PubMed Health⌕ Search

Biomedical subjects

A Sullivan

Publications and source records attributed to A Sullivan.

At least 37 records · Page 2Linked to original sources
PubMed2000

Growth/differentiation factor-15/macrophage inhibitory cytokine-1 is a novel trophic factor for midbrain dopaminergic neurons in vivo.

Transforming growth factor-betas (TGF-betas) constitute an expanding family of multifunctional cytokines with prominent roles in development, cell proliferation, differentiation, and repair. We have cloned, expressed, and raised antibodies against a distant member of the TGF-betas, growth/differentiation factor-15 (GDF-15). GDF-15 is identical to macrophage inhibitory cytokine-1 (MIC-1). GDF-15/MIC-1 mRNA and protein are widely distributed in the developing and adult CNS and peripheral nervous systems, including choroid plexus and CSF. GDF-15/MIC-1 is a potent survival promoting and protective factor for cultured and iron-intoxicated dopaminergic (DAergic) neurons cultured from the embryonic rat midbrain floor. The trophic effect of GDF-15/MIC-1 was not accompanied by an increase in cell proliferation and astroglial maturation, suggesting that GDF-15/MIC-1 probably acts directly on neurons. GDF-15/MIC-1 also protects 6-hydroxydopamine (6-OHDA)-lesioned nigrostriatal DAergic neurons in vivo. Unilateral injections of GDF-15/MIC-1 into the medial forebrain bundle just above the substantia nigra (SN) and into the left ventricle (20 microgram each) immediately before a 6-OHDA injection (8 microgram) prevented 6-OHDA-induced rotational behavior and significantly reduced losses of DAergic neurons in the SN. This protection was evident for at least 1 month. Administration of 5 microgram of GDF-15/MIC-1 in the same paradigm also provided significant neuroprotection. GDF-15/MIC-1 also promoted the serotonergic phenotype of cultured raphe neurons but did not support survival of rat motoneurons. Thus, GDF-15/MIC-1 is a novel neurotrophic factor with prominent effects on DAergic and serotonergic neurons. GDF-15/MIC-1 may therefore have a potential for the treatment of Parkinson's disease and disorders of the serotonergic system.

Animals↗
PubMed2000

Thalamic volume in pediatric obsessive-compulsive disorder patients before and after cognitive behavioral therapy.

BACKGROUND: Neurobiologic abnormalities in the thalamus have been implicated in the pathophysiology of obsessive-compulsive disorder. We recently reported increased thalamic volume in treatment-naive pediatric obsessive-compulsive disorder patients versus case-matched healthy comparison subjects that decreased to levels comparable to control subjects after effective paroxetine therapy. To our knowledge, no prior study has measured neuroanatomic changes in the thalamus of obsessive-compulsive disorder patients near illness onset before and after cognitive behavioral therapy. METHODS: Volumetric magnetic resonance imaging studies were conducted in 11 psychotropic drug-naive 8-17-year-old children with obsessive-compulsive disorder before and after 12 weeks of effective cognitive behavioral therapy monotherapy (> or =30% reduction in obsessive-compulsive disorder symptom severity). RESULTS: No significant change in thalamic volume was observed in obsessive-compulsive disorder patients before and after cognitive behavioral therapy. CONCLUSIONS: Our findings suggest that reduction in thalamic volume after paroxetine therapy may be specific to paroxetine treatment and not the result of a general treatment response or spontaneous improvement. These results are preliminary in view of the small sample studied.

Adolescent↗
PubMed2000

GDF-15/MIC-1 a novel member of the TGF-beta superfamily.

We have cloned, expressed, and raised antibodies against a novel member of the TGF-beta superfamily, growth/differentiation factor-15 (GDF-15). The predicted protein is identical to macrophage inhibitory cytokine-1 (MIC-1), which was discovered simultaneously. GDF-15 is a more distant member of the TGF-beta superfamily and does not belong to one of the known TGF-beta subfamilies. In the CNS, GDF-15/MIC-1 mRNA is abundantly expressed by the choroid plexus. In addition we have preliminary evidence that GDF-15/MIC-1 is a potent trophic factor for selected classes of neurons in vitro and in vivo. Thus, GDF-15 is a novel neurotrophic factor with prospects for the treatment of disorders of the CNS.

Animals↗
PubMed2000

Case management: the current best practices and the next generation of innovation.

Eight published literature reviews of case management were evaluated to determine areas of consensus regarding outcomes associated with full service, broker, and hybrid models. Full service was recommended for "best practice" status and the effectiveness of the broker model was seriously questioned. Research evaluating para-professional and peer assisted models of case management, a potential method for improving outcomes, was also reviewed. One promising peer-assisted model was identified and described. Although the use of paraprofessionals and peers in case management holds promise, much more research is needed before the effectiveness of this approach can be confidently determined.

Benchmarking↗
PubMed2000

Dental plaque mass and acid production activity of the microbiota on teeth.

With the purpose of elucidating the effect of dental plaque thickness on the acid production activity in dental plaque, we studied the prevalence of acid anions in dental plaque of children harbouring different amount of plaque on their teeth. On two occasions, the occurrence of plaque on the dentition was scored (Silness-Löe's index), and plaque on available smooth surfaces was collected and the wet weight determined. On the first occasion, the amount of acid anions in resting plaque, and on the second occasion, the acid anions of sucrose-exposed plaque were analysed with isotachophoresis. Mean value of plaque wet weights per individual dentition was 11.7 +/- 9.0 mg (first occasion) and 11.1 +/- 8.9 mg (second occasion). Dominating anions in resting plaque were acetate < propionate < lactate and in sucrose-exposed plaque lactate < acetate < propionate. The microbial acid production activity (acid anion per mg wet plaque weight) decreased with increasing weights of the plaque mass. The findings illustrate the cellular glycolytic metabolism of plaque microorganisms in thin and thick plaque, being a consequence of the diverse environmental condition existing in these ecosystems.

Acetic Acid↗
PubMed2000

Recombinant human thyroid peroxidase produced in insect cells has similar properties to native human thyroid peroxidase.

Purified native human thyroid peroxidase (nTPO) isolated from thyroid tissue and recombinant (r)TPO produced in High Five insect cells have been compared. nTPO and rTPO were purified to about 95% homogeneity and showed similar UV and visual spectra and similar 412 nm per 280 nm absorbance ratios (0.4 for nTPO and 0.4 for rTPO). The nTPO and rTPO guaiacol oxidation enzyme activities were about 1,000 guaiacol units per milligram of protein. TPO autoantibody binding characteristics of nTPO and rTPO were analyzed in an assay based on 125I-labeled nTPO and precipitation with protein A. In the assay, the effect of unlabeled nTPO or rTPO on TPO autoantibody binding from 25 patients sera was studied. Unlabeled nTPO or rTPO (from 0 to 160 ng/mL) inhibited the binding of TPO autoantibodies in a dose-dependent manner in the case of each serum studied (from 100% in the absence of unlabeled TPO to 5%-10% in the presence of 160 ng/mL of TPO). The inhibition profile for each serum was essentially identical in the case of both TPO preparations. The effect of TPO autoantibodies on enzyme activity of rTPO was analyzed after incubation of rTPO with TPO autoantibody-positive serum immunoglobulin G (IgG) (n = 12), TPO monoclonal antibodies reactive with two different epitopes on the TPO, IgG (n = 3) from glutamic acid decarboxylase autoantibody positive patient sera, and IgG (n = 3) from healthy blood donors. Effective complexing of TPO by TPO autoantibodies was tested by precipitating the complexes with solid phase protein A and measuring the TPO enzyme activity in the resulting supernatants. These studies showed that the TPO enzyme activity was not affected by incubation with TPO autoantibody-positive IgG or monoclonal antibodies despite effective complexing of the autoantibodies with TPO. Overall, our studies demonstrate that nTPO and rTPO produced in insect cells are very similar in terms of enzyme activity, UV and visible spectra, and reactivity with autoantibodies. Furthermore, in our study, TPO autoantibodies did not appear to inhibit TPO enzyme activity.

Animals↗
PubMed2000

A retrospective study of neutropenia in HIV disease.

In aiming to define the characteristics of HIV-infected subjects developing neutropenia and describe the causes, features and effects of neutropenia we undertook a retrospective study in a dedicated HIV unit in London, UK. Two hundred and forty-four patients with documented neutropenia, defined as absolute neutrophil count (ANC) < 1,000/mm3, during a 12-month period were studied. First neutropenia occurred at a median CD4 count of 30 cells/mm3. Low CD4 count was associated with longer episodes of neutropenia with a more profound nadir. Two-thirds of episodes lasted less than 2 weeks. ANC nadir was < 500 cells/mm3 in 45% of episodes. Infections were most frequent in patients with profound but brief neutropenic episodes. Neutropenia was generally mild, short-lived and associated with late-stage disease. However, profound neutropenia did develop suddenly in some patients with no prior history of neutropenia (in 13% first neutropenic ANC recorded was < or =500 cells/mm3), and at CD4 count > 200 cells/mm3. Most patients were receiving multiple myelosuppressive therapies. Infection was associated with brief, profound neutropenia.

Anti-HIV Agents↗
PubMed1999

Impaired collateral vessel development associated with reduced expression of vascular endothelial growth factor in ApoE-/- mice.

BACKGROUND: The impact of disordered lipid metabolism on collateral vessel development was studied in apolipoprotein (apo)E-/- mice with unilateral hindlimb ischemia. METHODS AND RESULTS: Hindlimb blood flow and capillary density were markedly reduced in apoE-/- mice versus C57 controls. This was associated with reduced expression of vascular endothelial growth factor (VEGF) in the ischemic limbs of apoE-/- mice. Cell-specific immunostaining localized VEGF protein expression to skeletal myocytes and infiltrating T cells in the ischemic limbs of C57 mice; in contrast, T-cell infiltrates in ischemic limbs of apoE-/- mice were severely reduced. The critical contribution of T cells to VEGF expression and collateral vessel growth was reinforced by the finding of accelerated limb necrosis in athymic nude mice with operatively induced hindlimb ischemia. Adenoviral VEGF gene transfer to apoE-/- mice resulted in marked augmentation of hindlimb blood flow and capillary density. CONCLUSIONS: These findings thus underscore the extent to which hyperlipidemia adversely affects native collateral development but does not preclude augmented collateral vessel growth in response to exogenous cytokines. Moreover, results obtained in the apoE-/- and athymic nude mice imply a critical role for infiltrating T cells as a source of VEGF in neovascularization of ischemic tissues.

Adenoviridae↗
PubMed1999

Xenotransplantation of cells using biodegradable microcapsules.

BACKGROUND: The use of immunoisolation to protect transplanted cells from the immune system of the host has broad application to the treatment of major diseases such as diabetes and a wide range of other disorders resulting from functional defects of native cell systems. In most cases, limitations in functional cell longevity will necessitate periodic replenishment of the cells. We describe a hydrogel-based microcapsule that breaks down at a rate that can be adjusted to correspond to the functional longevity of the encapsulated cells. These injectable capsules can be engineered to degrade over several weeks to months for short-term drug delivery, or to remain intact and immunoprotective for more extended periods. When the supply of cells needs to be replenished, no surgery will be required to localize and remove the old capsules. METHODS: Porcine and bovine islets were immobilized in "composite" microcapsules fabricated from alginate and low-relative molecular mass (Mr) poly (L-lysine[PLL]) (Mr exclusion <120 Kd) and implanted into the peritoneum of normal and streptozotocin-induced diabetic rats. In addition to demonstrating long-term islet viability and function, a series of in vitro studies were carried out to determine the permeability and biodegradability of the microcapsules used in the present system. RESULTS: Xenogeneic islets implanted in nonimmunosuppressed rats remained in excellent condition indefinitely (>40 weeks)(viability was comparable to that of preimplant control specimens). In contrast, no islets survived in uncoated alginate spheres after 2 weeks postimplantation. By changing the concentration of the alginate, it was possible to vary the rate of capsule breakdown in rats from mechanically unstable (outer matrix <0.5-0.75% alginate) to stable for >1 year (> or =1.5% alginate). In addition to in vivo breakdown studies, the biodegradability of the capsular components was verified in vitro using a mixture of tritosomes (enzymes isolated from animal cells). CONCLUSIONS: We have designed a microcapsule system with controllable biodegradability which allows breakdown and absorption of implants when the cells die or become functionally inactive. These results may have application to other alginate-PLL encapsulation systems. The ability to cross species lines using these biodegradable microcapsules has the potential to expand dramatically the number of patients and the scope of diseases that can be successfully treated with cellular therapy.

Absorbable Implants↗
PubMed1999

Choroid plexus cysts: Is biochemical testing a valuable adjunct to targeted ultrasonography?

OBJECTIVE: We sought to determine whether biochemical testing is a valuable adjunct to ultrasonography in selecting patients with fetal choroid plexus cysts for amniocentesis. STUDY DESIGN: The study population consists of 128 patients who had fetal choroid plexus cysts detected during ultrasonography performed between 18 and 22 weeks' gestation. The patients had genetic counseling, and amniocentesis and biochemical testing were offered to all patients. The data were analyzed by dividing the patients into 3 groups. Group 1 had targeted ultrasonography only, group 2 had ultrasonography and maternal serum alpha-fetoprotein testing, and group 3 had ultrasonography and triple-screen (maternal serum alpha-fetoprotein, human chorionic gonadotropin, and estriol) testing. Outcome was determined by fetal karyotype or by neonatal examination by a pediatrician for patients who declined amniocentesis. RESULTS: There were 25 patients in group 1. Isolated choroid plexus cysts were detected in 20 fetuses, and all had normal outcomes. Additional anomalies were detected in 5 fetuses. Two had normal karyotypes, and 3 had trisomy 18. There were 52 patients in group 2. The maternal serum alpha-fetoprotein levels were normal in 44 patients, 41 of whom had isolated fetal choroid plexus cysts. Of these 44 patients, 40 had normal outcomes, and 1 patient had a fetus with trisomy 18. The remaining 3 patients with normal maternal serum alpha-fetoprotein levels had additional fetal anomalies on ultrasonography, but the karyotypes were normal. The maternal serum alpha-fetoprotein levels were abnormal in 8 patients, of whom 6 had fetuses with isolated choroid plexus cysts and normal karyotypes. Two patients had additional fetal anomalies detected on ultrasonography and had abnormal karyotypes, 1 with trisomy 21 and 1 with trisomy 18. There were 51 patients in group 3. Results of the triple screen were normal in 32 patients. The choroid plexus cysts were isolated in 29 of the 32 patients, and all 29 fetuses had normal karyotypes. The other 3 patients with normal triple-screen results had additional fetal anomalies on ultrasonography. One fetus had normal chromosomes, and 2 had trisomy 18. The remaining 19 patients had abnormal triple-screen results. Among them, 16 fetuses had isolated choroid plexus cysts, 13 of whom were normal, 2 had trisomy 18, and 2 had a de novo unbalanced translocation. The remaining 3 fetuses had additional anomalies, and all 3 fetuses had trisomy 18. There were 14 fetuses with significant chromosomal abnormalities. Nine mothers were <35 years old, and 5 were >/=35 years old. CONCLUSIONS: This study shows the following: (1) The triple screen is a useful adjunct to targeted ultrasonography in selecting patients with fetal choroid plexus cysts for amniocentesis. (2) A normal triple-screen result and the absence of additional fetal anomalies on ultrasonography reliably exclude an underlying chromosomal abnormality, and amniocentesis is not indicated. (3) If the triple-screen result is abnormal, additional anomalies are seen on ultrasonography, or the mother is aged >/=35 years, then fetal karyotyping is recommended. (4) Patients who decline fetal karyotyping should have follow-up ultrasonography in 34 weeks' time.

Chorionic Gonadotropin↗
PubMed1999

Treatment outcome in presumed and confirmed AIDS-related primary cerebral lymphoma.

A retrospective analysis identified 38 HIV seropositive patients with a diagnosis of presumed (n = 26) or confirmed (n = 12) primary cerebral lymphoma (PCNSL). All patients had failed to respond to empirical antitoxoplasma therapy and the clinical diagnosis of PCNSL was confirmed by brain biopsy (n = 4), cerebrospinal fluid (CSF) examination for Epstein-Barr virus (EBV) by PCR (n = 7) or postmortem examination (n = 1). There was no difference in the age, performance status, CD4 counts, antiretroviral usage or interval since first HIV serodiagnosis between patients with presumed or confirmed PCNSL. 16 patients received either radiotherapy (n = 14) or chemotherapy (n = 2). Patients with confirmed or presumptive PCNSL were equally likely to receive treatment. The median overall survival, which was measured from the end of unsuccessful antitoxoplasma therapy, was 1.2 months for the whole cohort. There was no difference in overall survival between patients with presumptive (median 0.8 months) and confirmed (median 1.3 months) PCNSL (logrank P = 0.69). This suggests that there may be little value in positively diagnosing PCNSL in the current diagnostic algorithm. Recent improvements in outcome have been reported with systemic chemotherapy in HIV-PCNSL and may influence the need for earlier definitive diagnosis in the future.

Adult↗
PubMed1999

Spatial assimilation effects and error detection in rapid overlapping and sequential bimanual movements.

This study verified earlier anecdotal evidence indicating that spatial assimilations could be reduced by offsetting movements in time. In Experiment 1, 40 right-handed participants (ages 18-23 years) made single and dual quick lever reversals of 20 degrees and 60 degrees with the left and right limbs, respectively. Participants were assigned to either the Overlapping (O) group, in which one limb began when the other limb reached the reversal point, or to the Sequential (S) group in which one limb followed the other with a delay of 114 ms, on average. The shorter-distance limb of the O group overshot relative to the S group. Short-distance spatial assimilations were also shown in the S group in Experiment 2, when the delay was increased to 250, 500, or 1,500 ms (N = 30), suggesting that assimilation effects can be caused by command interactions at both the planning and the execution levels.

Adolescent↗
PubMed1999

Killing of Mycobacterium avium by neutrophils and monocytes from AIDS patients treated with recombinant granulocyte-macrophage colony-stimulating factor.

In this study, 30 AIDS patients without Mycobacterium avium infection were randomized to receive treatment with azithromycin (1200 mg), granulocyte-monocyte colony-stimulating factor (GM-CSF; 250 microg/m2/day for 5 days), or both agents. The M. avium killing capacity of neutrophils and monocytes harvested from each patient before intervention and during (day 4), and after therapy (day 8) was assessed. The mean virus load change in the groups receiving GM-CSF was +0.14 log human immunodeficiency virus RNA. After GM-CSF therapy, neither neutrophils nor monocytes could significantly reduce M. avium growth (P=.96 and.31, respectively). Bone pain, myalgia, presyncope, or fever occurred in 55% of patients receiving GM-CSF. Thus, the GM-CSF regimen used in this study did not affect virus load, frequently caused adverse reactions, and did not improve the M. avium killing capacity of neutrophils and monocytes. Future studies using a different GM-CSF regimen are indicated.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Role of endothelial nitric oxide synthase in endothelial cell migration.

Endothelium-derived nitric oxide (NO) and its precursor L-arginine have been implied to promote angiogenesis, but little is known about the precise mechanism. The inhibition of endogenous NO formation by Nomega-nitro-L-arginine methyl ester (L-NAME) (1 mmol/L) but not its inactive enantiomer D-NAME (1 mmol/L) inhibited endothelial cell sprouting from the scratched edge of the cultured bovine aortic endothelial cell monolayer. Inhibition of endogenous NO release by L-NAME was confirmed by amperometric measurement using an NO-specific electrode. In the modified Boyden chamber, L-NAME (1 mmol/L) significantly inhibited endothelial cell migration, whereas L-NAME did not affect endothelial DNA synthesis as assessed by analysis of [3H]thymidine incorporation. We then examined alteration of endothelial cell adhesion molecule expression after the inhibition of NO by L-NAME in cultured human umbilical vein endothelial cells. In both normoxic and hypoxic conditions, L-NAME (1 mmol/L) inhibited surface expression of integrin alphavbeta3, which is an important integrin facilitating endothelial cell survival and angiogenesis. However, L-NAME did not affect the expression of platelet endothelial cell adhesion molecule-1, intercellular adhesion molecule-1, vascular endothelial adhesion molecule-1, gap junction protein connexin 43, and VE-cadherin, which have been reported to potentially affect angiogenesis. In summary, inhibition of endothelial NO synthase by L-NAME attenuated endothelial cell migration but not proliferation in vitro. Furthermore, endogenous endothelium-derived NO maintains the functional expression of integrin alphavbeta3, a mediator for endothelial migration, survival, and angiogenesis. Endothelium-derived NO, thus, may play an important role in mediating angiogenesis by supporting endothelial cell migration, at least partly, via an integrin-dependent mechanism.

Animals↗
PubMed1998

Transmigration of CD34+ cells across specialized and nonspecialized endothelium requires prior activation by growth factors and is mediated by PECAM-1 (CD31).

The transmigration of hematopoietic progenitor cells (HPCs) across vascular endothelium is a critical step in the homing of transplanted stem cells, but the molecular basis for this is unknown. We used mobilized peripheral blood CD34(+) selected cells and cultured bone marrow microvascular (BMECs) and human umbilical vein endothelial cells (HUVECs) to investigate the adhesion and transendothelial migration of HPCs. Colony-forming cells (CFCs) in freshly isolated CD34(+) cells showed high levels of adhesion to both forms of endothelium (28% +/- 4% and 38% +/- 6% of granulocyte-macrophage colony-forming cells [GM-CFCs] adhering to HUVECs and BMECs, respectively), but were unable to migrate to any significant extent across either (1.0% +/- 0.3% and 1.1% +/- 0.6% of GM-CFCs migrating across HUVECs and BMECs, respectively). Greater than 95% of peripheral blood CD34(+) cells are in G0/G1 of the cell cycle, but after 48 to 72 hours of stimulation with growth factors (interleukin-3 [IL-3] 12 ng/mL, stem cell factor 10 ng/mL, and IL-6 10 ng/mL), 28% +/- 5% of cells were in S+G2/M. Growth factor stimulation had no effect on the adhesion of mobilized CFCs but resulted in enhanced migration of these cells (9.8% +/- 1.6% and 12. 6% +/- 3.1% of GM-CFCs migrating across HUVECs and BMECs, respectively; P < .01, n = 6). Assessment of cell proliferation by the 3H-thymidine suicide method showed that, whereas 11.7% +/- 3.3% of proliferating CFCs transmigrated across endothelium, only 1.3% +/- 0.3% of nonproliferating CFCs did so (P < .05, n = 5). Transmigration of growth factor-activated CFCs was inhibited by anti-CD18 monoclonal antibody (MoAb; 50% +/- 18% inhibition) and by anti-platelet endothelial cell adhesion molecule-1 (PECAM-1) MoAb (70.8% +/- 7.1% inhibition; P < .05, n = 3). IL-1 stimulation of HUVECs had no significant effect on CD34(+) cell transmigration, but caused marked enhancement of neutrophil migration. Stem cell homing may depend, in part, on the ability of local cytokines to upregulate the transmigratory ability of these cells. The transmigration of HPCs shares at least some molecular pathways with that of mature cells (CD18 and PECAM-1), but is differently affected by endothelial activation.

Antigens, CD34↗