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Biomedical subjects

Peter Jacobs

Publications and source records attributed to Peter Jacobs.

At least 19 recordsLinked to original sources
PubMed2005

The effect of peptide stimulation on haematopoietic stem cell mobilisation including engraftment characteristics and a note on donor side effects.

Aplasia or irreversible bone marrow failure and a variety of haematologic malignancies, as well as an increasing number of solid tumours, currently include various forms of marrow or equivalent transplantation in routine management. In both allogeneic and autologous procedures stable recipient immunohaematopoietic reconstitution depends upon infusing the requisite population harvested at a precise time following commencement of a stimulatory peptide. In a first step this prospective study documented the safety of apheresis, defined side effects and enumerated mononuclear, CD34+ and CD3+ cells obtained. In the second stage delivery of the graft, characterised in this way and with the additional measurement of in vitro growth in clonogenic assay, to the suitably conditioned patient was correlated with recovery of neutrophil and platelet numbers appearing in the circulation. In a third and ongoing analysis the influence of passenger T-lymphocytes is being evaluated for impact on infection and a potential anti-tumour effect. The conclusion is that this technology is reliable, has a high degree of patient acceptability without untoward complications, and that local results correspond to international experience thereby providing an important and relevant measure of quality control.

Antigens, CD34↗
PubMed2005

Estimation and predictive use of the corrected count increment--a proposed clinical guideline.

BACKGROUND AND OBJECTIVE: Platelets are frequently given inappropriately. The accepted indication is symptomatic thrombocytopaenia due to bone marrow failure. In contrast replacement therapy is contraindicated in immune mediated peripheral sequestration because it is almost always ineffective and also aggravates the already rapid rate of the clearance due to superimposed isoimmunisation. Furthermore circulating levels, rather than the clinical situation, customarily trigger the request and would typically be at 20 x 10(9)/l. Usage is under evaluated and, accordingly, current practice has been scrutinised and a guideline proposed that is applicable to user and vendor alike. DESIGN AND METHODOLOGY: Prospectively a consecutive series of eligible cases were selected and, with informed consent, all relevant information recorded. Specific observations were haematologic status, quality of the product and the impact of previous exposure to blood fractions on outcome. Additionally, factors that influence response were documented and included disseminated intravascular coagulation, splenomegaly and concurrent use of intravenous Amphotericin B. The absolute numbers infused, the increase in peripheral value recorded and this ratio which is designated as corrected count index generated in each instance. RESULTS: The CCI was computed for each of the 85 megaunits given to 29 individuals and subsequently estimated for the entire sample population using regression analysis. Each of the variables was used to test the hypothesis that such a figure might differ depending on patient sub-population. This approach was accurate in 60% of the time and predicates a more rational use of donor characteristics. The cardinal measurement is that supplied by the transfusion service which can be used as a basis for clinically important predictors of anticipated benefit. CONCLUSION: This data, in keeping with international practice, leads to the recommendation that commercial and other services routinely measure and specify absolute numbers. The clinicians, reciprocally, should always confirm this figure and then match anticipated to observed outcome. Failure to carry out these simple procedures lead to gross over utilisation of this expensive intervention, risks unnecessary sensitisation and furthers persistence with sub-optimum administration.

Blood Component Removal↗
PubMed2005

Clonogenic growth patterns correlate with chemotherapy response in acute myeloid leukaemia.

Cytosine arabinoside and anthracycline-containing regimens induce remission in upwards of 60% of previously untreated patients with adult acute myeloid leukaemia (AML). Despite this, in addition to primary drug resistance, the majority of these patients relapse. Reliable methods for uniformly recognising these two subgroups at presentation do not exist and therefore a further attempt has been made to relate in vitro toxicity, using a clonogenic assay, to clinical outcome. In 10 normal controls and 12 chemotherapy naïve cases, mononuclear cells harvested by density gradient separation were re-suspended at a concentration of 2 x 10(5)/ml and quadruplicates of 250 microl per well cultured in methycellulose containing foetal calf serum and phytohaemagglutinin stimulated leucocyte conditioned medium. Cell kill was determined for cytosine arabinoside, daunorubicin and etoposide either singly or in combination using both a pulsed and continuous exposure. Aggregates were scored after seven days and three distinct patterns recognised. The patients all received the same drugs in a standard protocol and achievement of complete remission correlated with growth pattern. The survival of normal marrow colony-forming cells or GM-CFUc and the leukemic equivalent designated L-CFUc were assessed and a sensitivity index (SI) determined as a ratio of these two values in which more reproducible results were found when the drug was continuously present. It is concluded that the microculture technique is feasible and clearly demonstrates chemotherapy effect but no correlation was demonstrated with clinical outcome. This is a negative pilot study and, as a means of recognising drug sensitivity or resistance, should be discarded in favour of currently available molecular techniques.

Adolescent↗
PubMed2004

Macronutrients.

Explore the source record for details and available documents.

Deficiency Diseases↗
PubMed2004

Interleukin/cytokine profiles in haemodialysis and in continuous peritoneal dialysis.

The uraemic syndrome is a complex condition that results from the retention of "waste" compounds that normally would be excreted into the urine or catabolized by the kidneys. In addition, inflammation has been implicated in symptoms associated with uraemia, including its role in the malnutrition-inflammation-atherosclerosis syndrome. Regarding vascular disease, traditional risk factors such as hypertension and gender do not seem to have the same significance in the uraemic population compared with patients without renal failure, and so the possibility has been raised that the uraemic toxins that result in the uraemic syndrome could play a role in this process. In this review, various questions are addressed regarding the involvement of cytokines in uraemia and the effects of dialysis membranes and fluids in patients receiving haemodialysis or peritoneal dialysis on cytokine levels. The effects of non-dialysis-related factors on levels of cytokines, mortality rates and other uraemic disorders are also discussed. It is concluded that cytokines are undoubtedly retained in uraemia, and that the loss of renal excretion almost certainly plays a key role in this process. Many cytokines have a pro-inflammatory role, probably resulting in a number of clinical events that are related to the increased morbidity and mortality of uraemic and haemodialysis patients. Any adjustment of the subtle balance between pro- and anti-inflammation by medical interventions should be conducted carefully because of an enhanced risk of serious infectious episodes. Bioincompatibility of dialysis techniques probably enhances the generation of cytokines as well as other uraemic toxins.

Cytokines↗
PubMed2004

In vitro study of the potential role of guanidines in leukocyte functions related to atherogenesis and infection.

BACKGROUND: The blunted immune response upon stimulation in chronic renal failure (CRF) is often coupled to a baseline inflammatory status which has been related to atherogenesis. Uremic biologic fluids and several specific uremic retention solutes alter cell-mediated immune responses, as well as the interaction of calcitriol with the immune system. METHODS: The present study evaluated the influence of different guanidino compounds on DNA synthesis, chemiluminescence production, and CD14 expression of undifferentiated and calcitriol-differentiated HL-60 cells. In a second setup, these guanidino compounds were evaluated for their specific effect on normal human leukocyte oxidative burst activity and tumor necrosis factor-alpha (TNF-alpha) expression. RESULTS: First, several guanidino compounds elicited proinflammatory effects on leukocytes. Methylguanidine and guanidine stimulated the proliferation of undifferentiated HL-60 cells and the antiproliferative effect of calcitriol (P < 0.05) was neutralized in the presence of methylguanidine (P < 0.05) and guanidinosuccinic acid (P < 0.05). The phorbol-myristate-acetate (PMA)-stimulated chemiluminescence production of the calcitriol differentiated HL-60 cells was enhanced in the presence of guanidine (P < 0.05). Methylguanidine and guanidinoacetic acid enhanced the lipopolysaccharide (LPS)-stimulated intracellular production of TNF-alpha by normal human monocytes (P < 0.05). Second, several guanidino compounds inhibited the function of leukocytes if they were activated. The PMA-stimulated chemiluminescence production of the calcitriol differentiated HL-60 cells was inhibited by the presence of methylguanidine (P < 0.05), guanidinoacetic acid (P < 0.05) and guanidinosuccinic acid (P < 0.05). After incubation of whole blood in the presence of methylguanidine, the Escherichia coli stimulated oxidative burst activity of the granulocyte population was significantly inhibited (P < 0.05). In addition, guanidinosuccinic acid had an inhibitory effect on the LPS-stimulated intracellular production of TNF-alpha by human monocytes (P < 0.01). CONCLUSION: Guanidino compounds exert proinflammatory as well as anti-inflammatory effects on monocyte/macrophage function. This could contribute to the altered prevalence of cardiovascular disease and propensity to infection in patients with CRF.

Arteriosclerosis↗
PubMed2003

Structure-activity relationship study of human liver microsomes-catalyzed hydrolysis rate of ester prodrugs of MENT by comparative molecular field analysis (CoMFA).

A series of MENT esters (3-71) was designed, prepared and tested to study the structure-activity relationship (SAR) of the hydrolysis rate with human liver microsomes of these prodrugs. Compounds were obtained covering a wide range of metabolic stability. The results are useful for the proper selection of prodrugs for different pharmaceutical formulations to deliver the potent and prostate-sparing androgen MENT. The MENT esters can especially be administered for male hormone replacement therapy and male contraception. Comparative molecular field analysis (CoMFA) was applied to a dataset of 28 esters, for which ED50 values could be obtained. The CoMFA model where the electrostatic and H-bond molecular fields were combined turned out to be most predictive. Despite the limited size of the dataset, CoMFA can help to rationalize the SAR of the ester hydrolysis rate of ester prodrugs of MENT.

Esters↗
PubMed2003

Eradication of invasive mucormycosis--effectiveness of the Echinocandin FK463.

BACKGROUND: Invasive rhinocerebral mucormycosis is a rare and often fatal opportunistic fungal infection. It is encountered in immunocompromised hosts exemplified by those with diabetes, human immunodeficiency viruses and particularly haematologic malignancies typically after high-dose chemotherapy and stem cell transplantation. In contrast to the more usual outcome with rapid progression and death. We now describe a successful eradication attributable to the use of a newly available antifungal agent. SETTING: Haematology department and bone marrow transplantation unit. MATERIAL AND METHOD: Two patients are contrasted. The first with acute leukaemia developed rapidly progressive facial swelling with mucormycosis proven on biopsy. Treatment over 2 months with maximally tolerated doses of amphotericin failed to halt intracranial extension and death resulted. The second, presented with acute lymphoblastic leukaemia in August 1997, underwent successful autologous bone marrow transplantation in February 1998. Relapse followed in March 1999 and after reinduction and consolidation receive a matched unrelated volunteer allograft in September 1999. A second recurrence was documented in April 2000 and in spite of achieving remission he developed a fever that was managed empirically with intravenous amphotericin and, on discharge, oral itraconazole. Left-sided facial swelling expanded rapidly and biopsy showed extensive invasion of the maxillary sinus with mucormycosis. FK463 was added on 5 June 2000 with gradual reduction in facial pain and within 1 month all clinical signs and resolved. Serial biopsies that included histopathologic investigation and microbiologic cultures confirmed eradication of the invasive mucor. In view of the potential danger of recrudescence this treatment regimen was continued through further chemotherapy and, once again disease-free, a second matched unrelated volunteer allograft took place in August 2000. Full reassessment at the time failed to demonstration any residual fungus. Engraftment was confirmed but neutropenic sepsis resulted in severe inflammatory response syndrome with progression to multiple organ dysfunction to which he succumbed without any evidence of leukaemic or systemic mycosis. CONCLUSION: Echinocandin FK463 is of documented value in managing invasive candidiasis and aspergillosis. This is believed to be the first case of successful outcome with one of the angiotrophic zygomycetes.

Acute Disease↗