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Biomedical subjects

F Jacobsen

Publications and source records attributed to F Jacobsen.

At least 19 recordsLinked to original sources
PubMed2005

Activity of histone H1.2 in infected burn wounds.

OBJECTIVES: Infections with multidrug-resistant microorganisms (e.g. Pseudomonas aeruginosa and Staphylococcus aureus) cause immense complications in wound care and in the treatment of immunosuppressed patients. Like most antimicrobial peptides, histones are relatively small polycationic proteins located in each eukaryotic nucleus, which naturally supercoil DNA. The aim of this study was to investigate the in vitro and in vivo activity of histone H1.2 in infected burn wounds and its potential toxicity. METHODS: To characterize the antimicrobial properties of histone H1.2 against potential causative organisms of burn wound infections, the in vitro radial diffusion assay and modified NCCLS microbroth dilution MIC assay were carried out. Haemolytic and cytotoxic properties were determined in human red blood cells and primary human keratinocytes. In vivo antimicrobial activity was tested in an infected rat burn model with P. aeruginosa (ATCC 27853). All results were compared with the naturally occurring broad-spectrum antimicrobial peptide protegrin-1 and with antibiotics clinically used against the corresponding bacteria. RESULTS: Human histone H1.2 exerted good antimicrobial activity against all tested microorganisms without significant haemolytic activity. Surprisingly, histone H1.2 showed cytotoxicity with an LD50 of 7.91 mg/L in primary human keratinocytes. The in vivo burn model data revealed a significant three-fold higher reduction in bacterial counts within 4 h compared with carrier control. CONCLUSIONS: These findings indicate that histone H1.2 is a potential candidate for use as a local and, because of its low haemolytic activity, systemic antimicrobial agent. However, further investigations are needed to specify the cytotoxicity and the dose-response relationship for histone H1.2.

Animals↗
PubMed2005

Transient cutaneous adenoviral gene therapy with human host defense peptide hCAP-18/LL-37 is effective for the treatment of burn wound infections.

Host defense peptides (HDP) are naturally occurring effector molecules of the innate immune system, which might be an alternative to currently used antibiotics. The objective of this study was to investigate the efficiency of transient cutaneous adenoviral transfection with human cathelicidin hCAP-18/LL-37 in infected burn wounds. Specific transgene expression was analyzed in vitro on mRNA and protein level using real-time PCR and Western-blot. Male Sprague-Dawley rats (n=40) received a second degree scald burn on both flanks (5% BSA), which were inoculated with 10(8) colony-forming units (CFU) Pseudomonas aeruginosa. Two days later, rats were randomized into the following groups: (1) adenoviral delivery of LL-37 (Ad5-hCAP-18, n=10), (2) synthetic host defense peptide LL-37 (1 mg; n=10), (3) carrier control (PBS, n=10) and (4) empty-virus control (Ad5-LacZ, n=10). Agents were injected intradermally and subcutaneously into both flanks. After either 2 or 7 days, skin samples were harvested and homogenized. CFU per gram tissue were determined. The hCAP-18/LL-37 expression was confirmed by real-time PCR and localized using in situ hybridization. In vitro transfection of cutaneous cells delivered a specific response on mRNA production. Western blot analysis revealed protein expression of hCAP-18/LL-37 in conditioned medium and cell pellet. The host defense peptide LL-37 was detectable after cleavage of the inactive pro-form hCAP-18/LL-37 with human elastase. Ad5-hCAP-18 showed a significant bacterial inhibition of approximately 10 000 fold compared to the control group (P<0.001) and 1000-fold (P<0.001) compared to the synthetic HDP LL-37 7 post-transfection. No inhibition was observed for the carrier or empty-virus control. Real-time PCR and in situ hybridization confirmed expression of hCAP-18/LL-37. In conclusion, transient cutaneous adenoviral delivery of the host defense peptide hCAP-18/LL-37 is significantly more effective than administration of synthetic host defense peptides and might be a potential adjunct for wound treatment in the near future.

Adenoviridae↗
PubMed2001

On the modeling of narrow gaps using the standard boundary element method.

Numerical methods based on the Helmholtz integral equation are well suited for solving acoustic scattering and diffraction problems at relatively low frequencies. However, it is well known that the standard method becomes degenerate if the objects that disturb the sound field are very thin. This paper makes use of a standard axisymmetric Helmholtz integral equation formulation and its boundary element method (BEM) implementation to study the behavior of the method on two test cases: a thin rigid disk of variable thickness and two rigid cylinders separated by a gap of variable width. Both problems give rise to the same kind of degeneracy in the method, and modified formulations have been proposed to overcome this difficulty. However, such techniques are better suited for the so-called thin-body problem than for the reciprocal narrow-gap problem, and only the first is usually dealt with in the literature. A simple integration technique that can extend the range of thicknesses/widths tractable by the otherwise unmodified standard formulation is presented and tested. This technique is valid for both cases. The modeling of acoustic transducers like sound intensity probes and condenser microphones has motivated this work, although the proposed technique has a wider range of applications.

Journal Article↗
PubMed2001

Highly active antiretroviral therapy in human immunodeficiency virus type 1-infected children: analysis of cellular immune responses.

The present study analyzes the effect of highly active antiretroviral therapy (HAART) on restoration of cellular immunity in human immunodeficiency virus (HIV)-infected children over a 24-week period following initiation of HAART with ritonavir, nevirapine, and stavudine. The immunological parameters evaluated at four time points (at enrollment and at 4, 12, and 24 weeks of therapy) included cytokine production by monocytes as well as T-cell proliferation in response to mitogen, alloantigen, and recall antigens including HIV type 1 envelope peptides. Circulating levels of interleukin-16 (IL-16) were measured, in addition to CD4+ T-cell counts, plasma HIV RNA levels, and the delayed-type hypersensitivity (DTH) response. At enrollment the children exhibited defects in several immune parameters measured. Therapy increased CD4+ T-cell counts and decreased viral loads significantly. By contrast, the only immunological parameter that was significantly increased was IL-12 p70 production by monocytes; the DTH response to Candida albicans also showed a strong increase in patients becoming positive. In conclusion, these results demonstrate that HAART in HIV-infected children affects the dynamics of HIV replication and the CD4+ T-cell count over 24 weeks, similar to the pattern seen in HIV-infected adults. Furthermore, these data indicate improvement in antigen-presenting cell immunological function in HIV-infected children induced by HAART.

Adolescent↗
PubMed2000

The coherence of reverberant sound fields.

A new method of measuring spatial correlation functions in reverberant sound fields is presented. It is shown that coherence functions determined with appropriate spectral resolution contain the same information as the corresponding correlation functions, and that measuring such coherence functions is a far more efficient way of obtaining this information. The technique is then used to verify theoretical predictions of the spatial correlation between various components of the particle velocity in a diffuse sound field. Other possible applications of the technique are discussed and illustrated with experimental results obtained in an ordinary room.

Models, Theoretical↗
PubMed1998

Amyloid precursor protein processing in sterol regulatory element-binding protein site 2 protease-deficient Chinese hamster ovary cells.

Amyloid peptides of 39-43 amino acids (Abeta) are the major constituents of amyloid plaques present in the brains of Alzheimer's (AD) patients. Proteolytic processing of the amyloid precursor protein (APP) by the yet unidentified beta- and gamma-secretases leads to the generation of the amyloidogenic Abeta peptides. Recent data suggest that all of the known mutations leading to early onset familial AD alter the processing of APP such that increased amounts of the 42-amino acid form of Abeta are generated by a gamma-secretase activity. Identification of the beta- and/or gamma-secretases is a major goal of current AD research, as they are prime targets for therapeutic intervention in AD. It has been suggested that the sterol regulatory element-binding protein site 2 protease (S2P) may be identical to the long sought gamma-secretase. We have directly tested this hypothesis using over-expression of the S2P cDNA in cells expressing APP and by characterizing APP processing in mutant Chinese hamster ovary cells that are deficient in S2P activity and expression. The data demonstrate that S2P does not play an essential role in the generation or secretion of Abeta peptides from cells, thus it is unlikely to be a gamma-secretase.

Amyloid Precursor Protein Secretases↗
PubMed1995

Disseminated intravascular coagulation associated with granulocyte colony-stimulating factor therapy in a child with human immunodeficiency virus infection.

We report a case of disseminated intravascular coagulopathy, apparently caused by exposure to granulocyte colony-stimulating factor (G-CSF). The medical records of patients treated for more than 30 consecutive days with subcutaneously administered G-CSF were reviewed for the occurrence of thrombocytopenia or coagulation abnormalities. New-onset thrombocytopenia with a platelet count less than 100 x 10(9) cells/L (< 100,000 cells/mm3) developed in 9 of 23 patients (39%) after a median of 11 weeks of treatment with G-CSF at dosages between 1 and 10 micrograms/kg per day.

Adolescent↗
PubMed1994

29-week doxazosin treatment in patients with symptomatic benign prostatic hyperplasia. A double-blind placebo-controlled study.

In a placebo-controlled study, the safety and efficacy of the selective alpha 1-adrenoceptor-blocking agent doxazosin 4 mg once daily in the symptomatic treatment of benign prostatic hyperplasia (BPH) were evaluated. One hundred patients were primarily included in a 9-weeks study, and after this 75 patients accepted to continue in the present 20 weeks extension. Of the patients in the doxazosin-group (DG) 61% reported overall improvement against 53% in the placebo-group (PG)--(p = 0.56). In the DG, 49% of obstructive symptoms were improved compared to 27% in the PG (p < 0.01), and a reduction of 60% of irritative symptoms was found in the DG against 36% in the PG (p < 0.01). Daytime frequency was reduced by median 1.5 in the DG and remained unchanged in the PG (p < 0.01). Nocturia was reduced by median 1 and 0.5 respectively (p = 0.06). Maximum urinary flow rate (MFR) was improved by median 1.5 ml/s in the DG, while it deteriorated by median 0.5 ml/s in the PG (p < 0.05), Considering postvoid residual urine volume, cystometry variables (first sensation and bladder capacity), changes in sexual function and adverse events there was no difference between the two groups. In conclusion, doxazosin 4 mg once daily in long-term treatment of patients with BPH reduces both obstructive and irritative symptoms, daytime voiding frequency and although only slightly, significantly augments MFR without interference with sexual function and without other serious adverse effects.

Aged↗
PubMed1993

Doxazosin treatment in patients with prostatic obstruction. A double-blind placebo-controlled study.

The safety and efficacy of the selective alpha 1-blocking agent doxazosin 4 mg once daily in the symptomatic treatment of benign prostatic hyperplasia were evaluated in a randomized, double-blind and placebo-controlled 9-week study of 100 patients. By patients' overall assessment of voiding difficulties, 79% in the doxazosin group (DG) and 44% in the placebo group (PG) reported improvement (p = 0.001). In the DG, improvement was noted in 63% of obstructive symptoms compared to 32% in the PG (p = 0.015), whereas improvement was noted in 76% and 45%, respectively, of irritative symptoms (p = 0.12). Daytime frequency was reduced by 1.5 in the DG and increased by 0.3 in the PG (p = 0.001), and nocturia was reduced by 1.1 and 1.0, respectively (p = 0.12). Maximum urinary flow rate was improved by 1.5 ml/s in the DG, while it deteriorated by 0.3 ml/s in the PG (p = 0.11). Considering postvoid residual urine volume, cystometry variables (first sensation and bladder capacity) and adverse events there was no difference between the two groups. In conclusion, doxazosin 4 mg once daily is safe and effective in relieving symptoms in patients with BPH.

Aged↗
PubMed1993

Pancreatitis in human immunodeficiency virus-infected children receiving dideoxyinosine.

To define predictive or contributory risk factors for pancreatitis in human immunodeficiency virus-infected children receiving dideoxyinosine (ddI), the authors evaluated 95 children, 3 months to 18 years of age, who had received ddI at 60 to 540 mg/m2 per day for a mean of 56 weeks. Pancreatitis developed in 7 patients (7%) but resolved in all upon withdrawal of ddI. Neither age, sex, nor CD4 count at study entry was predictive of pancreatitis, but pancreatitis appeared more likely to develop in hemophiliacs than in other patients (4 of 23 vs 3 of 72). Pancreatitis developed only in patients who received ddI at the highest dose levels (7 of 60 patients who received ddI at a dose > or = 360 mg/m2 per day vs 0 of 35 patients who received < or = 270 mg/m2 per day). Patients in whom pancreatitis developed had received a higher mean daily dose of ddI than patients with normal amylase and lipase levels throughout the study (348 mg/m2 vs 282 mg/m2), but no relationship with the cumulative dose or the duration of ddI therapy was observed. Although a statistically significant relationship between ddI plasma concentration (area under the curve) and pancreatitis was not conclusively demonstrated, as the number of patients in whom pancreatitis actually developed was small, such a relationship may have been obscured.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

Role of glycosylation on the secretion and biological activity of erythropoietin.

The erythropoietin (EPO) molecule contains four carbohydrate chains. Three contain N-linkages to asparagines at positions 24, 38, and 83, and one contains an O-linkage to a serine at position 126. We constructed human EPO variants that eliminated the three N-glycosylation sites by replacing the asparagines with glutamines singly or in combination. The O-linked carbohydrate chain was removed by replacing the serine with glutamine, valine, histidine, or alanine. A variant with a double mutation (Gln38,83) and another with a triple mutation (Gln24,38,83) were secreted poorly from COS1 and CHO cells even though RNA encoding these variants was present. All other variants with mutations in N-linked glycosylation sites were secreted normally. Removal of any of the N-glycosylation sites reduced the in vivo but not the in vitro biological activity of the EPO molecule. All the mutations at Ser126, the O-glycosylation site, were secreted normally. In vitro activity was also unaffected except for Ala126 which had a 50-fold decrease. The Val126 variant was tested in vivo, and its specific activity was only slightly less than that of the native EPO, which indicates that the O-linked carbohydrate is not essential for activity.

Animals↗
PubMed1992

Combination treatment with azidothymidine and granulocyte colony-stimulating factor in children with human immunodeficiency virus infection.

Bone marrow suppression is the major dose-limiting toxic effect of zidovudine (azidothymidine; AZT) in children with human immunodeficiency virus infection. We evaluated the effect of subcutaneously administered granulocyte colony-stimulating factor (G-CSF) in pediatric patients whose absolute neutrophil count was less than 0.8 x 10(9)/L during AZT therapy despite dosage reductions to 120 mg/m2 every 6 hours. Nineteen patients between 6 months and 20 years of age were treated with AZT and G-CSF and monitored for 2 to 12 months. All had previously shown improvement while receiving AZT but had required dosage reduction or discontinuation. By using a sliding dosing schedule of G-CSF, we attempted to maintain the absolute neutrophil count between 1.5 and 5.0 x 10(9)/L. Administration of G-CSF resulted in a significant increase in the median leukocyte count (2.0 x 10(9)/L to 4.14 x 10(9)/L; p = 0.004), and the median absolute neutrophil count (1.02 x 10(9)/L to 2.96 x 10(9)/L; p = 0.0006). G-CSF was well tolerated, but mild thrombocytopenia developed in nine children. Administration of G-CSF and AZT was discontinued in two patients because of continuing neutropenia. With doses of G-CSF ranging from 1 to 20 micrograms/kg per day, 17 of 19 patients were able to tolerate AZT at a dose of 120 to 180 mg/m2 every 6 hours. We conclude that G-CSF therapy enables patients who have had AZT-related neutropenia to receive therapeutic doses of AZT.

Adolescent↗
PubMed1992

Clinical pharmacology of 2',3'-dideoxyinosine in human immunodeficiency virus-infected children.

The pharmacokinetics of intravenous and oral 2',3'-dideoxyinosine (ddI) and the relationships between pharmacokinetic parameters and measures of response were studied in 48 human immunodeficiency virus-infected children. Disappearance of ddI from plasma after the intravenous dose was rapid and biexponential, with half-lives of 12 min and 1.0 h and a total clearance of 510 +/- 180 ml/min/m2. After oral administration, ddI absorption was limited and variable (mean bioavailability, 19% +/- 17%). A plasma ddI concentration-response relationship was observed for both decline in viral p24 antigen levels and improvement in intelligence quotient score. A limited sampling model was developed that accurately predicts the area under the ddI plasma concentration-time curve from one to three plasma samples. Although this pharmacokinetic study was done in children, the results also have relevance to adults and suggest that individualization of dose and schedule through therapeutic drug monitoring may be necessary to achieve optimal response.

Absorption↗
PubMed1991

Stereological estimates of nuclear volume in the prognostic evaluation of primary flat carcinoma in situ of the urinary bladder.

Primary, flat carcinoma in situ of the urinary bladder is rare and its behaviour is unpredictable. The aim of this retrospective study was to obtain base-line data and investigate the prognostic value of unbiased, stereological estimates of the volume-weighted mean nuclear volume, nuclear vv, in 78 bladder biopsies from 22 patients with primary flat carcinoma in situ (Bergkvist grades III-IV). On average, nuclear vv was 77 microns 3 in nine biopsies with morphologically normal urothelium, 292 microns 3 in 56 isolated primary lesions and 266 microns 3 in lesions of luminal urothelium in 13 biopsies with co-existing invasive carcinoma. No recognizable developmental pattern of nuclear vv in relation to the time course of disease was found. Nuclear volume in the first biopsy was of the same magnitude in lesions with and without co-existing invasive carcinoma (2P = 0.55), and in lesions with short and long duration of invasion-free period (2P greater than 0.20). Nuclear vv in the first biopsy did not differ between patients who survived and those who died from their primary flat carcinoma in situ (2P = 0.07). Dividing the patients on the basis of the group median of the first biopsy showing flat carcinoma in situ (nuclear vv = 261 microns 3), the survival was the same in patients with nuclear vv above and below the cut-off point (2P = 0.16). However, the survival curves showed a tendency to differ in the first 2-8 years of observation. Stereological estimates of nuclear vv provide objective, quantitative information, but their prognostic value in patients with primary flat carcinoma in situ of the bladder needs further clarification in larger data bases.

Aged↗