical subjects

M Majeed

Publications and source records attributed to M Majeed.

At least 19 recordsLinked to original sources
PubMed2004

Relationship between serum hyaluronic acid level and disease activity in early rheumatoid arthritis.

OBJECTIVES: To measure hyaluronic acid (HA) levels, which are raised in active rheumatoid arthritis (RA), in patients with early RA, and to assess the correlation with clinical and laboratory indices of disease activity and with subsequent radiographic erosive status. PATIENTS AND METHODS: Patients fulfilling ACR criteria were recruited into a prospective cohort within 6 months of disease onset and reviewed every 6 months. An HA binding protein based sandwich ELISA was used to measure HA in 240 sera from 82 patients at regular intervals. RESULTS: Patients had higher HA levels than age matched healthy blood donor controls (median 37.4 v 29.1 ng/ml, respectively, p<0.02), which increased with more prolonged disease. Baseline HA level correlated with measures of disease activity, including swollen and tender joint counts, HAQ, global assessments, ESR, and CRP; was higher in men; and increased with age. There was no relationship with HLA-DRB1 shared epitope or rheumatoid factor status. At 6 and 12 month follow up visits, HA levels were higher in patients who later developed erosions. However, a raised HA level was not a good predictor of erosions. CONCLUSIONS: Serum HA level correlates with clinical and laboratory measures of disease activity in early RA, but is unlikely to be of practical use in clinical practice.

Adult↗
PubMed2002

Pancreatic pseudocyst in paediatric systemic lupus erythematosus.

Pancreatitis is a rare complication of paediatric systemic lupus erythematosus (SLE). We describe a child with severe form of SLE who initially developed acute pancreatitis, subsequently complicated by extensive pancreatic pseudocyst. The treatment and outcome are discussed.

Adolescent↗
PubMed2001

Role of Src kinases and Syk in Fcgamma receptor-mediated phagocytosis and phagosome-lysosome fusion.

Phagocytosis is increased by Fcgamma receptors (FcgammaRs), and studies with syk(-/-) macrophages demonstrated that Syk kinase is required for FcgammaR phagocytosis. Similar studies with macrophages lacking the Src family kinases Hck, Fgr, and Lyn showed that these kinases are not required for phagocytosis but that they enhance the rate of particle engulfment. In this report we show that both wild-type and hck(-/-)fgr(-/-) macrophages expressed Fyn, Src, and Yes and that these kinases were activated on ingestion of immunoglobulin G (IgG)-coated particles and redistributed, together with Syk, to actin-rich phagocytic cups and the phagosomal membrane. At doses blocking IgG-dependent phagocytosis, the tyrosine kinase inhibitors PP1 and piceatannol inhibited both Src family kinase and Syk activities, as well as their redistribution to actin-rich phagocytic cups. Hck, Fgr, and Lyn were dispensable for lysosome-phagosome fusion (PLF) induced by IgG-coated particles. However, PP1 or piceatannol hampered unopsonized yeast-induced PLF despite the fact that they did not block yeast internalization.

Actins↗
PubMed2000

New form of idiopathic osteolysis: nodulosis, arthropathy and osteolysis (NAO) syndrome.

We describe 10 patients (6 females and 4 males) from 6 unrelated families with an autosomal recessive disease characterized by simultaneous presentation of nodulosis, arthropathy and osteolysis. They were followed up regularly at King Faisal Specialist Hospital and Research Center in Saudi Arabia for clinical evaluation, serial blood work-up, and evaluating radiological changes. Nodulosis and arthropathy were the clinical criteria for inclusion in this study, and the ten patients fulfilled these criteria. All patients had nodulosis and distal arthropathy. Eight patients (80%) presented with deformed hands and four (40%) with painful hands. All patients had parents who were first cousins and three families had more than one affected child, the finding suggesting autosomal recessive inheritance. Osteopenia and undertubulation of bones distally more than proximally, and upper limbs affected more often than lower limbs, were found in all patients. Osteolysis was seen in carpal and tarsal bones. Other common findings were sclerotic cranial sutures, brachycephaly, and broad medial clavicles. This novel phenotype should be considered in the differential diagnosis of chronic arthritis. Familial arthropathies are more often seen in communities where interfamilial marriage is common. Such a collection of patients is ideal for homozygosity mapping of the disease locus.

Adult↗
PubMed2000

Activation of cAMP-dependent protein kinase is necessary for actin rearrangements in human neutrophils during phagocytosis.

We have investigated the role of cAMP and cAMP-dependent protein kinase (cAPK) in neutrophil phagocytosis. Inhibition of cAPK with H-89 reduced complement- and IgG-dependent phagocytosis to 83 and 46%, respectively. Fluorescence intensity measurements of phalloidin-stained actin in neutrophils showed a reduced amount of filamentous actin (F-actin) in pseudopods and around the phagosome in cells treated with H-89 or cAMP-elevating agents (forskolin and rolipram). The amount of phosphotyrosine-containing proteins was also reduced in pseudopods and around the phagosome. Taken together, the data show that cAMP/cAPK regulates F-actin reorganization during receptor-mediated phagocytosis, particularly triggered by IgG-FcR interaction. Our results support the hypothesis that active subcortical reorganization of F-actin is a prerequisite for FcR-mediated phagocytosis, but is less important during CR3-mediated ingestion.

Cyclic AMP-Dependent Protein Kinases↗
PubMed2000

Piperine derived from black pepper increases the plasma levels of coenzyme Q10 following oral supplementation.

An extract from the fruits of black pepper consisting of a minimum of 98% pure piperine was evaluated in a clinical study using a double-blind design. The relative bioavailability of 90 mg and 120 mg of coenzyme Q10 administered in a single-dose experiment or in separate experiments for 14 and 21 days with placebo or with 5 mg of piperine was determined by comparing measured changes in plasma concentration. The inter-subject variability was minimized by limiting the selection of individuals to healthy adult male volunteers with (presupplementation) fasting coenzyme Q10 values between 0.30 and 0.60 mg/L. The results of the single-dose study and the 14-day study indicate smaller, but not significant, increases in plasma concentrations of coenzyme Q10 in the control group compared with the group receiving coenzyme Q10 with a supplement of piperine. Supplementation of 120 mg coenzyme Q10 with piperine for 21 days produced a statistically significant (p = 0.0348), approximately 30% greater, area under the plasma curve than was observed during supplementation with coenzyme Q10 plus placebo. It is postulated that the bioenhancing mechanism of piperine to increase plasma levels of supplemental coenzyme Q10 is nonspecific and possibly based on its description in the literature as a thermonutrient.

Journal Article↗
PubMed2000

Chemokines trigger immediate beta2 integrin affinity and mobility changes: differential regulation and roles in lymphocyte arrest under flow.

Chemokines trigger rapid integrin-dependent lymphocyte arrest to vascular endothelium. We show that the chemokines SLC, ELC, and SDF-1alpha rapidly induce lateral mobility and transient increase of affinity of the beta2 integrin LFA-1. Inhibition of phosphatidylinositol 3-OH kinase (PI(3)K) activity blocks mobility but not affinity changes and prevents lymphocyte adhesion to ICAM-1 immobilized at low but not high densities, suggesting that mobility enhances the frequency of encounters between high-affinity integrin and ligand but that at higher ligand density affinity changes are sufficient for arrest. Thus, chemokines trigger, through distinct signaling pathways, both a high-affinity state and lateral mobility of LFA-1 that can coordinately determine the vascular arrest of circulating lymphocytes under physiologic conditions.

Animals↗
PubMed1999

Vanadium: a review of its potential role in the fight against diabetes.

The potential role of vanadium in human health is described as a building material of bones and teeth. However, another very interesting and promising application for vanadium in human health emerges from recent studies that evaluated the role of vanadium in the management of diabetes. Vanadium is present in a variety of foods that we commonly eat. Skim milk, lobster, vegetable oils, many vegetables, grains and cereals are rich source of vanadium (>1 ppm). Fruits, meats, fish, butter, cheese, and beverages are relatively poor sources of vanadium. The daily dietary intake in humans has been estimated to vary from 10 microg to 2 mg of elemental vanadium, depending on the environmental sources of this mineral in the air, water, and food of the particular region tested. In animals, vanadium has been shown essential (1-10 microg vanadium per gram of diet). There is only circumstantial evidence that vanadium is essential for humans. However, in doses ranging from 0.083 mmol/d to 0.42 mmol/d, vanadium has shown therapeutic potential in clinical studies with patients of both insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM) type. Although vanadium has a significant biological potential, it has a poor therapeutic index, and attempts have been made to reduce the dose of vanadium required for therapeutic effectiveness. Organic forms of vanadium, as opposed to the inorganic sulfate salt of vanadium, are recognized as safer, more absorbable, and able to deliver a therapeutic effect up to 50% greater than the inorganic forms. The goal is to provide vanadium with better gastrointestinal absorption, and in a form that is best able to produce the desired biological effects. As a result, numerous organic complexes of vanadium have been developed including bis(maltolato)oxovanadium (BMOV), bis(cysteinamide N-octyl)oxovanadium known as Naglivan, bis(pyrrolidine-N-carbodithioato)oxovanadium, vanadyl-cysteine methyl ester, and bis-glycinato oxovanadium (BGOV). The health benefits of vanadium and the safety and efficacy of the available vanadium supplements are discussed in this review.

Diabetes Mellitus, Type 1↗
PubMed1999

Yersinia pseudotuberculosis-induced calcium signaling in neutrophils is blocked by the virulence effector YopH.

Pathogenic species of the genus Yersinia evade the bactericidal functions of phagocytes. This evasion is mediated through their virulence effectors, Yops, which act within target cells. In this study we investigated the effect of Yersinia pseudotuberculosis on Ca2+ signaling in polymorphonuclear neutrophils. The intracellular free calcium concentration in single adherent human neutrophils was monitored during bacterial infection and, in parallel, the encounter between the bacteria and cells was observed. When a plasmid-cured strain was used for infection, adherence of a single bacterium to the cellular surface induced a beta1 integrin-dependent transient increase in the intracellular concentration of free calcium. This was, however, not seen with Yop-expressing wild-type bacteria, which adhered to the cell surface without generating any Ca2+ signal. Importantly, the overall Ca2+ homeostasis was not affected by the wild-type strain; the Ca2+ signal mediated by the G-protein-coupled formyl-methionyl-leucyl-phenylalanine receptor was still functioning. Hence, the blocking effect was restricted to certain receptors and their signaling pathways. The use of different Yop mutant strains revealed that the protein tyrosine phosphatase YopH was responsible for the inhibition. This virulence determinant has previously been implicated in very rapid Yersinia-mediated effects on target cells as the key effector in the blockage of phagocytic uptake. The present finding, that Y. pseudotuberculosis, via YopH, specifically inhibits a self-induced immediate-early Ca2+ signal in neutrophils, offers more-detailed information concerning the effectiveness of this virulence effector and implies an effect on Ca2+-dependent, downstream signals.

Bacterial Adhesion↗
PubMed1999

Localization of intracellular Ca2+ stores in HeLa cells during infection with Chlamydia trachomatis.

Chlamydia trachomatis elementary bodies (EBs) enter epithelial cells within membrane-bound endosomes that aggregate with each other in a calcium-regulated process, but avoid fusion with lysosomes. Annexin III but not I translocates to chlamydial aggregates and inclusions. In this study, we localize the intracellular Ca2+ stores during the course of infection by analyzing the distribution of three intracellular Ca2+ store proteins: calreticulin, type-1 inositol-1,4, 5-trisphosphate receptor (IP3-R), and Sarcoplasmic/Endoplasmic Reticulum Ca2+ ATPase type 2 (SERCA2) in HeLa cells infected with C. trachomatis serovar L2. In uninfected cells, immunofluorescence staining of the proteins showed a fine granular distributed pattern for all three proteins. After infection with C. trachomatis, calreticulin was found at the periphery of chlamydial aggregates and inclusions from 3 to 48 hours post-infection. In infected cells, SERCA2 was intimately associated with chlamydial inclusions after 3 and 24 hours, but not after 48 hours. Moreover, IP3-R was translocated to and colocalized with EB aggregates and chlamydial inclusions and had a distribution very similar to that of SERCA 2. After 24 hours incubation with chlamydiae, there was a local accumulation of [Ca2+]i (105+/-17 nM) in the proximity of chlamydial inclusions, compared to 50+/-13 nM in other parts of the cell cytoplasm. In the absence of extracellular Ca2+, this local accumulation of Ca2+ increased to 295+/-50 nM after adding 50 microM ATP, and to a similar extent after adding 100 nM thapsigargin (Tg). These data indicate that during infection of HeLa cells with chlamydiae, intracellular Ca2+ stores are redistributed, causing local accumulation of Ca2+ in the vicinity of chlamydial inclusions. These changes may trigger the association of certain proteins such as annexins with chlamydia-containing vesicles, and thereby regulation of membrane-membrane interaction during endosome aggregation and inclusion formation.

Adenosine Triphosphate↗
PubMed1998

Roles of calcium and annexins in phagocytosis and elimination of an attenuated strain of Mycobacterium tuberculosis in human neutrophils.

The phagocytic function of neutrophils is a crucial element in the host defence against invading microorganisms. We investigated phagocytosis and intracellular killing of an attenuated strain of Mycobacterium tuberculosis(H37Ra) by human neutrophils focusing on the role of the cytosolic free calcium concentration [Ca2+]i and certain cytosolic calcium-dependent membrane-binding proteins annexins. Phagocytic uptake did not trigger a calcium rise and occurred independently of different calcium conditions, and in a serum-dependent manner. Changes in the viability of H37Ra were determined by agar plate colony count and a radiometric assay. Neutrophils showed a capacity to kill ingested mycobacteria and this occurred without a rise in [Ca2+]i. The ability to kill H37Ra decreased in the absence of extracellular calcium and when intra-extracellular calcium was reduced. Immunofluorescence staining revealed that during phagocytosis of H37Ra, annexins III, IV and VI translocated from cytoplasm to the proximity of the H37Ra-containing phagosomes, whereas the localization of annexin I and V remained unchanged. The translocation of annexin IV occurred even when Ca2+-depleted neutrophils ingested H37Ra in the absence of extracellular calcium. We concluded that neutrophil-mediated killing of mycobacteria is a Ca2+-dependent process. The fact that the association of certain annexins to the membrane vesicle containing H37Ra differ from other phagosomes suggests a selective regulatory mechanism during phagocytosis of mycobacteria by neutrophils.

Annexins↗
PubMed1998

Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers.

The medicinal properties of curcumin obtained from Curcuma longa L. cannot be utilised because of poor bioavailability due to its rapid metabolism in the liver and intestinal wall. In this study, the effect of combining piperine, a known inhibitor of hepatic and intestinal glucuronidation, was evaluated on the bioavailability of curcumin in rats and healthy human volunteers. When curcumin was given alone, in the dose 2 g/kg to rats, moderate serum concentrations were achieved over a period of 4 h. Concomitant administration of piperine 20 mg/kg increased the serum concentration of curcumin for a short period of 1-2 h post drug. Time to maximum was significantly increased (P < 0.02) while elimination half life and clearance significantly decreased (P < 0.02), and the bioavailability was increased by 154%. On the other hand in humans after a dose of 2 g curcumin alone, serum levels were either undetectable or very low. Concomitant administration of piperine 20 mg produced much higher concentrations from 0.25 to 1 h post drug (P < 0.01 at 0.25 and 0.5 h; P < 0.001 at 1 h), the increase in bioavailability was 2000%. The study shows that in the dosages used, piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in both rats and humans with no adverse effects.

Adult↗
PubMed1997

Role of annexins in endocytosis of antigens in immature human dendritic cells.

We have evaluated the uptake of a soluble protein antigen, denitrophenylated human serum albumin (DNP-HSA), and two different intracellular bacteria; Chlamydia trachomatis serovar L2 and Mycobacterium tuberculosis strain H37Ra, by immature human dendritic cells. These were generated by culturing progenitor cells from blood in the presence of cytokines (granulocyte-macrophage colony-stimulating factor and interleukin-4). Dendritic cells play a crucial part in antigen presentation for the induction of T-cell-dependent immune responses in various tissues. Recently, macropinocytic and phagocytic activity has been shown for immature dendritic cells of mouse, rat and human origin. In the present study, macropinocytosis characterized the uptake of the soluble protein-antigen DNP-HSA, whereas the C. trachomatis were ingested via receptor-mediated endocytosis in coated pits, and opsonized M. tuberculosis via phagocytosis. To follow the intracellular routes of the antigens, their positions were compared with the localization of annexins, a family of Ca(2+)-and phospholipid-binding proteins, involved in membrane fusion, aggregation and transport of different vesicles. To elucidate further the intracellular pathway of the antigens, two other proteins, lysosome-associated membrane protein-1 (LAMP-1) and cathepsin D, were labelled. They are known to colocalize with major histocompatibility complex class II compartments in the immature dendritic cells. We observed a distinct translocation of annexin V to DNP-HSA containing endosomes, and annexin III to vesicles with C. trachomatis. Furthermore, annexin III, IV and V redistributed to phagosomes with M. tuberculosis. Both LAMP-1 and cathepsin D colocalized with DNP-HSA endosomes, and with phagosomes with M. tuberculosis. Thus, immature human dendritic cells have the capacity to phagocytose. Moreover, the handling of these antigens by dendritic cells may represent three distinct intracellular pathways, albeit some properties and compartments are shared.

Annexins↗
PubMed1996

Phagosome-lysosome fusion is a calcium-independent event in macrophages.

Phagosome-lysosome membrane fusion is a highly regulated event that is essential for intracellular killing of microorganisms. Functionally, it represents a form of polarized regulated secretion, which is classically dependent on increases in intracellular ionized calcium ([Ca2+]i). Indeed, increases in [Ca2+]i are essential for phagosome-granule (lysosome) fusion in neutrophils and for lysosomal fusion events that mediate host cell invasion by Trypanosoma cruzi trypomastigotes. Since several intracellular pathogens survive in macrophage phagosomes that do not fuse with lysosomes, we examined the regulation of phagosome-lysosome fusion in macrophages. Macrophages (M phi) were treated with 12.5 microM bis-(2-amino-S-methylphenoxy) ethane-N,N,N',N',-tetraacetic acid tetraacetoxymethyl ester (MAPT/AM), a cell-permeant calcium chelator which reduced resting cytoplasmic [Ca2+]; from 80 nM to < or = 20 nM and completely blocked increases in [Ca2+]i in response to multiple stimuli, even in the presence of extracellular calcium. Subsequently, M phi phagocytosed serum-opsonized zymosan, staphylococci, or Mycobacterium bovis. Microbes were enumerated by 4',6-diamidino-2-phenylindole, dihydrochloride (DAPI) staining, and phagosome-lysosome fusion was scored using both lysosome-associated membrane protein (LAMP-1) as a membrane marker and rhodamine dextran as a content marker for lysosomes. Confirmation of phagosome-lysosome fusion by electron microscopy validated the fluorescence microscopy findings. We found that phagosome-lysosome fusion in M phi occurs noramlly at very low [Ca2+]i (< or = 20 nM). Kinetic analysis showed that in M phi none of the steps leading from particle binding to eventual phagosome-lysosome fusion are regulated by [Ca2+]i in a rate-limiting way. Furthermore, confocal microscopy revealed no difference in the intensity of LAMP-1 immunofluorescence in phagolysosome membranes in calcium-buffered vs. control macrophages. We conclude that neither membrane recognition nor fusion events in the phagosomal pathway in macrophages are dependent on or regulated by calcium.

Animals↗
PubMed1996

Selenium: a quest for better understanding.

Selenium is an essential trace element in nutrition for the prevention of disease in humans. Epidemiological studies indicate an association between low nutritional selenium status and increased risks of cardiomyopathy, cardiovascular disease, and carcinogenesis in various sites of the body. The role of selenium supplementation in the prevention and treatment of AIDS-related pathology has been considered. Selenoproteins discovered in mammalian cells may account for the essentiality of selenium in the body's antioxidant defense; thyroid hormone function; immune system function, particularly the cellular immunity; formation of sperm; and functioning of the prostate gland. The seleno-organic compounds, primarily L-(+)-selenomethionine, generally are recognized as safe and effective forms of selenium supplementation. The nutritionally recommended dose of elemental selenium is estimated at 50 to 200 micrograms [corrected] per day. There is, however, increased discussion of a pharmacological dose of selenium, significantly higher than the nutritional dose of the microelement, to treat active conditions. One way of increasing the tissue levels of selenium is to combine its ingestible form with a nutrient bioavailability enhancing compound.

Humans↗