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Biomedical subjects

P Jacobs

Publications and source records attributed to P Jacobs.

At least 127 records · Page 7Linked to original sources
PubMed1996

Population screening at the FRAXA and FRAXE loci: molecular analyses of boys with learning difficulties and their mothers.

Preliminary results on a large population-based molecular survey of FRAXA and FRAXE are reported. All boys with unexplained learning difficulties are eligible for inclusion in the study and data are presented on the first 1013 tested. Individuals were tested for the number of trinucleotide repeats at FRAXA and FRAXE and typed for four flanking microsatellite markers. Mothers of 760 boys were tested to determine the stability of the FRAXA and FRAXE repeats during transmission and to provide a population of control chromosomes. The frequency of FRAXA full mutations was 0.5%, which gives a population frequency of 1 in 4994, considerably less than previous reports suggest. No FRAXE full mutations were detected, confirming the rarity of this mutation. In the boys' X chromosomes, we detected one FRAXA premutation with 152 repeats and one putative FRAXE premutation of 87 repeats. No full or premutations were seen in the control chromosomes. A significant excess of intermediate alleles at both FRAXA and FRAXE was detected in the boys' X chromosomes by comparison with the maternal control chromosomes. This suggests that relatively large unmethylated repeats of sizes 41-60 for FRAXA and 31-60 for FRAXE may play some role in mental impairment. No instability was found in transmissions of minimal or common alleles in either FRAXA or FRAXE, but we saw two possible instabilities in transmission of FRAXA and two definite instabilities in transmission of FRAXE among 43 meioses involving intermediate or premutation sized alleles. We found no linkage disequilibrium between FRAXA and FRAXE but did find significant linkage disequilibrium between large alleles at FRAXE and allele 3 at the polymorphic locus DXS1691 situated 5 kb distal to FRAXE.

Adolescent↗
PubMed1996

Use of New York Medicaid PASs (Products of Ambulatory Surgery) with emergency surgical episodes.

The New York Products of Ambulatory Surgery (PAS) patient classification system was implemented by the state of New York for reimbursement of Medicaid ambulatory surgery claims. Using a national claims based database, the PAS system was evaluated for use with emergency department-generated surgical episodes. The PAS system performed well, but would benefit from the inclusion of age, comorbidity, and presence of multiple surgical procedures. Further, model power increased significantly when focused on total episode versus surgical charges alone. The study indicated the high degree to which emergency department-generated charges are closely tied to other charges in any overall care delivery system.

Ambulatory Surgical Procedures↗
PubMed1996

In vivo regulation of nitric oxide production by tumor necrosis factor alpha and gamma interferon, but not by interleukin-4, during blood stage malaria in mice.

We investigated whether gamma interferon (IFN-gamma; a Th1 cytokine), tumor necrosis factor alpha (TNF-alpha), and interleukin-4 (IL-4; a Th2 cytokine) modulate nitric oxide (NO) production in vivo during blood stage infection with Plasmodium chabaudi AS. Treatment of resistant C57BL/6 mice, which resolve infection with P. chabaudi AS and produce increased levels of IFN-gamma, TNF-alpha, and NO early during infection, with anti-IFN- gamma plus anti-TNF-alpha monoclonal antibodies (MAbs) resulted in a reduction of both splenic inducible NO synthase mRNA and serum NO3- levels by 50 and 100%, respectively. Treatment with the anti-TNF-alpha MAb alone reduced only serum NO3- levels by 35%, and treatment with the anti-IFN-gamma MAb alone had no effect on NO production by these mice during infection. Susceptible A/J mice, which succumb to infection with P. chabaudi AS and produce increased levels of IL-4 but low levels of IFN-gamma, TNF-alpha, and NO early during infection, were treated with an anti-IL-4 MAb. The latter treatment had no effect on NO production by this mouse strain during infection. In addition, our results also demonstrate that treatment of resistant C57BL/6 mice with anti-IFN-gamma plus anti-TNF-alpha MAbs affects, in addition to NO production, other traits of resistance to P. chabaudi AS malaria such as the peak level of parasitemia and the development of splenomegaly. Furthermore, the change in spleen weight was shown to be an IFN-gamma-independent effect of TNF-alpha. Treatment of susceptible A/J mice during infection with an anti IL-4 MAb had no effect on these markers of resistance. Thus, these results demonstrate that TNF-alpha and IFN-gamma are critical in the regulation of NO production and other traits of resistance during P. chabaudi AS malaria in C57BL/6 mice. These data also indicate that treatment with an anti-IL-4 antibody alone is not able to induce NO production or confer resistance to A/J mice against P. chabaudi AS malaria.

Animals↗
PubMed1996

A Th1-associated increase in tumor necrosis factor alpha expression in the spleen correlates with resistance to blood-stage malaria in mice.

We investigated the kinetics of tissue-specific mRNA expression and systemic production of tumor necrosis factor alpha (TNF-alpha) and the kinetics of splenic expression of mRNAs of gamma interferon (INF-gamma) and interleukin-4 (IL-4), cytokines that may regulate TNF-alpha production, during the early phase of blood-stage infection with Plasmodium chabaudi AS. Northern blot analysis revealed that resistant C57BL/6 mice, which clear the infection by 4 weeks, had higher levels of TNF-alpha mRNA in the spleen and liver early during infection that did susceptible A/J mice, which succumb to the disease 10 days after initiation of infection. Treatment of resistant mice with a polyclonal anti-TNF-alpha antibody confirmed the protective role of TNF-alpha early during the course of infection. Furthermore, resistant C57BL/6 mice also expressed high levels of mRNA of IFN-gamma (a Th1 marker) and low levels of mRNA of IL-4 (a Th2 marker) in the spleen, whereas susceptible A/J mice had low levels of IFN-gamma mRNA but high levels of TNF-alpha mRNA in the liver and had high levels of TNF-alpha protein in serum, as measured by enzyme-linked immunosorbent assay, later during infection just before death occurred. These results demonstrate that a Th1-associated increase in TNF-alpha mRNA expression in the spleen early during infection correlates with resistance to P. chabaudi AS, whereas increased TNF-alpha mRNA levels in the liver and excessive levels of the TNF-alpha protein in serum later during infection correlate with susceptibility. Thus, the role of the TNF-alpha during malaria appears to depend on the timing and site of its expression and the presence of cytokines regulating its production.

Animals↗
PubMed1996

Fludarabine monophosphate as salvage for refractory chronic lymphocytic leukaemia.

OBJECTIVE: To assess the efficacy of the purine analogue fludarabine monophosphate (FAMP) as salvage therapy in patients at Groote Schuur Hospital with chronic lymphocytic leukaemia (CLL) refractory to standard therapy. DESIGN: Non-randomised trial. SETTING: Tertiary care, referral academic hospital. PATIENTS: Seven patients with B-lineage CLL, 4 in Rai stage IV and 1 each in stages A(I), A(II) and A(III), refractory to treatment with chlorambucil or cyclophosphamide, with or without whole-body irradiation. INTERVENTION: Intravenous FAMP at a dose of 25 mg/m2 daily for 5 days every 28 days. MAIN OUTCOME MEASURES: Partial remission, complete remission, stable disease or progressive disease. RESULTS: Two patients entered CR and 4 PR after a median of 8 courses of treatment (range 2 - 12). One patient died of Pneumocystis carinii pneumonia after 3 courses of therapy. The most common adverse effect of the treatment was myelosuppression, with the nadir of neutrophil counts being less than 0.5 x 10(9)/1 in 5 patients. Three developed infections and required hospitalisation while on therapy. CONCLUSION: FAMP is effective as a cytoreductive agent in patients with CLL refractory to alkylating agents, with or without whole-body irradiation.

Antimetabolites, Antineoplastic↗
PubMed1996

The effect of recombinant human erythropoietin on haematopoiesis in patients undergoing haemodialysis.

OBJECTIVE: To define the effect of intravenous recombinant human erythropoietin (rHuEPO) in patients with anaemia caused by chronic renal failure. Data collection included bone marrow response, ferrokinetics, red cell survival as well as the influence on red cell mass and plasma volume. DESIGN: A convenience sample of stable individuals on haemodialysis, with haemoglobin (Hb) levels of less than 80 g/l, was surveyed over a 12-week period while they were receiving the hormone. Blood counts and iron studies were monitored serially, while 51Cr-labelled red cells and 59Fe (III) citrate were used in the radionuclide investigations carried out before and after the course of replacement therapy was completed (pre and post injection). Bone marrow aspiration and trephine biopsy were performed at each of these times. RESULTS: The actual mean trial period was 14 weeks. Eight patients were enrolled but 1 was withdrawn after developing tuberculosis at the start of the study. Haemoglobin levels rose from 59 g/l (SD 8.8) to 96 g/l (SD 13.9) (P < 0.0001); mean red cell mass rose from 675 ml to 954 ml (P < 0.01). Concurrently, the serial studies in 6 patients showed prominent erythroid hyperplasia. Plasma iron turnover increased insignificantly from 42.5 to 118.9 mumol/l/day; erythron turnover increased from 42.5 to 87.3 mumol/l/day (P < 0.01). There was a marked shortening of the marrow transit time from 4.4 to 3.3 days (P < 0.03). Efficacy of erythropoiesis decreased from 1.17 to 0.65 (P < 0.05). Red cell survival was not altered. CONCLUSIONS: The patient with end-stage renal failure remains fully responsive to erythropoietin therapy. This is reflected in improved ferrokinetics, red cell hyperplasia in the marrow and rise in haemoglobin level without alteration in mean erythrocyte lifespan. Simple hormonal replacement is therefore a rational approach to management.

Anemia↗
PubMed1996

The lymphomas.

Hodgkin's disease and the malignant lymphomas are, by all available evidence, eminently curable neoplasms. The debates, therefore, on how best the largest numbers of individuals in any community can receive appropriate treatment and this implies their ready access to an experienced multi disciplinary combined clinic. It is important that proper perspective be retained in the African context so that preventive medicine can be employed where appropriate but, based on current understanding, those with lymphoreticular malignancy become immediate beneficiaries of whatever diagnostic and therapeutic resources need to be expended in ensuring optimal outcome. The last word is far from written on how we, as inhabitants of the African continent, will achieve this goal and so measure up to our obligation. However, as resources continue to contract, three observations justify reiteration. Firstly, diagnostic skills need to be honed by experienced pathologists together reviewing all biopsy material and, wherever possible, participating in national or international study groups. Secondly, the silly distinction propagated by some self serving individuals who fantasize that state hospitals and private clinics somehow differ, must be replaced by a more responsible attitude in which resources are pooled in the common quest for maintaining academic standards. Thirdly, given acceptance of the above common sense proposals, a mechanism will exist for the establishment and constant upgrading of national guidelines for management on agreed and achievable protocols. Whilst the theme remains that of tested conventional treatment, flexibility must exist, where appropriate, for palliative care on the one hand with scientific growth and exploration of innovative options on the other. One might conclude by observing that Africa is most certainly unique and this extends to the frequency with which some of these tumours occur; a classical example would be Burkitt's Lymphoma. This places an obligation on all of us to gather and record such experiences and, from this basis, sustain our intellectual drive by forging international bonds with colleagues in the First World. Such collaboration will provide the natural bridge between clinical studies in Africa and the more sophisticated cellular and molecular biology that is being provided by basic scientists in other parts of the world. Such a marriage is practical and both parties stand to gain significantly in the research, development and evaluation of new drugs and protocols that, ultimately, serve the best interests of patients and do so on a world-wide basis.

Africa↗
PubMed1995

Nitric oxide expression in the spleen, but not in the liver, correlates with resistance to blood-stage malaria in mice.

The production and function of nitric oxide during the early phase of blood-stage infection with Plasmodium chabaudi AS was analyzed using two inbred strains of mice that differ in the level of resistance to this parasite. Northern blot analysis of in vivo expression of inducible nitric oxide synthase (iNOS) revealed that early during infection resistant C57BL/6 mice, which clear the infection by 4 wk, have higher levels of iNOS mRNA in the spleen than susceptible A/J mice. In contrast, susceptible A/J mice have significantly increased levels of iNOS mRNA in the liver later in the course of infection just before death occurs. Splenic macrophages recovered from resistant C57BL/6 mice on day 7 postinfection express iNOS mRNA which is up-regulated following overnight stimulation of the cells with LPS. Furthermore, during the first week postinfection, splenic macrophages recovered from resistant hosts produce significantly higher levels of nitrite (NO2-) in vitro in response to LPS than similarly stimulated macrophages from susceptible A/J mice. Increased levels of nitrate (NO3-) were only detected in serum of resistant C57BL/6 mice at the time of peak parasitemia. Treatment with the iNOS inhibitor, aminoguanidine, reduced NO3- levels in serum of C57BL/6 mice and eliminated resistance of these hosts to P. chabaudi AS malaria without affecting parasitemia. These results demonstrate that the ability to produce high amounts of nitric oxide (NO) early during infection with blood-stage P. chabaudi AS correlates with resistance, but that NO may not be involved in parasite killing. Moreover, the tissue site of NO production, that is, spleen vs liver, appears to be critical and correlates with resistance vs susceptibility to P. chabaudi AS malaria, respectively.

Animals↗
PubMed1995

Treatment of aggressive non-Hodgkin's lymphoma in the elderly.

A nonanthracycline-containing chemotherapeutic combination for the treatment of intermediate and high-grade non-Hodgkin's lymphoma was evaluated. Thirty-four consecutive and previously untreated patients, with a median age of 75 (range 54-86) years, with aggressive lymphoma, received daily etoposide (60 mg/m2 intravenous infusion [IVI]), cytosine arabinoside (50 mg/m2 subcutaneously), and methylprednisolone (60 mg/m2 IVI) on each of 5 consecutive days. Individuals with limited disease (stages I and II) (n = 9) received six, 3-day cycles of the same therapy and involved field radiation (36 Gy in 20 fractions) between the third and fourth courses. Patients with disseminated lymphoma (n = 25) received 10 cycles over 8 months of the same combination, with the addition of methotrexate (200 mg/m2 on days 8 and 15), followed by leucovorin rescue (10 mg/m2 orally every 6 hr for 8 doses). Of the 34 patients, 44% entered complete remission (CR), and 7 died before completing the first cycle of chemotherapy. Fifty-six percent of the patients with limited disease and 40% with disseminated lymphoma (P > 0.05) achieved CR. For all patients, median survival was 14 months (range 3 days- > 54 months), this being 12 and 15 months, respectively. For the entire population of responding patients, median survival has not been reached at a median follow-up of 39 months, while the median CR duration is 21 months. Ten of the 15 responders are alive in unmaintained CR at a median of 41 (range 30-54) months. Myelotoxicity was the major side effect, leading to adjustments in dose and schedule in two-thirds of the patients, although treatment changes did not affect outcome. Of the 15 deaths that occurred in this trial, in 53.3% it was unrelated to lymphoma or its therapy. Four patients that had achieved CR died of cardiovascular events (n = 2) or of progressive second malignancies (n = 2). It is concluded that cytosine arabinoside in combination regimens is effective in selected patients; this is particularly relevant in the elderly.

Aged↗
PubMed1995

Role of macrophage-derived nitric oxide in suppression of lymphocyte proliferation during blood-stage malaria.

Examination of the proliferative responses in vitro to mitogens (concanavalin A, phytohemagglutinin, lipopolysaccharide) of spleen cells recovered from C57BL/6 mice during blood-stage Plasmodium chabaudi AS infection revealed that the most severe suppression occurred during the first 14 days post infection, that is, during the acute phase of infection. Coincidently, inducible nitric oxide synthase gene expression was found to be up-regulated in the spleens of infected mice, and both splenic and peritoneal macrophages produced high levels of NO in vitro in response to stimulation with lipopolysaccharide (LPS). The roles of NO, a molecule recently found to mediate immunosuppression during parasitic infections, and of the well-recognized immunosuppressive molecule prostaglandin were, therefore, investigated in the suppression of proliferation to mitogens and specific antigen of spleen cells from 7- and 14-day P. chabaudi AS-infected mice. Addition of either 0.5 mM NG-monomethyl-L-arginine (L-NMMA) or 0.5 mM aminoguanidine (AG), inhibitors of NO synthase, or 10 micrograms/ml indomethacin (INDO), a prostaglandin inhibitor, partially but significantly abrogated the suppression in response to concanavalin A (Con A) and phytohemagglutinin (PHA). Only the addition of INDO significantly increased the responses to LPS. Addition of L-NMMA or AG in combination with INDO partially but significantly abrogated the suppression in response to Con A and completely abrogated the suppression in response to PHA. The addition of L-NMMA or AG also significantly increased proliferation in response to parasite antigen. The contribution of NO to suppression of lymphoproliferation was confirmed by adding 3-morpholino-sydnonimine-hydrochloride (SIN-1), a chemical generator of NO, to mitogen-stimulated splenocyte cultures prepared from normal mice. The mechanism of NO-mediated suppression was investigated in coculture experiments using spleen cells from normal mice and peritoneal macrophages from either normal or day 7 infected mice. The addition of 5-10 x 10(4) peritoneal macrophages from infected mice significantly and consistently suppressed Con A- or PHA-stimulated proliferation of normal splenocytes. Moreover, suppression correlated with production of NO and could be reversed by the addition of L-NMMA or AG. These results suggest that, in addition to prostaglandin, increased NO production by macrophages within the first 2 weeks after infection with P. chabaudi AS contributes to immunosuppression associated with blood-stage malaria.

Amino Acid Oxidoreductases↗
PubMed1995

Purification and characterization of recombinant varicella-zoster virus glycoprotein gpII, secreted by Chinese hamster ovary cells.

Chinese hamster ovary cells have been engineered to secrete an anchorless form of the varicella-zoster virus gpII protein. Purification of the recombinant product was achieved by a combination of hydrophobic and gel filtration chromatography giving rise to a protein more than 85% pure. Recombinant gpII was composed of several polypeptides which, on the basis of amino-terminal sequence analysis, corresponded to a 93-kDa precursor and to the N- and C-terminal subunits of the molecule (64 and 39/36 kDa, respectively). All polypeptides carried N-linked high-mannose and complex glycosylations, whereas O-glycosylations were carried by the precursor and the N-terminal subunits only. Surprisingly, purified recombinant gpII spontaneously formed large oligomeric structures of variable size. These complexes contained noncovalently linked lipids. Mice inoculated with the recombinant gpII absorbed onto the weak adjuvant, aluminium hydroxide, produced virus neutralizing antibodies. The recombinant gpII may thus constitute a good candidate for the development of a subunit vaccine against varicella-zoster virus.

Amino Acid Sequence↗
PubMed1995

Design optimisation of planar electrolytic conductivity sensors.

Planar conductivity sensors are the subject of increasing interest as basic transducers for biosensors. The high degree of control of the performance characteristics undoubtedly forms an important argument in favour of conductivity-based sensing. The paper provides an outline of the design rules to be followed if an optimal design of a planar conductivity cell is required. Based on a simplified model, it is shown that the required accuracy establishes a lower limit to the overall sensor dimensions. This lower limit is expressed as a minimum longitudinal path length necessary to obtain the desired accuracy. Given an available area, the optimum ratio of electrode-width over inter-electrode spacing for a basic two-electrode structure is shown to be close to unity. Furthermore, it is shown that the decomposition of the two electrodes into an interdigitated structure decreases the accuracy of the device if all other parameters are considered constant. If the sensing region has to be limited to within a thin sensitive layer, the splitting is proposed of one of the electrodes into a compound electrode. The optimum lay-out of this compound structure is calculated as a function of the layer thickness.

Biosensing Techniques↗