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Biomedical subjects

P Jacobs

Publications and source records attributed to P Jacobs.

At least 19 recordsLinked to original sources
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

ICU and non-ICU cost per day.

The purpose of this study was to compare the cost of a day spent in an intensive care unit and a day spent on a general nursing unit. A descriptive design was used, based on patient level data, to examine and compare unit costs per day for each of the ICU and non-ICU portions of a patient's hospital stay. Records from 386 patients who were treated in a general medical/surgical ICU were analyzed. Records for patients who received both ICU and non-ICU care during their stay were retained. Patients were categorized according to whether they had received surgical care prior to admission to the ICU (surgical group) or had no surgical care (medical group). The groups were further divided, based on whether they were discharged from hospital (survivors), or died following transfers from the ICU (non-survivors). All four groups; surgical or medical, survivors and non-survivors, were analyzed separately. The ICU direct costs per day for survivors were between six and seven times those for non-ICU care. A one day substitution of general ward for ICU care would result in a cost reduction of $1,200 per patient for survivors. The results suggest that the savings achieved by moving a patient from ICU to non-ICU care are considerable, particularly for less severe surviving patients. In making such decisions, however, clinicians must examine prospective benefits as well as costs. If the health outcomes are not influenced, the savings from substitution are considerable, and there is a strong economic argument for substitution.

Adult↗
PubMed1995

Extensive bone marrow necrosis associated with antiphospholipid antibodies.

Bone marrow necrosis (BMN), defined morphologically by destruction of hematopoietic tissue, including the stroma, with preservation of the bone, is a rare syndrome. The conditions in which it is seen include sickle cell disease, acute leukemia, metastatic neoplasia, and bacterial infection, particularly when hypovolemia and septic shock are present. BMN is also associated with disseminated intravascular coagulation (DIC) following irradiation and antineoplastic therapy. The antiphospolipid syndrome (APS) is characterized by antibodies directed against the antiphospolipid substrate. Because this substrate is prominently involved in the coagulation cascade and widely distributed on cell walls, patients present with venous or arterial thromboses, recurrent abortion, thrombocytopenia, and Coombs' positive hemolytic anemia, typically with raised anticardiolipin antibodies or a diagnostic lupus anticoagulant test. BMN does not appear to have been previously recognized in this context. We report what we believe to be the first such case and suggest that the high titers of antibodies present may have played a central role in its pathogenesis.

Adult↗
PubMed1995

Immune response of mice infected with Schistosoma mansoni is modulated by antifibrotic treatment.

Mice infected with Schistosoma mansoni treated with beta-aminopropionitrile (BAPN), an antifibrotic agent, and the antischistosomal drug praziquantel (PZQ) were resistant to challenge for up to 5 weeks post-treatment. The combined treatment resulted in profound changes to the liver granuloma cell matrix and the composition and function of the cellular infiltrate. Although granulocytes always predominated in the infiltrate, the proportion of the cells which were macrophages was higher in mice treated with BAPN alone (39.2%) than in infected mice which were untreated (15.2%) or treated with PZQ alone (12.4%), and much higher than in mice given the combined treatment (1.8%). Two products associated with macrophage activation and cytotoxicity [tumour necrosis factor-alpha (TNF-alpha) and nitric oxide] were only detected in mice harbouring a patent infection and there was a strong positive correlation between the concentrations of each. The relatively low TNF-alpha concentrations in BAPN-treated mice seemed to be associated with the relatively small granulomas observed in these mice. BAPN treatment also led to changes in the proliferative response of the treated mice's macrophages to mitogen and soluble schistosome-egg antigen and in spleen cellularity; these changes are probably associated with the resistance to challenge infection observed in mice given BAPN with PZQ. It is clear that BAPN treatment changes the dynamics of the delayed-type hypersensitivity response within the granuloma and that this impacts on other immunological sites. How this relates to the maintenance of post-treatment resistance to a challenge infection has still to be elucidated.

Aminopropionitrile↗
PubMed1995

Fe-52 imaging of intrathoracic extramedullary hematopoiesis in a patient with beta-thalassemia.

Fe-52 scintigraphy was used to confirm extramedullary hematopoiesis in a patient with beta-thalassemia and intrathoracic masses. Imaging was performed on a standard gamma camera with a high-energy collimator. Tc-99m labeled tin colloid and In-111 chloride scintigraphy failed to reveal uptake by the masses. The exclusion of malignancy obviated the need for invasive diagnostic measures.

Diagnosis, Differential↗
PubMed1995

A comparison of intensive care unit utilization in Alberta and western Massachusetts.

OBJECTIVE: To analyze differences in intensive care unit (ICU) utilization between a Canadian province and a U.S. area. DESIGN: Retrospective data analysis of hospital discharge data and existing data from an international study of severity of illness in ICU patients. SETTING: Administrative data for the province of Alberta and the four counties of western Massachusetts for the years 1990 to 1991 were used. Detailed data on consecutive ICU admissions from two Alberta hospitals, one western Massachusetts hospital, and 24 other U.S. hospitals for 3 months in 1991 were used. MEASUREMENTS AND MAIN RESULTS: ICU use and hospital mortality rates were compared for 50,030 hospital admissions divided into 11 patient groups. ICU days per million population were two to three times as great in western Massachusetts as in Alberta. The primary reason was higher ICU incidence (percent of hospitalized patients treated in the ICU) rather than a difference in hospital admission rate or length of ICU stay. ICU incidence in western Massachusetts was significantly higher in ten of 11 patient groups--for the coronary bypass surgery group, there was no difference. The hospital mortality rate in western Massachusetts was similar to, or higher than, the mortality rate in Alberta. In Alberta, a much higher proportion of ICU patients received mechanical ventilation. For elective surgery patients, the ICU severity of illness was lower in western Massachusetts and in other U.S. hospitals than in Alberta. CONCLUSIONS: Western Massachusetts hospitalized patients are more likely to be treated in an ICU than are similar patients in Alberta. There is no evidence that the greater ICU utilization in western Massachusetts led to a lower hospital mortality rate.

Aged↗
PubMed1995

Blunted erythropoietin response to anaemia in tuberculosis.

The precise cause of the anaemia that is commonly associated with severe pulmonary tuberculosis (PTB) has not been elucidated. The role of erythropoietin (Epo), the central hormone regulating red cell formation, still awaits clarification. We therefore determined serum Epo levels in patients with PTB; group 1, haemoglobin less than 110 g/L, group 2, haemoglobin greater than 110 g/L; group 3, controls, consisted of matched individuals with uncomplicated iron deficiency; group 4, healthy volunteers. Peripheral blood monocytes were obtained from patients with PTB and the controls, cultured, and the supernatant fluid (SNF) harvested. Tumour necrosis factor alpha (TNF alpha) levels were determined in the SNF, which were then added in various dilutions to a hepatocellular carcinoma cell line (HepG2) capable of regulated EPO synthesis in vitro. The influence of this cytokine was defined by the addition of specific neutralising anti-TNF alpha antibodies in this assay system. Patients in group 1 had significantly lower Epo levels (54 + 11 mU/mL) compared with those in group 3 (142 +/- 41 mU/mL) (p < 0.01). Monocyte supernatants from patients in the anaemic PTB group had markedly elevated TNF alpha levels and significantly suppressed Epo output by HepG2 cells in vitro (p < 0.01). This inhibition was consistently abrogated by anti-TNF alpha antibodies. Serum Epo levels were inappropriately low in untreated PTB patients when compared with corresponding haemoglobin levels in iron deficient controls. This blunted response could be ascribed to release of TNF alpha or other cytokines by activated monocytes.

Anemia↗
PubMed1995

Prognostic factors in allogeneic bone marrow transplantation for multiple myeloma.

PURPOSE: To analyze prognostic factors for allogeneic bone marrow transplantation (BMT) in multiple myeloma. PATIENTS AND METHODS: One hundred sixty-two reports of allogeneic matched sibling-donor transplants in multiple myeloma received by the European Group for Blood and Marrow Transplantation (EBMT) registry between 1983 and early 1993 were analyzed for prognostic factors. End points were complete remission, survival, and duration of complete remission. RESULTS: Following BMT, 44% of all patients and 60% of assessable patients entered complete remission. The overall actuarial survival rate was 32% at 4 years and 28% at 7 years. The overall relapse-free survival rate of 72 patients who were in complete remission after BMT was 34% at 6 years. Favorable pretransplant prognostic factors for survival were female sex (41% at 4 years), stage I disease at diagnosis (52% at 4 years), one line of previous treatment (42% at 4 years), and being in complete remission before conditioning (64% at 3 years). The subtype immunoglobulin A (IgA) myeloma and a low beta 2-microglobulin level (< 4 g/L) also tended to have a favorable prognostic impact. The most important post-transplant prognostic factor was to enter a complete remission. Grade III to IV graft-versus-host disease (GVHD) was associated with poor survival. CONCLUSION: Patients with a low tumor burden who respond to treatment before BMT and are transplanted after first-line therapy have the best prognosis following BMT.

Adult↗
PubMed1995

Bone marrow failure: pathophysiology and management.

Morphologically, bone marrow is made up of a relatively mature but heterogenous population, fueled by a tiny pool of microscopically unrecognizable stem and progenitor cells. This complex tissue has the responsibility of maintaining our hematopoietic and, to a large extent, immunologic integrity, both of which are indispensable for health and, indeed, survival. Perhaps not surprisingly, bone marrow is the target of genetic, autoimmune, and environmental insults. Although robust, it has only a limited number of responses, one of which is reduction in cellular output, sometimes with superimposed qualitative abnormalities, and this is defined as bone marrow failure. Bone marrow failure is a diverse entity but can be logically explained and classified on a pathophysiologic basis. Thus the major recognizable categories of bone marrow failure are congenital and acquired defects. Each of these is subdivided according to the number of cell lines involved, over and above which the severity of the damage will determine reversibility. In each case, the natural history dictates management, and this ranges from short-term growth factor support to biologic immune response modulation and finally to bone marrow transplantation. In the past, many clinicopathologic variants of bone marrow failure were described, although their etiology was obscure and effective therapy was unavailable. This changed dramatically, however, when experimental hematologists, using radiobiology models, uncovered the dynamic nature of blood formation. Cardinal observations included the way in which spontaneous recovery followed irradiation, the central role played by pluripotential stem cells, and the integral participation of stroma in modulating this entire process. Understanding was refined once bone marrow cultures became available while, in parallel, the use of in-bred mouse strains launched the era of allogeneic transplantation. These approaches were combined, and the broad principles that govern basal or constitutive production emerged. Stem cells, with their characteristic commitment to self-renewal, exist at the apex of a hierarchy and generate a tier of proliferating progenitors that, in turn, give rise to a large postmitotic compartment of precursors that mature into distinctive myeloid and lymphoid lineages. The reserve potential is enormous, and output can be induced to meet even greatly increased demands. These events reflect the interaction of growth factors with a balancing set of negative regulators. The link between such diverse functions resides, to a large extent, in accessory cells and matrix geographically organized in what is now described as the hematopoietic inductive microenvironment. Many details of these meticulously orchestrated processes are obscure.(ABSTRACT TRUNCATED AT 400 WORDS)

Agranulocytosis↗