Biomedical subjects

D Abraham

Publications and source records attributed to D Abraham.

At least 19 recordsLinked to original sources

PubMed2002

Upregulation of vascular endothelial growth factor receptors is associated with advanced neuroblastoma.

BACKGROUND: Angiogenesis is essential for tumor growth and relies on the production of angiogenic factors. Vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis that binds to tyrosine kinase receptors Flt-1 and KDR. The interaction of VEGF and its receptors at gene and protein levels in neuroblastoma remains widely unknown. METHODS: Tumor biopsy specimens and serum were obtained from 37 neuroblastoma patients; adrenal biopsy sections and sera of 7 normal children served as controls. Biopsy specimens were examined by real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blotting; serum was analyzed by enzyme-linked immunosorbent assay (ELISA). VEGF-A(165), B, C, Flt-1, and KDR were analyzed. RESULTS: VEGF isoforms and its receptors' mRNA were expressed in neuroblastoma and control tissues. Whereas the ligands were increased in stages III and IV, the receptors were upregulated in stage III only. At protein level, VEGF-B and C, Flt-1, and KDR were not detectable in tissue lysates, whereas VEGF-A was increased in stages III and IV. Serum VEGF protein levels were upregulated in stage III. CONCLUSIONS: VEGF-A(165) is one of the major angiogenesis regulators among the ligands' family of VEGF, whereas its receptors KDR, and most probably Flt-1, may contribute to a poor prognosis (angiogenic) phenotype, as indicated by their upregulated MRNA levels in stage III neuroblastoma. VEGF-A(165) mainly contributes to increased serum VEGF levels and may serve as a diagnostic tool in advanced-stage neuroblastoma.

Adrenal Gland Neoplasms↗

PubMed2002

Determining the explanatory potential of variables.

A meta-analysis may not be the most appropriate method for the extraction of information on independent variables from the scientific literature. A formal quantitative review method is proposed for reducing a literature review variable list to a manageable list of explanatory variables. The proposed method synthesizes the information in a standard literature review into two steps. First, the hypothesis "independent variable 'X' had no effect on utilization" is tested by means of binomial, one-sided testing. If it is rejected, then the hypothesis "The effect of independent variable 'X' is as likely to be in the same direction as it is to be in the opposite direction" is tested, by an extended version of the binomial formula. In two steps, the presence of a consistent direction of significant effects is calculated. This method is tested on dental utilization publications. It is concluded that the method is an effective tool for the creation of a manageable variable list.

Analysis of Variance↗

PubMed2002

Pituitary radiographic abnormalities and clinical correlates of hypogonadism in elderly males presenting with erectile dysfunction.

The prevalence of erectile dysfunction rises rapidly with age and is a frequent complaint presented in clinical practice. Although the etiology of erectile dysfunction is multifactorial, 10-20% of evaluations demonstrate testosterone deficiency. Testosterone deficiency due to secondary hypogonadism increases with age. Despite a higher prevalence of secondary hypogonadism in the elderly, there are no studies addressing hypothalamic-pituitary structural abnormalities in elderly impotent men with testosterone deficiency. We retrospectively reviewed the records of all elderly men who presented for general outpatient evaluation of erectile dysfunction from 1996 to 1999. To obtain a cohort control population, the records of 300 patients without erectile dysfunction were also reviewed. Amongst the erectile dysfunction patients, 225 were found to be testosterone deficient (testosterone < 300 ng/dl). Of these patients, 29 were additionally diagnosed with secondary hypogonadism based on a luteinizing hormone (LH) < 13 mIU/ml. Magnetic resonance imaging (MRI) or computed tomography (CT) imaging was available and reviewed in all patients diagnosed with secondary hypogonadism. Ten per cent of these patients had hypothalamic-pituitary imaging abnormalities. The prevalence of pituitary tumors within our population was not significantly elevated compared to the previous general population studies. Small-vessel white matter disease, hyperlipidemia and history of compression fractures were significantly increased in both univariate and multivariate analysis in the erectile dysfunction group compared with the control cohort. This study does not suggest that the use of hypothalamic-pituitary imaging in the evaluation of impotence in elderly men, in the absence of clinical characteristics of other hormonal loss or sella compression symptoms, will increase diagnosis of structural hypothalamic-pituitary abnormalities over that of the general population. However, the yield may increase with very low testosterone levels. These data suggest that there is an increase in ischemic white matter disease in elderly men with hypogonadism that may reflect microvascular injury to the hypothalamic-pituitary. Furthermore, these data confirm that low testosterone is associated with hyperlipidemia in the elderly. Future studies are required to assess the role of hypogonadism and hyperlipidemia, and to determine if treatment of the hormone deficiency improves the lipid profile.

Aged↗

PubMed2001

Impact of cardiac transplantation on molecular pathology of ET-1, VEGF-C, and mitochondrial metabolism and morphology in dilated versus ischemic cardiomyopathic patients.

Little is known about the long-term impact of cardiac transplantation on activity and modifications of endothelin (ET)-1 system, vascular endothelial growth factor (VEGF), and mitochondrial metabolism and morphology in patients with ischemic cardiomyopathy (ICM) versus dilated cardiomyopathy (DCM). Messenger RNA (mRNA) expression levels of ET-1, endothelin converting enzyme (ECE)-1, VEGF-C, carnitine palmitoyltransferase (CPT)-1, and carnitine acetyltransferase (CARAT), as well as the number of normal, edematous, and degenerated mitochondria were assessed in left ventricular biopsies of 21 patients with DCM and 20 with ICM (New York Heart Association class III-IV) before and up to 3 months after cardiac transplantation. Cardiac samples of donated, nonfailing hearts served as controls (n=10). In cardiac biopsies of both ICM and DCM patients, ET-1, VEGF-C, CPT-1, and CARAT mRNA were up-regulated, whereas ECE-1 mRNA was down-regulated (P<0.05). Degenerated mitochondria had the highest number in both groups, followed by normal and edematous mitochondria. After cardiac transplantation, in ICM patients impaired gene expression levels decreased to, or below, normal levels, and the number of normal mitochondria increased (P<0.05). In implanted hearts of DCM patients, however, up-regulated ET-1 transcript levels persisted and the number of normal mitochondria decreased, whereas the number of degenerated mitochondria increased (P<0.05), and edematous mitochondria remained unchanged in number. These results show that cardiac transplantation corrects the impaired hemodynamic and echocardiographic parameters in both groups, whereas in DCM, the molecular pathology of ET-1 system and mitochondria persists. Therefore, it is more likely that these changes are the cause rather than a consequence of DCM.

Adult↗

PubMed2001

Molecular phylogeny of the subfamilies in Geometridae (Geometroidea: Lepidoptera).

Molecular sequence data from three gene fragments were used to examine critically a provisional phylogenetic classification based on morphological characters of the Geometridae, one of the most species-rich families of moths. The sister group relationship between Geometridae and Drepanidae gained further support from the molecular analysis, which was based on the ND1 mitochondrial gene and the first and second expansion segments of the 28S ribosomal RNA gene. Although the alignment of the second expansion segment contained regions with many gaps, it provided the most resolution of the gene fragments. Parsimony analysis of the combined data resulted in a cladogram in which species belonging to Drepanidae, Larentiinae, and Sterrhinae formed monophyletic groups. The Ennominae did not form a monophyletic group but rather were contained within a broader monophyletic group including Archiearinae, Geometrinae, and Alsophilinae (represented by only one species per group in the present study). The molecular results were used to explore further the relationship between Sterrhinae and Larentiinae, the question as to whether Ennominae actually represent a monophyletic group, and the relationships between Ennominae and some of the other subfamilies.

Amino Acid Sequence↗

PubMed2001

Valvular density alone cannot account for sites of chronic venous insufficiency and ulceration in the lower extremity.

OBJECTIVE: Class 6 chronic venous stasis is associated with abnormal venous hemodynamics and ulceration. Ulcers primarily occur over bones and tendon prominences but very rarely over muscular compartments. We hypothesized that the anatomical distribution of venous stasis ulcers in the lower extremity is related to a lower density of venous valves. METHODS: The venous vasculature of six normal human legs was cast with resin, and their microvenous valvular anatomy was examined. Skin samples were obtained from the skin overlying the 1) Achilles' tendon, 2) anterior tibia, 3) medial malleolus, 4) lateral malleolus, 5) dorsal surface of the foot, 6) planta pedis, 7) dorsal aspect of the great toe; and from the skin regions overlying the 8) gastrocnemius, 9) tibialis anterior, and 10) peroneus muscles. The valvular and venous densities were determined in a scanning electron microscope, normalized to the size of specimens, and the valvular index was calculated. Analysis of variance with Bonferroni t-test was used to compare the valvular index between the regions. RESULTS: Venous valves were observed in all tissue regions. The diameter of veins with valves ranged from 18 microm to 803 microm. The valvular index for regions overlying bones/tendons (i.e., regions 1-7) was significantly higher versus those overlying muscular regions (i.e., regions 8-10) (p < 0.05). The valvular index was not different (p = 0.51) when regions 1 and 2 (where ulcers almost never occur) were compared to regions 3, 4, 5, 6, and 7 (where ulcers frequently occur); nor were there differences between the vascular indexes of regions overlying muscle. The largest venous valves were observed in the plantar region, and the smallest-sized ones were present in the peroneal region. CONCLUSIONS: This study shows that the density of venous valves is actually higher in regions of the human lower extremity overlying bones and tendons, where venous stasis ulcers are common, than those overlying muscular areas, where ulcers are rarely seen. Thus, valvular quantity alone cannot account for the higher clinical incidence of ulceration. It is likely that muscular pumping and/or valvular quality are important factors in preventing the development of venous stasis and ulceration in the lower extremity.

Aged↗

PubMed2001

Infection of mice with the helminth Strongyloides stercoralis suppresses pulmonary allergic responses to ovalbumin.

Asthma and helminth infections induce similar immune responses characterized by the presence of peripheral blood eosinophilia and elevated serum IgE levels. Epidemiological surveys have reported either increases or decreases in the development of atopic diseases and asthma based on the prevalence of helminth infections in the population. The aim of this study was to determine if a pre-existing helminth infection would increase or decrease subsequent allergic responses to an unrelated allergen in the lungs. BALB/cByJ mice were infected with the nematode parasite Strongyloides stercoralis prior to ovalbumin (OVA) immunization and intratracheal challenge. Bronchoalveolar lavage (BAL) and fluid (BALF) were collected 3 days post-challenge and cellular and humoral immune responses were measured. Intracellular cytokine staining revealed increased IL-4 and IL-5 producing cells in BAL from mice infected with S. stercoralis before OVA sensitization. Increased IL-5 protein levels and decreased IFN-gamma protein levels were also observed in the BALF. There was, however, no increase in airway eosinophil accumulation in mice infectd with parasites before sensitization with OVA as compared to mice exposed to OVA alone. Furthermore, eotaxin levels in the lungs induced by OVA was suppressed in mice infected with the parasite before OVA sensitization. The development of OVA specific IgE responses in BALF was also impaired in mice infected with the parasite before sensitization with OVA. These results suggest that a pre-existing helminth infection may potentiate a systemic Type 2-type response yet simultaneously suppress in the lungs allergen-specific IgE responses and eotaxin levels in response to subsequent exposure to allergens.

Allergens↗

PubMed2001

Doxepin plasma concentrations: is there really a therapeutic range?

Despite the introduction of numerous new agents, tricyclic antidepressants remain an important option for the treatment of depression. Doxepin is still in wide use, and determining its concentration is a standard procedure in many psychiatric clinics. Some widely cited reviews indicate a therapeutic range from 150 to 250 ng/mL (parent plus desmethyl metabolite). The vast majority of the authors' patients fell short of these concentrations under customary doses. To resolve this issue, the authors' serum-level databank was analyzed, a questionnaire was sent to U.S. and German psychiatric university departments and laboratories, and the literature was reviewed. The main results were the following: (1) Only 9% of all samples analyzed (N = 217) displayed plasma levels (high-performance liquid chromatography) between 150 and 250 ng/mL; 88% were subtherapeutic. The mean doxepin + desmethyldoxepin steady-state serum concentration was 89+/-75 ng/mL (N = 32, doxepin >3 weeks). The mean daily dose was 143+/-30 mg. There was no correlation between concentrations and improvement. (2) A wide variety of recommendations is given by the different university departments (10-1,000 ng/mL). (3) According to the studies published to date, there is not enough evidence for recommending a therapeutic range. The preliminary suggestions given in some influential reviews have been widely adopted without critical re-evaluation. Compared with the concentrations found in the original studies, the therapeutic ranges suggested are too high. A methodologically sound study to determine a therapeutic range is required for the rational monitoring of this drug. Meanwhile, a preliminary working range of 50 to 250 ng/mL is proposed on the basis of critical reassessment of published data.

Aged↗

PubMed2001

Development of a recombinant antigen vaccine against infection with the filarial worm Onchocerca volvulus.

Efforts to control Onchocerca volvulus, the etiologic agent of river blindness, have been limited to vector control and drug treatment to eliminate microfilariae, with no means available to prevent infection. The goal of this study was to develop a vaccine against this infection using recombinant antigens that are expressed in the early larval stages of the parasite. Five recombinant antigens, Ov7, Ov64, OvB8, Ov9M, and Ov73k, were identified by screening adult and larval cDNA libraries with antibodies from immune humans, chimpanzees, or rabbits. When mice were immunized with the five individual recombinant antigens, statistically significant reductions in parasite survival were induced in mice immunized with Ov7, OvB8, or Ov64, when administered in alum but not when injected in Freund's complete adjuvant (FCA). Live larvae recovered from control and immunized mice were analyzed to determine their developmental stages. A decrease in the percentage of larvae molting from the third stage to the fourth stage was observed with mice immunized with Ov7, Ov64, or OvB8 in alum but not with mice immunized with Ov9 and Ov73k or with mice immunized with any of the five antigens in FCA. Mice immunized with a cocktail of the three protective antigens developed protective immunity equal to that seen with mice immunized with individual antigens. This study has identified, for the first time, three recombinant antigens capable of inducing protective immunity to O. volvulus. Furthermore, since the antigens functioned with alum as the adjuvant, this vaccine could potentially be used clinically to prevent river blindness in humans.

Adjuvants, Immunologic↗

PubMed2001

Iloprost suppresses connective tissue growth factor production in fibroblasts and in the skin of scleroderma patients.

Patients with scleroderma receiving Iloprost as a treatment for severe Raynaud's phenomenon report a reduction in skin tightness, suggesting that this drug inhibits skin fibrosis. Connective tissue growth factor (CTGF), a recently described profibrotic cytokine, acts downstream and in concert with TGF-beta to stimulate the fibrotic process and is involved in the fibrosis seen in scleroderma. Here we show that Iloprost, acting by elevation of cAMP, blocks the induction of CTGF and the increase in collagen synthesis in fibroblasts exposed to TGF-beta. The potency of Iloprost with respect to suppression of CTGF far exceeds that of other prostanoid receptor agonists, suggesting that its effect is mediated by the prostacyclin receptor IP. By sampling dermal interstitial fluid using a suction blister device, we show that CTGF levels are greatly elevated in the dermis of scleroderma patients compared with healthy controls and that Iloprost infusion causes a marked decrease in dermal CTGF levels. These studies suggest that Iloprost could be reducing the level of a key profibrotic cytokine in scleroderma patients and that endogenous production of eicosanoids may limit the fibrotic response to TGF-beta.

Cells, Cultured↗

PubMed2001

Effect of chronic ethanol consumption on protective T-helper 1 and T-helper 2 immune responses against the parasites Leishmania major and Strongyloides stercoralis in mice.

BACKGROUND: Chronic alcohol consumption has been associated with significant increases in the prevalence of infectious diseases, and it has been suggested that these increases are caused by a direct effect of ethanol on the immune response. The objective of this study was to determine whether chronic ethanol consumption would affect the development of protective immunity to Leishmania major, which is controlled by the T-helper 1 (Th1) subset of CD4 cells, and Strongyloides stercoralis, which is controlled by the Th2 subset. METHODS: Mice were fed ethanol-containing liquid diet (25% ethanol-derived calories), liquid isocaloric diet without ethanol, or solid chow and then exposed to either of the two parasites. The ability of the mice chronically consuming alcohol to eliminate the infections was determined, as were the levels of parasite-specific humoral and cellular immune responses. RESULTS: Mice chronically consuming alcohol were capable of eliminating both of these infections in a manner identical to the control mice. In addition, splenocytes from mice chronically consuming alcohol infected with L. major produced nitric oxide at the same levels as in control mice. Antibody responses were altered in a manner suggesting an increase in Th2 immunity and a decrease in Th1 immunity in the mice chronically consuming alcohol. In mice chronically consuming alcohol that were infected with S. stercoralis, eosinophils migrated to the parasite's microenvironment, and antibodies were produced at levels equivalent to those seen in control mice. CONCLUSIONS: Mice maintained on an ethanol-containing liquid diet had some alteration in their ability to produce Th1 and Th2 immune responses yet were capable of generating unimpaired protective Th1 and Th2 responses.

Alcohol Drinking↗

PubMed2000

Role of IL-5 in innate and adaptive immunity to larval Strongyloides stercoralis in mice.

Protective immunity to Strongyloides stercoralis infective larvae in mice has been shown to be dependent on IL-5 based on mAb depletion studies. The goal of this study was to determine the functional role of IL-5 during the innate and adaptive immune response to larval S. stercoralis in mice. In these studies, three strains of mice were used: wild-type C57BL/6J (WT), IL-5 knockout (KO), and IL-5 transgenic (TG). Innate responses to the larvae indicated that there was enhanced survival in the KO animals and decreased survival in the TG animals compared with WT. Furthermore, killing of larvae in TG mice was associated with eosinophil infiltration and degranulation. In studying the adaptive immune response, it was observed that immunization of KO mice did not lead to the development of protective immunity. Experiments were then performed to determine whether KO mice reconstituted with Abs or cells could then develop protective immunity. KO mice displayed protective immunity via a granulocyte-dependent mechanism following injection of purified IgM from immune wild-type animals. Immunity in KO mice could also be reconstituted by the injection of eosinophils at the time of immunization. These eosinophils did not participate in actively killing the challenge infection, but rather were responsible for the induction of a protective Ab response. We conclude that IL-5 is required in the protective immune response for the production of eosinophils, and that eosinophils were involved in larval killing during innate immunity and in the induction of protective Abs in the adaptive immune response.

Animals↗

PubMed2000

Selective downregulation of VEGF-A(165), VEGF-R(1), and decreased capillary density in patients with dilative but not ischemic cardiomyopathy.

Cardiomyopathy (CM) comprises a heterogeneous group of diseases, including ischemic (ICM) and dilative (DCM) forms. The pathogenesis of primary DCM is not clearly understood. Recent studies in mice show that vascular endothelial growth factor (VEGF) is involved in ICM. Whether VEGF plays a role in human CM is unknown. We examined the mRNA and protein expression of VEGF and its receptors in hearts of patients with end-stage DCM and ICM and in healthy individuals using real-time polymerase chain reaction and Western blotting. Number of capillaries, area of myocytes, and collagen were calculated in cardiac biopsies using transmission electron microscopy. In DCM, except for VEGF-C, mRNA transcript levels of VEGF-A(165), VEGF-A(189), and VEGF-B and the protein level of VEGF-A and VEGF-R(1) were downregulated compared with controls (P:<0.05). However, in ICM, mRNA transcript levels of VEGF isoforms and protein levels of VEGF-C were upregulated. The vascular density was decreased in DCM but increased in ICM compared with controls (P:<0. 05). Muscular hypertrophy was not different for ICM and DCM, although DCM had more collagen (P:<0.05). Blunted VEGF-A and VEGF-R(1) protein expression and downregulated mRNA of the predominant isoform of VEGF-A, VEGF-A(165), to our knowledge shown here for the first time, provide evidence that the VEGF-A defect in DCM is located upstream. Whether downregulation of certain VEGF isoforms in DCM is a cause or consequence of this disorder remains unclear, although upregulated VEGF levels in ICM are most likely the result of ischemia.

Adult↗

PubMed2000

Raf-1-associated protein phosphatase 2A as a positive regulator of kinase activation.

The Raf-1 kinase plays a key role in relaying proliferation signals elicited by mitogens or oncogenes. Raf-1 is regulated by complex and incompletely understood mechanisms including phosphorylation. A number of studies have indicated that phosphorylation of serines 259 and 621 can inhibit the Raf-1 kinase. We show that both serines are hypophosphorylated during early mitogenic stimulation and that hypophosphorylation correlates with peak Raf-1 activation. Concentrations of okadaic acid that selectively inhibit protein phosphatase 2A (PP2A) induce phosphorylation of these residues and prevent maximal activation of the Raf-1 kinase. This effect is mediated via phosphorylation of serine 259. The PP2A core heterodimer forms complexes with Raf-1 in vivo and in vitro. These data identify PP2A as a positive regulator of Raf-1 activation and are the first indication that PP2A may support the activation of an associated kinase.

Animals↗

PubMed2000

Utilization of "used" vials: cost-effective technique for MR arthrography.

Because full vials of commercially available MR arthrographic contrast are expensive, we hypothesized that the small residual contrast in a "used" vial would be adequate for MR arthrography. After sterility testing and quantity analysis of the residual contrast in 28 vials, this method was successfully used in 10 patients. J. Magn. Reson. Imaging 2000;12:953-955.

Adult↗

PubMed2000

TBI treatment planning using the ADAC pinnacle treatment planning system.

The use of total-body irradiation (TBI) for the purpose of bone marrow transplant is an established procedure at many institutions. In our institution, the TBI monitor unit (MU) calculation starts with the calibration done at the same conditions of the treatment source-axis distance (SAD) = 350 cm for the field size of 40 x 40 cm at a depth of 10 cm). The dose rate in the central axis of the beam at this distance is measured in cGy/MU. A tissue phantom ratio table obtained in the condition of treatment together with off-axis factors is used in the MU calculation for each particular patient. The treatment is done with the patient lying on his/her back and the beam is delivered using right-to-left lateral beams. Due to different thickness' of the patient, a lead compensator is built to compensate for the different parts of the body. Eighteen or 10-MV x-ray photons are used in the TBI treatment, and a 1-cm-thick lucite plate is placed near the patient to increase the dose to the surface. In vivo dosimetry using diodes is done to verify the calculations. The Rando-Phantom was computed-tomography scanned from the head to the abdomen with 1-cm-thick slices covering 70 cm of the phantom. This simulated the TBI treatment and correlated the calculations done by the ADAC treatment planning system to film measurements at the pelvis and lung levels. These results agreed within 5% of the measured dose. The use of the upper arms to reduce the dose to the lungs and optimization of dose using special compensators has been studied using the treatment planning system. Use of the multileaf collimator to compensate the dose received by the patient has been explored in this paper.

Humans↗

PubMed1999

Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials.

The objective of this meta-analysis is to summarize the efficacy and tolerability of the new antipsychotics risperidone, olanzapine, sertindole and quetiapine in schizophrenia compared to placebo and conventional antipsychotics. The main results are: (1) All of the 4 new drugs are more effective than placebo, but the magnitude of the effect is only moderate [mean effect size, r, of all antipsychotics vs. placebo = 0.25, with a 95% confidence interval (CI) = 0.22-0.28, n = 2477]. (2) According to the studies published to date, sertindole and quetiapine are as effective as haloperidol, and risperidone and olanzapine are slightly more effective than haloperidol in the treatment of global schizophrenic symptomatology. (3) With respect to negative symptoms, all new antipsychotics are more effective than placebo. However, contrary to widespread opinion, so is the 'conventional' antipsychotic haloperidol. Risperidone and olanzapine are slightly superior, sertindole is as effective and--according to the only study fully published to date--quetiapine is even slightly less effective than haloperidol in this regard. (4) All new antipsychotics are associated with less frequent use of antiparkinson medication than haloperidol, with risperidone appearing to have a slightly less favourable EPS-profile than the other new antipsychotics. The methodological limitations of this review, the generalizability of the results and expectations from future research are discussed.

Antipsychotic Agents↗

PubMed1999

Lung fibrosis.

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Animals↗