Biomedical subjects

Daniel Schmitz

Publications and source records attributed to Daniel Schmitz.

10 recordsLinked to original sources

PubMed2026

Nallo: a Nextflow pipeline for comprehensive human long-read genome analysis.

MOTIVATION: Long-read sequencing (LRS) is increasingly used for human medical research and clinical diagnostics due to its capacity to generate complete genome information. However, there is a lack of robust and easy-to-use pipelines for comprehensive LRS data analysis. RESULTS: Here we present Nallo, a Nextflow pipeline for analysis of PacBio and Oxford Nanopore data, with additional support for rare disease research projects. The pipeline detects a wide range of genetic variants, performs genome assembly, and reports CpG methylation. It also enables annotation and ranking of variants based on their predicted functional consequences. AVAILABILITY AND IMPLEMENTATION: Nallo is available from GitHub: https://github.com/genomic-medicine-sweden/nallo.

Humans↗

PubMed2006

beta-Adrenergic blockade during systemic inflammation: impact on cellular immune functions and survival in a murine model of sepsis.

AIM OF THE STUDY: Adrenergic immuno-modulation mediated by beta-adrenergic receptors has been demonstrated. Pharmacological blockade of beta-adrenergic receptors is a therapeutic intervention frequently used in critically ill patients. The effect of beta-adrenergic blockade on cellular immune functions in a critical illness, such as polymicrobial sepsis, has not been investigated. METHODS: Male NMRI-mice were subjected to sham operation or to sepsis (caecal ligation and puncture, CLP) following administration of either the non-selective beta-adrenergic antagonist propranolol (0.5 mg/kg s.c. every 12 h in 1 ml vehicle) or saline 0.9% (1 ml s.c. every 12 h). Mice were kept in metabolic cages and were sacrificed 48 h after induction of sepsis. Survival rate, clinical situation (body weight and temperature, fluid and food intake, urine output), and immunological variables (splenocyte proliferation, apoptosis, and IFN-gamma and IL-6 release) were determined. RESULTS: Administration of propranolol in septic mice increased the splenocyte apoptosis rate, reduced the proliferative capacity of splenocytes, and modulated cellular cytokine release (IL-6, IFN-gamma). This was paralleled by a higher loss of body weight and temperature, and a decreased urine output. Furthermore, treatment with propranolol increased the sepsis-induced lethality from 47% up to 68%, respectively. CONCLUSION: beta-Adrenergic blockade was accompanied by alterations of cellular immune functions, a deterioration in the clinical situation and a reduced survival in a murine model of sepsis. These data demonstrate the potential immuno-modulatory effects of beta-adrenergic antagonists.

Adrenergic beta-Antagonists↗

PubMed2006

Screening for the formation of reactive oxygen species and of NO in muscle tissue and remote organs upon mechanical trauma to the mouse hind limb.

BACKGROUND: Until now, no systematic surveys exist in the literature on the early local and systemic generation of reactive oxygen species and of nitric oxide in response to muscle crush injury. Therefore, this study aims to evaluate the formation of reactive oxygen species and nitric oxide in different tissues (injured and contralateral muscle, liver, kidney, spleen and blood) that is induced by closed muscle trauma. METHODS: 5, 45 and 180 min after induction of blunt trauma to the mouse gastrocnemius muscle, animals were sacrificed, tissues harvested and homogenized, and analyzed for their content of glutathione, nitrate and thiobarbituric acid-reactive substances. RESULTS: The local formation of reactive oxygen species in the injured muscle started immediately upon induction of the mechanical trauma as indicated by changes in the glutathione redox balance. Liver and kidney did not show any response to trauma; however, a marked and immediate increase in the splenic nitrate content was detected, thus suggesting a specific nitric oxide-dependent response of splenic cells to injury. CONCLUSION: We conclude that immediately after the induction of trauma a formation of reactive oxygen species takes place at the site of crush injury. This might constitute the basis of further damage to the injured tissue by free radical-dependent mechanisms. The immediate formation of nitric oxide within the spleen upon muscle crush appears to represent a specific signalling mechanism of the body in response to distant organ injury.

Animals↗

PubMed2006

Dopamine affects cellular immune functions during polymicrobial sepsis.

OBJECTIVE: To determine whether infusion of dopamine modulates cellular immune functions and survival during systemic inflammation. DESIGN AND SETTING: Randomized animal study, university research laboratory, Level I trauma center. SUBJECTS: Male NMRI mice. INTERVENTIONS: Mice were subjected to laparotomy (sham intervention, LAP) or polymicrobial sepsis induced by cecal ligation and puncture (CLP). Mice in each of these conditions received either an intraperitoneal infusion of 0.9% saline (CLP/saline; LAP/saline) or an intraperitoneal infusion of dopamine (1.0 microg/kg/min i.p., CLP/DOP; LAP/DOP). Metabolic data and survival were monitored 24 h and 48 h after onset of sepsis, and animals were terminated 48 h after induction of sepsis to determine splenocyte apoptosis (Annexin V binding capacity), splenocyte proliferation (3H-Thymidine incorporation assay), splenocyte IL-2, IL-6 and IFN-gamma release (ELISA) and leukocyte distribution (WBC; CD3, CD4, CD8, B220, F4/80, NK1.1). MEASUREMENTS AND RESULTS: Infusion of dopamine in septic mice increased splenocyte apoptosis and decreased splenocyte proliferation and IL-2 release of septic mice. Furthermore, an inhibitory effect of dopamine infusion on splenocyte proliferation and the release of the TH1-cytokines IL-2 and IFN-gamma was observed in sham operated control mice. These effects were paralleled by a decreased survival of dopamine-treated septic animals (47% vs. 67%). Treatment with DOP did not affect sepsis-induced changes of leukocyte distribution. CONCLUSIONS: We conclude that dopamine is capable of modulating cellular immune functions in a murine model of sepsis.

Animals↗

PubMed2005

Dendritic cells during polymicrobial sepsis rapidly mature but fail to initiate a protective Th1-type immune response.

Polymicrobial sepsis is associated with immunosuppression caused by the predominance of anti-inflammatory mediators and profound loss of lymphocytes through apoptosis. Dendritic cells (DC) are potent antigen-presenting cells and play a key role in T cell activation. We tested the hypothesis that DC are involved in sepsis-mediated immunosuppression in a mouse cecal ligation and puncture (CLP) model, which resembles human polymicrobial sepsis. At different time-points after CLP, DC from the spleen and peripheral lymph nodes were characterized in terms of expression of costimulatory molecules, cytokine synthesis, and subset composition. Splenic DC strongly up-regulated CD86 and CD40 but not CD80 as soon as 8 h after CLP. In contrast, lymph node DC equally increased the expression of CD86, CD40, and CD80. However, this process of maturation occurred later in the lymph nodes than in the spleen. Splenic DC from septic mice were unable to secrete interleukin (IL)-12, even upon stimulation with CpG or lipopolysaccharide+CD40 ligand, but released high levels of IL-10 in comparison to DC from control mice. Neutralization of endogenous IL-10 could not restore IL-12 secretion by DC of septic mice. In addition, the splenic CD4+CD8- and CD4-CD8+ subpopulations were lost during sepsis, and the remaining DC showed a reduced capacity for allogeneic T cell activation associated with decreased IL-2 synthesis. Thus, during sepsis, splenic DC acquire a state of aberrant responsiveness to bacterial stimuli, and two DC subtypes are selectively lost. These changes in DC behavior might contribute to impaired host response against bacteria during sepsis.

Animals↗

PubMed2004

Dopexamine and cellular immune functions during systemic inflammation.

An immune-neuroendocrine interaction that is mediated via beta2-adrenergic receptors has been demonstrated previously. Dopexamine is a substance with strong beta2-adrenergic effects and is used in the treatment of critically ill patients. We therefore investigated the effect of dopexamine infusion on survival and cellular immune functions during systemic inflammation. Sepsis (CLP) was induced in male NMRI mice that received either 0.9% saline, dopexamine (0.05 mg/kg/hour ip, DPX), the selective beta2-adrenergic antagonist ICI 118.551 (0.5 mg/kg ip every 12 hours, ICI) or a combination of both drugs. 48 hours after onset of sepsis, survival rate, splenocyte apoptosis, splenocyte proliferation, splenocyte IL-2, IL-6 and IFN-gamma release, and leukocyte distribution were monitored. Dopexamine increased splenocyte apoptosis and normalized the distribution of circulating lymphocytes but did not affect sepsis-induced mortality. ICI 118.551 induced a dramatic increase of mortality paralleled by a decreased splenocyte proliferation and the strongest increase in splenocyte apoptosis. Co-administration of dopexamine abolished the ICI 118.551-induced alterations but this effect seemed to be mediated via a pathway other than adrenergic beta2-receptors. We conclude that dopexamine modulates cellular immune functions during systemic inflammation and that different receptor systems are involved in the mediation of this process. Furthermore, the immunomodulatory effect of beta2-adrenergic blockade was demonstrated.

Adrenergic beta-Antagonists↗

PubMed2004

Adrenergic modulation of survival and cellular immune functions during polymicrobial sepsis.

OBJECTIVE: An immunomodulatory effect of epinephrine has been reported that is supposed to be mediated via beta-adrenergic receptors. The effect of epinephrine and/or beta-adrenergic blockade on cellular immune functions during systemic inflammation has not yet been investigated. METHODS: Male NMRI mice were treated with either an infusion of epinephrine (0.05 mg/kg/h i.p.), administration of the nonselective beta-adrenoceptor antagonist propranolol (0.5 mg/kg s.c.), or a combination of epinephrine and propranolol after induction of a polymicrobial sepsis by cecal ligation and puncture. Forty-eight hours thereafter survival and cellular immune functions (splenocyte proliferation, splenocyte apoptosis and cytokine release, distribution of leukocyte subsets) were determined. RESULTS: Infusion of epinephrine did not affect lethality of septic mice but induced alterations of splenocyte apoptosis, splenocyte proliferation and IL-2 release and was associated with profound changes of circulating immune cell subpopulations. Treatment with propranolol augmented the epinephrine-induced increase of splenocyte apoptosis, did not affect the decrease of splenocyte proliferation and IL-2 release, augmented the release of IL-6 and antagonized the mobilization of natural killer cells observed in epinephrine-treated animals. Furthermore, these immunologic alterations were accompanied by a significant increase of sepsis-induced mortality. Coadministration of propranolol and epinephrine augmented the propranolol-induced changes of splenocyte apoptosis and IL-6 release and was associated with the highest mortality of septic mice. CONCLUSION: Epinephrine infusion modulated cellular immune functions during systemic inflammation without an impact on survival. A pharmacologic beta-adrenergic blockade partly augmented the epinephrine-induced immune alterations and was associated with a pronounced increase of mortality. This effect was further augmented by a combination of epinephrine infusion and beta-adrenergic blockade. These data indicate that adrenergic mechanisms modulate cellular immune functions and survival during sepsis, with these effects being mediated via alpha- and beta-adrenergic pathways.

Adrenergic beta-Antagonists↗

PubMed2003

Prolactin modulates survival and cellular immune functions in septic mice.

BACKGROUND: The immunomodulatory properties of the pituitary hormone prolactin have been demonstrated. It was proposed that prolactin is important in maintaining normal immune response in several pathological states. We investigated the effect of prolactin administration on the survival and cellular immune functions during systemic inflammation. MATERIALS AND METHODS: Male NMRI mice were subjected to laparotomy (LAP) or sepsis induced by cecal ligation and puncture (CLP). Mice were treated with either saline (LAP/saline; CLP/saline) or prolactin (LAP/PRL, CLP/RPL; 4 mg/kg s.c.). Survival of septic mice was determined 24 and 48 h after CLP. Forty-eight hours after the septic challenge, the proliferative capacity, cytokine release (IL-2, IL-6, IFN-gamma) and apoptosis of splenocytes were determined. Additionally, monitoring of circulating leukocyte distribution was performed (WBC; CD3+, CD4+, CD8+, B220+, NK1.1+, F4/80+ cells by FASCan). RESULTS: CLP was accompanied by a mortality of 47% and induced a decrease in splenocyte proliferation and apoptosis rate. Administration of prolactin significantly increased the mortality of septic mice (81%). This was paralleled by a further decrease of splenocyte proliferation and an increased splenocyte apoptosis. In addition, administration of prolactin augmented the sepsis-induced inhibition of IL-2 release, attenuated the sepsis-induced inhibition of IFN-gamma release, and did not affect the release of IL-6. However, prolactin did not affect the sepsis-induced changes of circulating leukocyte subpopulations. CONCLUSIONS: We conclude that prolactin has profound immunomodulatory properties and that administration of prolactin in pharmacological doses is associated with a decreased survival and an inhibition of cellular immune functions in septic mice.

Animals↗

PubMed2002

The effect of dehydroepiandrosterone on hemorrhage-induced suppression of cellular immune function.

OBJECTIVE: To determine whether the steroid hormone dehydroepiandrosterone (DHEA) improves cellular immune functions after hemorrhagic shock. DESIGN AND SETTING: Prospective controlled study in a research laboratory at an university medical center. SUBJECTS: Male NMRI mice. INTERVENTIONS: Animals received 0.9% saline or DHEA (20 mg/kg subcutaneously) before induction of a volume-controlled hemorrhagic shock (55% of estimated circulating blood volume) by retro-orbital puncture. One hour after hemorrhage mice underwent fluid resuscitation by intravenous infusion of lactated Ringer's solution (300% of the shed blood). Separate groups of mice were killed to obtain whole blood and spleen 1 h after hemorrhage, 1 h after fluid resuscitation, and 24 h after hemorrhage to determine lymphocyte distribution (CD4(+), CD8(+), NK1.1-AG(+)), splenocyte apoptosis, and plasma concentrations of tumor necrosis factor-alpha and interleukin-10. MEASUREMENTS AND RESULTS: Hemorrhage in control mice was associated with a rapid increase in circulating NK cell numbers. Elevated splenocyte apoptosis, an increased CD4/CD8 ratio, and decreased number of circulating CD8(+) T-cells was observed 24 h after hemorrhagic shock. DHEA administration was accompanied by a normalization of splenocyte apoptosis and lymphocyte migration. Induction of hemorrhagic shock did not affect TNF-alpha or IL-10 plasma concentrations in either treatment group. CONCLUSIONS: DHEA administration improves cellular immune function after hemorrhage and may therefore be beneficial in patients with hemorrhagic shock.

Animals↗

PubMed2002

Quantification of the wall inhomogeneity in B-mode sonographic images of the carotid artery.

OBJECTIVE: The process of atherosclerosis has been assessed increasingly by sonography in B-mode images of the carotid arteries. Carotid artery atherosclerosis is thought to be associated with major atherosclerotic diseases in other regions of the arterial bed, especially the coronary arteries. In addition to the intima-media thickening as an established surrogate parameter of the atherosclerotic wall process, changes of the sonographic morphologic pattern of the intima-media layer might reflect this process. METHODS: After automatic identification of the intimal and adventitial boundaries of the distal common carotid artery wall, the gray level inhomogeneity of the circumscribed intima-media area was quantified. Older subjects without cardiovascular disease (mean +/- SD, 66.2 +/- 3.8 years; n = 43) were compared with young subjects without cardiovascular disease (24.4 +/- 5.3 years; n = 34) and patients with manifest coronary artery disease (65.0 +/- 9.2 years; n = 69). RESULTS: Patients with coronary artery disease had a significantly higher intima-media thickness (0.92 +/- 0.21 mm; P < .05) and wall inhomogeneity (4.56 +/- 0.97; P < .001) than the old group (0.86 +/- 0.15 mm and 3.83 +/- 0.62). Both parameters were lowest in the young group (0.56 +/- 0.05 mm and 2.53 +/- 0.76; P < .05 for both parameters and groups). CONCLUSIONS: Measurement of gray level wall inhomogeneity of the intima-media layer of the common carotid artery may help discriminate between subjects with high and low atherosclerotic burden and may show age-related changes of the intima-media layer. This new quantitative parameter is thought to reflect the atherosclerotic wall process in addition to the intima-media thickness measurement.

Adult↗