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Biomedical subjects

D Jacobs

Publications and source records attributed to D Jacobs.

At least 19 recordsLinked to original sources
PubMed2000

DNA vaccination with genes encoding Toxoplasma gondii antigens GRA1, GRA7, and ROP2 induces partially protective immunity against lethal challenge in mice.

C57BL/6, C3H, and BALB/c mice were vaccinated with plasmids encoding Toxoplasma gondii antigens GRA1, GRA7, and ROP2, previously described as strong inducers of immunity. Seroconversion for the relevant antigen was obtained in the majority of the animals. T. gondii lysate stimulated specific T-cell proliferation and secretion of gamma interferon (IFN-gamma) in spleen cell cultures from vaccinated BALB/c and C3H mice but not in those from control mice. Although not proliferating, stimulated splenocytes from DNA-vaccinated C57BL/6 mice also produced IFN-gamma. No interleukin-4 was detected in the supernatants of lysate-stimulated splenocytes from DNA-vaccinated mice in any of the mouse strains evaluated. As in infected animals, a high ratio of specific immunoglobulin G2a (IgG2a) to IgG1 antibodies was found in DNA-vaccinated C3H mice, suggesting that a Th1-type response had been induced. For BALB/c mice, the isotype ratio of the antibody response to DNA vaccination was less polarized. The protective potential of DNA vaccination was demonstrated in C3H mice. C3H mice vaccinated with plasmid encoding GRA1, GRA7, or ROP2 were partially protected against a lethal oral challenge with cysts of two different T. gondii strains: survival rates increased from 10% in controls to at least 70% after vaccination in one case and from 50% to at least 90% in the other. In vaccinated C3H mice challenged with a nonlethal T. gondii dose, the number of brain cysts was significantly lower than in controls. DNA vaccination did not protect BALB/c or C57BL/6 mice. Our results demonstrate for the first time in an animal model a partially protective effect of DNA vaccination against T. gondii.

Animals↗
PubMed1999

Multiple docking sites on substrate proteins form a modular system that mediates recognition by ERK MAP kinase.

MAP kinases phosphorylate specific groups of substrate proteins. Here we show that the amino acid sequence FXFP is an evolutionarily conserved docking site that mediates ERK MAP kinase binding to substrates in multiple protein families. FXFP and the D box, a different docking site, form a modular recognition system, as they can function independently or in combination. FXFP is specific for ERK, whereas the D box mediates binding to ERK and JNK MAP kinase, suggesting that the partially overlapping substrate specificities of ERK and JNK result from recognition of shared and unique docking sites. These findings enabled us to predict new ERK substrates and design peptide inhibitors of ERK that functioned in vitro and in vivo.

3T3 Cells↗
PubMed1999

How to improve lithotripsy and chemolitholysis of brushite-stones: an in vitro study.

Because of their resistance to fragmentation, treatment of brushite stones is a big problem. This study was performed to look for an improvement in therapeutic strategies by using artificial stones made of brushite (Bon(n)-stones), which are comparable to their natural counterparts. Using an ultrasound transmission technique, longitudinal wave propagation speeds were measured at different time intervals during treatment with hemiacidrin. From these and density measurements, transverse wave speed, wave impedance and dynamic mechanical properties of the artificial stones were calculated. Moreover, the microhardness of artificial stones was measured and investigations on shock wave lithotripsy (SWL) combined with initial chemolytic treatment of the stones were performed. The suggestion was confirmed that stone fragility and thus SWL can be improved by varying the physical properties of brushite stones through treatment with hemiacidrin. Additionally, we demonstrated the efficacy of Suby G in dissolving artificial brushite stones using an experimental arrangement simulating the physiological conditions in the upper urinary tract. Moreover, the efficacy of four different intracorporeal lithotripsy devices (electrohydraulic, pneumatic, laser and ultrasound) was tested and it was shown that electrohydraulic lithotripsy seems to be the best system for comminution of brushite stones.

Calcium Phosphates↗
PubMed1999

Pulse cyclophosphamide for steroid-resistant focal segmental glomerulosclerosis.

We report the response of ten patients (6 male, 4 female) with steroid-resistant focal segmental glomerulosclerosis (FSGS) to treatment with intravenous pulse cyclophosphamide (IVCP) together with oral prednisone. All patients had been treated with 60 mg/m2 oral prednisone daily for 2 months upon initial presentation. IVCP was given monthly at a dose of 500 mg/m2 over 6 months. Oral prednisone was given concurrently at 60 mg/m2 daily for 2 months and then on alternate days for 4 months, followed by 30 mg/m2 on alternate days for 6 months. Prednisone was then tapered monthly by 10 mg and finally discontinued. Five patients failed to respond to steroids from the onset and were considered as primary steroid resistant. Two of these patients achieved sustained remission after IVCP, one patient showed a partial response, with loss of edema, normalization of serum albumin, and persistent proteinuria, while two patients showed no response to IVCP. The other five patients had achieved remission after 2 months of daily prednisone at 60 mg/m2 upon initial presentation, but had suffered from more than three relapses per year and had eventually become steroid resistant. They were considered secondary steroid resistant. All five patients achieved sustained remission after IVCP. None of our patients suffered from adverse effects of IVCP. We suggest IVCP as an adjunctive therapy for steroid-resistant FSGS, particularly for patients with secondary steroid resistance.

Adolescent↗
PubMed1999

In vivo expression and distribution of dense granule protein 7 (GRA7) in the exoenteric (tachyzoite, bradyzoite) and enteric (coccidian) forms of Toxoplasma gondii.

The in vivo expression and distribution of the dense granule protein GRA7 was examined in both the exoenteric (tachyzoite and bradyzoite) and enteric (coccidian) forms of Toxoplasma gondii by immunocytochemistry. There was strong staining of GRA7 in granules within all the infectious stages (tachyzoite, bradyzoite, merozoite and sporozoite). During tachyzoite development, GRA7 was secreted and was associated with the parasitophorous vacuole. In contrast, although there was staining of granules within the bradyzoites of more mature cysts, there appeared to be little staining of the tissue cyst wall or host cell. The apparent stage-specific variation in secretion of GRA7 between tachyzoites and bradyzoites was confirmed by double labelling using stage-specific markers (SAG1 and BAG1). In the enteric forms in the cat gut there was strong labelling of the PV containing early asexual and sexual stages and staining of a few granules in the apical cytoplasm of the merozoite. The positive enteric staining pattern differentiates GRA7 from the other GRA proteins (GRA1-6) which were absent in the merozoites and enteric stages. The staining pattern of GRA7 with strong staining during tachyzoite and enteric development and reduced staining in the tissue cysts is similar to that seen for NTPases. The function of GRA7 is unknown but it is unique among the dense granule proteins in being expressed in all the infectious forms of T. gondii which would point to a basic role in the vacuolar adaptations required for active parasite development.

Animals↗
PubMed1999

Evaluation of recombinant dense granule antigen 7 (GRA7) of Toxoplasma gondii for detection of immunoglobulin G antibodies and analysis of a major antigenic domain.

Dense granule protein 7 (GRA7) of Toxoplasma gondii was expressed in Escherichia coli as a fusion protein. The leader peptide contained a 25-amino-acid mouse tumor necrosis factor fragment and six histidyl residues. After purification by metal chelate affinity chromatography, the antigen was evaluated in an enzyme-linked immunosorbent assay for detection of immunoglobulin G (IgG). For two sets of IgG-positive human serum samples, obtained from routine screening, an overall sensitivity of 81% was obtained. For chronic-phase sera, the sensitivity of detection was 79%, but chronic-phase sera with low titers were more difficult to detect (65% sensitivity for sera with immunofluorescence titer of 1/64). When GRA7 was combined with Tg34AR (rhoptry protein 2 C-terminal fragment), the sensitivity rose to 96%. For a set of acute-phase serum samples tested on GRA7, the sensitivity of detection was 94%, and high-titer IgM-positive sera were detected at an especially high rate. In contrast, when Tg34AR was used, the sensitivity was only 85% for this latter set of serum samples. Three truncated GRA7 fragments containing the same leader peptide as that of recombinant GRA7 were produced. The shortest fragment (97 N-terminal amino acids) was not reactive with human sera or with a specific anti-GRA7 monoclonal antibody, while the two larger fragments were reactive. The most important antigenic domain of GRA7 for human sera was localized between residues 97 and 146. The epitope for the specific monoclonal antibody could be further narrowed down by the use of synthetic peptides, but this epitope is not recognized by sera from T. gondii-infected humans. These results indicate that GRA7 may be considered as an additional tool for studying the immune response to T. gondii.

Animals↗
PubMed1998

Identification and heterologous expression of a new dense granule protein (GRA7) from Toxoplasma gondii.

Immunoscreening of an expression library constructed with Toxoplasma gondii tachyzoite mRNA with sera from toxoplasmosis-positive humans has led to the identification of a new parasite antigen. Sequence analysis of the gene encoding this antigen allowed the calculation of the theoretical molecular mass (25,857 Da) and showed that the protein contains a putative signal sequence. The C-terminal region contains two hydrophobic regions, the last of which has the characteristics of a membrane-spanning domain. When the protein was heterologously expressed in E. coli and tested by Western blot, it reacted with the human sera originally used for screening. The new antigen also reacted with a monoclonal antibody raised against the entire parasite. Ultrastructural analysis showed that the protein is localized in the dense granules. After host cell invasion, the protein is secreted into the vacuolar network, the parasitophorous vacuole membrane, and into extensions protruding in the cytoplasm. Therefore, it is suggested to designate this new dense granule protein GRA7, following the established nomenclature for this protein family.

Amino Acid Sequence↗
PubMed1998

A study of the efficacy of a comprehensive memory enhancement program in healthy elderly persons.

Well educated, high functioning older adults (ages 60-90) were given a comprehensive memory enhancement training program to determine the effectiveness of the program in increasing cognitive performance and positively influencing self-assessments of memory efficacy. The 68 subjects who participated in the memory enhancement training were compared to 74 subjects who were enrolled in a video control group. Between subject differences were analyzed prior to the interventions and at three time points following the interventions (immediately post, 3 months and 6 months). Only one cognitive measure, assessing verbal memory, revealed a significant difference between the groups, with participants in the memory enhancement group showing less decline from baseline than the video control group immediately following the intervention but with no difference between groups at 6 months post-intervention. Several self-report measures showed that the memory enhancement training subjects experienced improved memory functioning and decreased memory concerns relative to the video control group. The self-reported effects of the training were sustained over the 6-month follow-up period.

Adult↗
PubMed1998

Determining the similarity of deformable shapes.

Determining the similarity of two shapes is a significant task in both machine and human vision systems that must recognize or classify objects. The exact properties of human shape similarity judgements are not well understood yet, and this task is particularly difficult in domains where the shapes are not related by rigid transformation. In this paper we identify a number of possibly desirable properties of a shape similarity method, and determine the extent to which these properties can be captured by approaches that compare local properties of the contours of the shapes, through elastic matching. Special attention is devoted to objects that possess articulations, i.e. articulated parts. Elastic matching evaluates the similarity of two shapes as the sum of local deformations needed to change one shape into another. We show that similarities of part structure can be captured by such an approach, without the explicit computation of part structure. This may be of importance, since although parts appear to play a significant role in visual recognition, it is difficult to stably determine part structure. We also show novel results about how one can evaluate smooth and polyhedral shapes with the same method. Finally, we describe shape similarity effects that cannot be handled by current approaches.

Algorithms↗
PubMed1998

Factors that mediate and moderate the link between partner abuse and suicidal behavior in African American women.

Findings from a study comparing partner abuse in African American women suicide attempters (n = 148) and nonattempters (n = 137) revealed higher rates of physical and nonphysical partner abuse among attempters than their demographically similar nonsuicidal counterparts. The partner abuse--suicidal behavior link was mediated by psychological distress, hopelessness, and drug use and moderated by social support. Results also revealed that nonphysical partner abuse accounted for unique variance in the prediction of suicide attempt status beyond that attributable to childhood maltreatment. Implications of the findings for assessing both suicidal and abused women are discussed, and recommendations for preventive interventions for women at risk for suicidal behavior are provided.

Adolescent↗
PubMed1998

Gain-of-function mutations in the Caenorhabditis elegans lin-1 ETS gene identify a C-terminal regulatory domain phosphorylated by ERK MAP kinase.

Genetic analysis of lin-1 loss-of-function mutations suggests that lin-1 controls multiple cell-fate decisions during Caenorhabditis elegans development and is negatively regulated by a conserved receptor tyrosine kinase-Ras-ERK mitogen-activated protein (MAP) kinase signal transduction pathway. LIN-1 protein contains an ETS domain and presumably regulates transcription. We identified and characterized six gain-of-function mutations that define a new class of lin-1 allele. These lin-1 alleles appeared to be constitutively active and unresponsive to negative regulation. Each allele has a single-base change that affects the predicted C terminus of LIN-1, suggesting this region is required for negative regulation. The C terminus of LIN-1 was a high-affinity substrate for Erk2 in vitro, suggesting that LIN-1 is directly regulated by ERK MAP kinase. Because mpk-1 ERK MAP kinase controls at least one cell-fate decision that does not require lin-1, our results suggest that MPK-1 contributes to the specificity of this receptor tyrosine kinase-Ras-MAP kinase signal transduction pathway by phosphorylating different proteins in different developmental contexts. These lin-1 mutations all affect a four-amino-acid motif, FQFP, that is conserved in vertebrate and Drosophila ETS proteins that are also phosphorylated by ERK MAP kinase. This sequence may be a substrate recognition motif for the ERK subfamily of MAP kinases.

Amino Acid Sequence↗
PubMed1998

Cyclosporin A and hydroxycyclosporine (M-17) affect the secretory phenotype of human gingival fibroblasts.

The responsiveness of human gingival fibroblast populations to cyclosporin A (CsA) and its principal metabolite, hydroxycyclosporine (M17), was evaluated in cell culture. Gingival fibroblasts exhibited a dose-dependent accumulation and bell-shaped distribution of dansylated CsA. A 100-fold excess of non-labeled CsA prevented the accumulation of the fluorescent probe in the fibroblasts. Both CsA (400 ng/ml) and M17 (100 ng/ml) stimulated mean gingival fibroblast cell number to 23.2% and 36.7% above controls, and reduced mean collagen production by 37.7% and 37.4% below controls, respectively; however, neither CsA nor M17 affected mean protein production in comparison to control cultures. Analyses of responses to CsA and M17 by ligand-accumulating and non-accumulating fibroblasts sorted out from the parent cultures did not provide consistent interstrain responses either by cells representing the upper quartile of fluorescence or cells representing the bottom quartiles of fluorescence. These data demonstrate that CsA is accumulated by gingival fibroblasts and that CsA and M17 are potent modulators of gingival fibroblast phenotype.

Adolescent↗
PubMed1998

Postmenopausal estrogen use and Parkinson's disease with and without dementia.

We investigated the effects of estrogen replacement therapy (ERT) on the risk of development of dementia in 87 women with Parkinson's disease without dementia (PDND), 80 women with Parkinson's disease with dementia (PDD), and 989 nondemented healthy women from the same community. ERT was protective for the development of dementia within the setting of PD (OR 0.22, 95% CI 0.05-1.0) and when PDD patients were compared with controls (OR 0.24, 95% CI 0.07-0.78), but did not affect the risk of PD. The results of the study suggest that a randomized clinical trial of ERT may be warranted.

Aged↗
PubMed1997

Suicide: a four-pathway clinical-biochemical model.

This chapter, based on a review of recent research as well as data presented in this report, proposes four hypothetical pathways leading to suicide in clinical depression: (1) an acute pathway involving severe anxiety/agitation associated with high brain corticotrophin-releasing factor (CRF or CRH) levels, (2) trait baseline and reactivity hopelessness, (3) severe anhedonia, and (4) trait impulsiveness associated with low brain serotonin turnover and low total cholesterol as a possible peripheral correlate. Clinical research showing evidence for acute versus chronic high-risk suicide factors and other studies linking severe anxiety/agitation to high CRF levels will be presented as associated with acute suicidal risk, which is potentially reversible with recognition and treatment. Evidence for anhedonia severity as a risk factor and trait, as well as evidence that baseline hopelessness and sensitivity are traits related to chronic suicide risk, will be presented. Finally, evidence relating low serum cholesterol to suicide in depressed inpatients will be presented in the context of literature suggesting a relationship between low serum cholesterol and violent death and suicide in population studies. Data suggesting a relationship between low serum cholesterol and decreased CSF 5-HIAA, suggesting reduced serotonin turnover, will be presented, in light of prior studies relating low CSF 5-HIAA and violent suicide. These data taken together suggest four pathways to suicide that are worth investigating in order to better understand the mechanisms leading to this behavior. Future possibilities and applications of these findings are discussed.

Cholesterol↗
PubMed1997

A universal procedure for primer labelling of amplicons.

Detection and visualisation of nucleic acids is integral to genome analyses. Exponential amplification procedures have provided the means for the manipulation of nucleic acid sequences, which were otherwise inaccessible. We describe the development and application of a universal method for the labelling of any PCR product using a single end-labelled primer. Amplification was performed in a single reaction with the resulting amplicon labelled to a high specific activity. The method was adapted to a wide range of PCRs and significantly reduced the expense of such analyses.

DNA Primers↗
PubMed1997

Improved methods for in situ enzymatic amplification and detection of low copy number genes in bacteria.

We present alternative and improved protocols for in situ analysis of single copy genes in prokaryotes. Primed in situ amplification (PRINS) and cycle PRINS were used to detect, via the incorporation of a fluorescein labelled nucleotide, the presence of specific genes carried on both high and low copy number plasmids in individual cells of Escherichia coli and a marine bacterium, SW5. The optimised protocols described enabled a significant reduction in non-specific signals whilst maintaining high fluorescent activity via labelled nucleotide incorporation. In addition, nucleic acids were amplified linearly and were retained within the permeabilised microbial cells. These methods provide considerable advances in sensitivity, specificity and reliability compared to current protocols for bacterial in situ nucleic acid amplification.

Gene Dosage↗
PubMed1997

The validity of new memory complaints in the elderly.

OBJECTIVE: To determine the validity of new subjective memory complaints (MCs) from individuals who previously, when without dementia, denied having MCs. DESIGN: Prospective cohort. SETTING: Longitudinal, community-based study of aging and dementia. PATIENTS: One hundred thirty-three community-dwelling elderly individuals who were part of a registry for the study of conditions related to aging in North Manhattan, NY. Patients were selected if they were initially without dementia and had completed at least 2 successive annual clinical and neuropsychological evaluations and provided their own medical history. MAIN OUTCOME MEASURES: Performance on memory tests--the Buschke Selective Reminding Test and a visual memory task--and global performance on a neuropsychological test battery and clinical evaluation, by which questionable dementia or dementia was diagnosed according to a well-defined paradigm. RESULTS: Fifty-three subjects with MCs at the initial evaluation performed no worse on the memory test than the 80 subjects who denied MCs initially. There was a weak association between MCs and the diagnosis of questionable dementia at baseline (P = .04), but this was nonsignificant after adjusting for age and education. At 1-year follow-up, 21 of the 80 without baseline MCs now reported MCs. At the follow-up evaluation, these 21 subjects performed significantly worse on the memory tests, were 5 times more likely to have significant cognitive impairment, and had shown significantly greater decline over the preceding year on several of the cognitive measures than the 59 who continued to deny MCs. CONCLUSION: New MCs from individuals, who when without dementia recently denied MCs, may suggest the presence of significant impairment of memory or cognition.

Aged↗