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H Jacobs

Publications and source records attributed to H Jacobs.

At least 55 records · Page 3Linked to original sources
PubMed1999

Search for the PARK3 founder haplotype in a large cohort of patients with Parkinson's disease from northern Germany.

A founder haplotype on chromosome 2p for autosomal dominant Parkinson's disease (PD) has been postulated for two families of Northern European descent, and a new mutation in the alpha-synuclein gene (Ala30Pro) has been found in a German PD family. We evaluated 85 German PD patients and 85 ethnically matched controls for shared markers on chromosome 2p and for the new alpha-synuclein mutation. We found no evidence for linkage disequilibrium, suggesting that the putative founder mutation on chromosome 2p is not a common cause of PD in the local population. Furthermore, no patient carried the Ala30Pro change, supporting earlier findings that mutations in the alpha-synuclein gene are extremely rare.

Aged↗
PubMed1999

Improving educational needs assessment for general practitioners.

OBJECTIVE: To improve the quality of educational needs analysis for groups of general practitioners through the development of a range of simple, inexpensive practice based performance measures of general practice. METHOD: Members of one volunteer semi rural division of general practice were allocated randomly to groups that collected or provided data on: local referral patterns; consulting, prescribing and ordering, as collected by the Health Insurance Commission; and age, gender, reasons for encounter and management of a sample of patients. Other information was provided by a recent division community needs analysis, a consumer survey, national health targets and local health professionals. These data were combined to develop a list of educational topics that deserved attention. RESULTS: A total of 56% of GPs agreed to participate, providing Health Insurance Commission data for seven GPs, referral patterns for 11 GPs and BEACH surveys for five GPs. Much of the data collected for other purposes proved to be of little value in determining specific educational needs and the more time consuming methods attracted poor participation rates. The most useful data were those collected locally by the division. CONCLUSION: Educational needs analyses for groups of GPs should consider the perspectives of the profession, funders and patients, in addition to those of individual GPs. Practice based measures of GP performance need to be made more relevant to current practice, while remaining inexpensive and not intruding too much into GPs' time. A range of potential measures is provided.

Australia↗
PubMed1998

Hypermutation of immunoglobulin genes in memory B cells of DNA repair-deficient mice.

To investigate the possible involvement of DNA repair in the process of somatic hypermutation of rearranged immunoglobulin variable (V) region genes, we have analyzed the occurrence, frequency, distribution, and pattern of mutations in rearranged Vlambda1 light chain genes from naive and memory B cells in DNA repair-deficient mutant mouse strains. Hypermutation was found unaffected in mice carrying mutations in either of the following DNA repair genes: xeroderma pigmentosum complementation group (XP)A and XPD, Cockayne syndrome complementation group B (CSB), mutS homologue 2 (MSH2), radiation sensitivity 54 (RAD54), poly (ADP-ribose) polymerase (PARP), and 3-alkyladenine DNA-glycosylase (AAG). These results indicate that both subpathways of nucleotide excision repair, global genome repair, and transcription-coupled repair are not required for somatic hypermutation. This appears also to be true for mismatch repair, RAD54-dependent double-strand-break repair, and AAG-mediated base excision repair.

Animals↗
PubMed1998

Continuous Cyclin E expression inhibits progression through endoreduplication cycles in Drosophila.

Entry into S phase of the mitotic cell cycle is normally strictly dependent on progression through the preceding M phase. In contrast, during endoreduplication, which accompanies post-mitotic cell growth in many organisms, repeated S phases occur without intervening M phases. Upon transition from mitotic to endoreduplication cycles in Drosophila embryos, expression of the mitotic cyclins A, B and B3 is terminated and Cyclin E expression is changed from a continuous into a periodic mode [1-3]. Here, we address whether these changes in cyclin expression are required for endoreduplication by continuously expressing Cyclin A, B, B3 or E in the salivary glands of Drosophila throughout late embryonic and larval development. With the exception of Cyclin A, expression of which inhibited endoreduplication effectively but only in a few, apparently randomly distributed, cells of the salivary gland, mitotic cyclin expression was found to have no effect. In contrast, Cyclin E expression resulted in a striking inhibition of endoreduplication and growth, preceded initially by an ectopic S phase occurring just after the onset of ectopic Cyclin E expression. This observation is consistent with our previous findings that Cyclin E is required, and pulses of ectopic expression are sufficient, for triggering endoreduplication S phases [4]. Our results indicate that Cyclin E activity, which triggers DNA replication, needs to be down-regulated to allow a subsequent S phase in vivo.

Animals↗
PubMed1998

Tumour necrosis factor-alpha, but not septic plasma depresses cardiac myofilament contraction.

PURPOSE: In sepsis, myocardial depression may be caused by mediators released as part of the inflammatory reaction, lumour necrosis factor alpha (TNF alpha) is one mediator that may contribute to this depression. In the present study, we contrasted the effects of TNF alpha and septic plasma fraction (SP) obtained from an E. coli model on contractile tension in intact and skinned canine ventricular trabecular (VT) preparations. The objectives were to determine whether SP or TNF alpha could impair contractile tension at the level of the myofilaments, and to determine the extent to which TNF alpha may account for myocardial depression found in E. coli sepsis. METHODS: Measurements of isometric tensions were made after TNF alpha and SP (10,000 to 30,000 MW fraction) were added to respective intact or skinned canine VT preparations. In the skinned preparation, trabeculae were chemically skinned with Triton X-100. RESULTS: Septic plasma caused a decrease in contraction in the intact preparation compared with preseptic plasma (50 +/- 7 vs 33 +/- 7%, P < 0.05), but had no effect in the skinned preparation. On the other hand, TNF alpha (30 ng.ml-1) caused an approximately 50% reduction in tension (29 +/- 2 mg vs 16 +/- 5 mg) in the skinned preparation (P < 0.05), but had no effect in the intact preparation. CONCLUSION: These results suggest that TNF alpha and SP act through different mechanisms. While SP requires an intact membrane, TNF alpha impairs function by a direct effect on the myofilaments.

Actin Cytoskeleton↗
PubMed1998

A screen for lethal mutations in the chromosomal region 59AB suggests that bellwether encodes the alpha subunit of the mitochondrial ATP synthase in Drosophila melanogaster.

We report the isolation and complementation mapping of lethal mutations within the 59AB region on the second chromosome of Drosophila melanogaster. The newly induced lethal mutations in this region define four different complementation groups. Using existing and newly induced deficiencies, these loci can be assigned to three different chromosomal intervals. Moreover, complementation analysis with chromosomes carrying various P element insertions, in combination with a molecular characterization of the corresponding insertion sites, suggests that the previously described male sterile mutation bellwether is an allele of an essential gene that encodes the alpha subunit of the mitochondrial ATP synthase.

Alleles↗
PubMed1998

Serum vascular endothelial growth factor and Doppler blood flow velocities in in vitro fertilization: relevance to ovarian hyperstimulation syndrome and polycystic ovaries.

OBJECTIVE: To relate changes in serum and follicular fluid vascular endothelial growth factor (VEGF) concentrations to Doppler blood flow velocities within ovarian and uterine blood vessels during IVF cycles and to assess their relation to ovarian hyperstimulation syndrome (OHSS) and polycystic ovaries (PCO)/polycystic ovary syndrome (PCOS). DESIGN: Prospective descriptive study. SETTING: The London Women's Clinic. PATIENT(S): One hundred seven patients receiving a "long" stimulation protocol of IVF. INTERVENTION(S): Doppler blood flows were recorded in ovarian stromal and uterine arteries; serum VEGF was measured in the early follicular phase, after pituitary desensitization, on the day of hCG administration, on the day of oocyte retrieval, and on the day of ET. MAIN OUTCOME MEASURE(S): Serum and follicular fluid VEGF concentrations and Doppler blood flow measurements. RESULT(S): Serum VEGF concentrations rose after hCG administration. The rise was higher in women in whom OHSS developed. Women with PCO/PCOS had higher serum VEGF concentrations throughout the IVF cycle irrespective of whether OHSS developed. Follicular fluid VEGF concentrations were higher in women in whom OHSS developed and in women with PCO/PCOS. Doppler blood flow velocities in the ovarian blood vessels were higher in women in whom OHSS developed. Within ovarian and uterine blood vessels, blood flow velocities were higher in the early follicular phase and on the day of hCG administration in women with PCO/PCOS. A positive correlation was observed between the serum VEGF and E2 concentrations on the days of hCG administration and oocyte retrieval and between the serum VEGF concentration and Doppler blood flow velocities throughout the IVF cycle. CONCLUSION(S): Our results support the role of VEGF as a mediator of OHSS and establish a possible link between VEGF, OHSS, and PCO.

Adult↗
PubMed1998

Somatic hypermutation in the heavy chain locus correlates with transcription.

Three mutant immunoglobulin heavy chain (IgH) insertion mice were generated in which a targeted nonfunctional IgH passenger transgene was either devoid of promoter (pdelta) or was placed under the transcriptional control of either its own RNA polymerase II-dependent IgH promoter (pII) or a RNA polymerase I-dependent promoter (pI). While the transgene mutation-frequency (0.85%) in memory B cells of pI mice was reduced compared to that in pII mice (1.4%), the distribution and the base exchange pattern of point mutations were comparable. In pdelta mice, the mutation frequency was drastically reduced (0.09%). The mutation frequencies correlated with the levels of transgene-specific pre-mRNA expressed in germinal center B cells isolated from the mutant mice.

Animals↗
PubMed1998

Blood flow changes in the ovarian and uterine arteries in women with polycystic ovary syndrome who respond to clomiphene citrate: correlation with serum hormone concentrations.

OBJECTIVE: Our purpose was to study the hemodynamic changes in the uterine and intraovarian vessels in women with polycystic ovary syndrome (PCOS) and to relate the vascular changes to hormonal indices. METHODS: Six women with a history of previous anovulatory cycles and/or oligomenorrhea and/or elevated serum luteinizing hormone concentrations in addition to polycystic ovaries underwent induction of ovulation with clomiphene citrate. Serial transvaginal ultrasonography was performed on menstrual cycle day 2, daily from the estimated day of ovulation minus 6, 6-hourly from the estimated day of ovulation minus 2 or when the mean follicular diameter was greater than 16 mm (whichever was earlier) until 6 h after follicular rupture, and once 7 days after follicular rupture. At each scan, uterine and intraovarian blood flow was assessed by transvaginal color Doppler ultrasound, and serum concentrations of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol and progesterone were assessed by fluoroimmunoassay. RESULTS: All six women demonstrated ultrasonographic features of ovulation. Follicular peak systolic blood flow velocity (Vmax) and ovarian stromal Vmax in the dominant ovary increased during the follicular phase of the menstrual cycle and reached a peak at 36 and 42 h after the onset of the LH surge of 30.7 +/- 4.6 cm/s and 37.0 +/- 3.9 cm/s, respectively. There was no significant change in the ovarian stromal Vmax of the non-dominant ovary. There was no significant change in the pulsatility index (PI) in either the follicular or the ovarian stromal vessels during the menstrual cycle. The changes in follicular Vmax correlated significantly with changes in serum concentrations of FSH, LH and progesterone. Uterine artery time-averaged maximum velocity (TAMX) declined to its lowest levels at LH surge minus 6 days, and thereafter increased. In contrast, the PI increased during the follicular phase of the cycle, reaching a peak at LH surge minus 4 days, and thereafter declined. The changes in uterine artery PI correlated inversely with serum estradiol and serum progesterone concentrations. CONCLUSIONS: Women with PCOS have significant differences in intraovarian and uterine artery hemodynamics, both at the baseline ultrasound scan and during the clomiphene-induced menstrual cycle, compared with women with normal ovaries. The intraovarian and uterine artery vascular differences are likely to be due to a primary disorder within the polycystic ovary and their different hormonal status. Clomiphene citrate may have an effect on uterine artery blood flow.

Adult↗
PubMed1998

Histamine H3 activation depresses cardiac function in experimental sepsis.

In the heart, histamine (H3) receptors may function as inhibitory presynaptic receptors that decrease adrenergic norepinephrine release in conditions of enhanced sympathetic neural activity. We hypothesized that H3-receptor blockade might improve cardiovascular function in sepsis. In a canine model of Escherichia coli sepsis, we found that H3-receptor blockade increased cardiac output (3.6 to 5.3 l/min, P < 0.05), systemic blood pressure (mean 76 to 96 mmHg, P < 0.05), and left ventricular contractility compared with pretreatment values. Plasma histamine concentrations increased modestly in the H3-blocker-sepsis group compared with values obtained in a nonsepsis-time-control group. In an in vitro preparation, histamine H3 activation could be identified under conditions of septic plasma. We conclude that activation of H3 receptors may contribute to cardiovascular collapse in sepsis.

Animals↗
PubMed1998

Leptin levels in women with polycystic ovary syndrome before and after treatment with diazoxide.

Leptin, a product of the ob gene, is a 16 kDa protein which is produced by adipocytes. In humans, obesity is a common finding in women with polycystic ovary syndrome (PCOS). The role, however, of leptin in PCOS is not clear. Some studies have reported increased levels of leptin in PCOS, while others report that they are normal. Also, insulin resistance is a common finding in PCOS. The aim of this study was to investigate further the role of insulin in leptin secretion in patients with PCOS by treating them for 10 days with diazoxide, an insulin-reducing compound. Eight women with PCOS, mean age 22.1 +/- 2.7 years, with mean body mass index (BMI) 28.4 +/- 5.7kg/m2, were studied. An oral glucose tolerance test (OGTT) was performed in all women and blood samples were taken before and at 30, 60, 90, 120 and 150 min after the administration of glucose. Glucose, insulin, leptin, free testosterone, delta4 androstenedione, sex hormone binding globulin (SHBG), LH, FSH, IGF-I and insulin-like growth factor-binding protein-3 (IGFBP-3) were measured in the sera taken before the administration of glucose, while glucose and insulin levels were measured in all samples which were collected after the administration of glucose. Diazoxide 300 mg daily was given to all women starting after the end of the OGTT for 10 days. A second OGTT was performed the day after the discontinuation of the diazoxide treatment. The same hormonal and biochemical parameters were also measured in all patients during the second OGTT. After the administration of diazoxide a reduction in sum insulin (262 +/- 147 vs 679 +/- 341 microU/ml. P<().01), leptin (18.5 +/- 10.6 vs 24.2 +/- 10.2 ng/ml, P<0.01), free testosterone (3.0 +/- 1.9 vs 5.1 +/- 1.9 pg/ml, P<0.01), delta4 androstenedione (3.8 +/- 1.9 vs 5.7 +/- 2.0 ng/ml, P<0.01) and IGF-I (219.5 +/- 69.2 vs 314.5 +/- 82.3 ng/ml, P<0.01) levels was observed. Serum SHBG (38.8 +/- 16.8 vs 27.8 +/- 12.1 nmol/l, P<0.01) and sum glucose levels (994.1 +/- 252.7 vs 711.1 +/- 166.1 mg/dl, P<0.05) were increased while IGFBP-3 (3.96 +/- 2.49 vs 3.75 +/- 2.24mg/l), FSH (6.2 +/- 1.8 vs 6.0 +/- 2.5 mU/l) and LH (18.9 +/- 6.7 vs 21.4 +/- 6.7 mU/l) concentrations did not change significantly. A significant positive correlation was found between serum leptin and BMI values before and after administration of diazoxide as well as between leptin, insulin and IGFBP-3 values. Also, sum insulin values correlated significantly with BMI. However, when multiple regression analysis was used this correlation was eliminated except that between leptin and BMI. This was most probably due to the small number of cases. The mechanism of the reduction of leptin levels is unclear. However, it is suggested that the concomitant decrease of insulin levels may play a role.

Adipose Tissue↗
PubMed1997

Pertubation of B and T cell development and predisposition to lymphomagenesis in Emu Bmi1 transgenic mice require the Bmi1 RING finger.

Proviral activation of the Bmi1 gene has implicated Bmi1 as a collaborator of c-Myc in lymphomagenesis. To determine the effect of Bmi1 overexpression on hematopoiesis and lymphomagenesis transgenic mice were generated that overexpress different forms of the Bmi1 protein in their lymphoid compartment. Emu Bmi1 transgenic mice, overexpressing the wild type Bmi1 protein showed a perturbed lymphoid development and were highly susceptible to B and T cell lymphomagenesis. Mutational analysis of the Bmi1 protein demonstrated that the conserved N-terminal RING finger and central part of Bmi1 are essential for its oncogenic potential whereas the C-terminal Pro-Ser rich region is not required. We have used provirus tagging in the Emu Bmi1 mice to identify genes that cooperate with Bmi1 in lymphomagenesis. MoMLV infection in Emu Bmi1 transgenic mice accelerated lymphoma development. Proviral activation of the Pim and Myc genes but not the Gfi1 gene were frequently observed in these tumors. These results demonstrate that Bmi1 is a potent oncogene and suggest that it plays an important role in early lymphoid development.

Animals↗
PubMed1997

Bcl-2 reduces lymphomagenesis in deltaV-TCRbeta transgenic mice.

Overexpression of the bcl-2 oncogene in the lymphoid compartment of transgenic mice prolongs the lifespan of lymphocytes and leads to a low incidence of lymphomas at later age. Transgenic mice carrying a mutated T-cell receptor lacking the variable domain (deltaV-TCRbeta) suffer from lymphocyte depletion and are highly predisposed to lymphoma development. We intercrossed Bcl-2-Ig and deltaV-TCRbeta transgenic mice to assess whether Bcl-2 could synergize with deltaV-TCRbeta in tumorigenesis as reported previously for other oncogenes. Surprisingly, bitransgenic deltaV-TCRbeta; bcl-2-Ig mice showed a reduction in the incidence of lymphomas. Analyses of prelymphomatous mice showed that Bcl-2 restored some of the phenotypic aberrations caused by the deltaV-TCRbeta transgene in the lymphoid compartment. The inhibitory activity of Bcl-2 on deltaVTCRbeta-induced lymphomagenesis was not observed when both transgenes were crossed into the RAG-1-/- background suggesting an important role for more mature lymphocytes in this phenomenon. These results show that, depending on the specific conditions, overexpression of Bcl-2 can both promote as well as impair lymphoma development.

Animals↗
PubMed1997

Overexpression of the FosB2 gene in thymocytes causes aberrant development of T cells and thymic epithelial cells.

We have examined the role of the AP-1 transcription factor on thymocyte maturation and thymus architecture by overexpressing FosB2 in transgenic mice. FosB2 is a naturally occurring splice variant of the FosB2 gene, encoding a truncated protein which lacks two domains necessary for transcriptional activation. The expression of FosB2 in the thymocytes severely affected their maturation and the structure of the whole thymus: the phenotype developed slowly during the first months of life, resulting in a progressive expansion of the medulla and concomitant reduction of the cortex. CD4+ thymocytes represented the major thymocyte population, whereas the CD4+ 8+ thymocytes were virtually absent. This phenotype appeared to be an intrinsic property of bone marrow derived cells, as it could be reproduced in bone marrow chimaeric mice. This pathology was very reminiscent to that observed in mice overexpressing c-Fos in thymic epithelium: also in that case the thymus underwent with age a progressive expansion of the epithelium and major changes in the ratio of thymocyte subsets, but the phenotype appeared to be an intrinsic property of the epithelial cells since it could not be reproduced by transgenic bone marrow transplantation. We speculate that both overexpression of FosB2 in thymocytes and overexpression of c-Fos in thymic epithelium results in aberrant signaling between thymocytes and stroma, that ultimately alters the thymic micromilieu, leading to this severe pathology.

Age Factors↗
PubMed1997

Microvascular blood flow resistance: role of endothelial surface layer.

Observations of blood flow in microvascular networks have shown that the resistance to blood flow is about twice that expected from studies using narrow glass tubes. The goal of the present study was to test the hypothesis that a macromolecular layer (glycocalyx) lining the endothelial surface contributes to blood flow resistance. Changes in flow resistance in microvascular networks of the rat mesentery were observed with microinfusion of enzymes targeted at oligosaccharide side chains in the glycocalyx. Infusion of heparinase resulted in a sustained decrease in estimated flow resistance of 14-21%, hydrodynamically equivalent to a uniform increase of vessel diameter by approximately 1 micron. Infusion of neuraminidase led to accumulation of platelets on the endothelium and doubled flow resistance. Additional experiments in untreated vascular networks in which microvascular blood flow was reduced by partial microocclusion of the feeding arteriole showed a substantial increase of flow resistance at low flow rates (average capillary flow velocities < 100 diameters/s). These observations indicate that the glycocalyx has significant hemodynamic relevance that may increase at low flow rates, possibly because of a shear-dependent variation in glycocalyx thickness.

Animals↗
PubMed1997

Pre-TCR/CD3 and TCR/CD3 complexes: decamers with differential signalling properties?

Currently, the favoured model for the structure of the T-cell receptor (TCR)/CD3 complex proposes a monovalent TCR alpha beta/CD3 gamma epsilon delta epsilon zeta zeta octameric complex. However, other biochemical, structural and functional data point to a bivalent (TCR alpha beta)2/CD3 gamma epsilon delta epsilon zeta zeta decameric organization, which has a favourable neutral transmembrane net charge within the complex. Here, Heinz Jacobs proposes a model for the organization of the pre-TCR and discusses its function in signal transduction.

CD3 Complex↗