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Biomedical subjects

N Klein

Publications and source records attributed to N Klein.

At least 37 records · Page 2Linked to original sources
PubMed2003

Surgical infants on total parenteral nutrition have impaired cytokine responses to microbial challenge.

BACKGROUND/PURPOSE: Cytokines are essential for the prevention of microbial infections. Total parenteral nutrition (TPN) in infancy is associated with an increased risk of infection, and this could be related to altered cytokine production. The aim of the study was to determine if cytokine production is altered in monocytes from surgical infants receiving TPN. METHODS: There were 3 study groups: (a) infants receiving TPN, (b) enterally fed healthy control infants, and (c) enterally fed healthy control adults. Blood samples were incubated with either Escherichia coli LPS, Staphylococcus epidermidis, or with medium alone. Flow cytometry was used to measure monocyte intracellular cytokine: tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-1beta. RESULTS: After LPS stimulation, the percent of monocytes producing TNF-alpha and IL-6 were lower in infants on TPN than both control infants and adults. This was most apparent for TNF-alpha. The difference for IL-1beta was significant only between infant on TPN and control adults. When blood was stimulated with S. epidermidis, all 3 cytokines were significantly lower in the TPN group compared with control adults. However, the differences between infants on TPN and infant controls only reached statistical significance for IL-6. CONCLUSIONS: The inflammatory response to bacterial challenge is impaired in infants on TPN compared with enterally fed infants or adults. The pattern of this response may be dependent on the nature of the microbial challenge. Our results indicate that the susceptibility of TPN-fed surgical infants to bacterial infections may in part be caused by impaired cytokine responses after bacterial invasion.

Adult↗
PubMed2002

Kawasaki disease: an evidence based approach to diagnosis, treatment, and proposals for future research.

This article proposes a clinical guideline for the diagnosis and treatment of Kawasaki disease in the UK based on the best available evidence to date, and highlights areas of practice where evidence is anecdotal or based on retrospective data. Future research as proposed by the London Kawasaki Disease Research Group is outlined, and clinicians are invited to prospectively enroll their suspected cases into this collaborative research project.

Adrenal Cortex Hormones↗
PubMed2002

[Epidermoid cyst of the fourth ventricle: four case reports].

Patients with epidermoid cyst of the fourth ventricle usually present with headaches and/or disequilibrium. These cysts are characterized by a focal lesion that is nearly isodense to CSF at CT and nearly isointense to CSF on T1W and T2W MR images. MRI using FLAIR and diffusion weighted images as well as 3D CISS acquisitions is useful to better characterize the lesions and their relation with the vermis, foramen magnum and CP angle cisterns. DWI images are useful for postsurgical evaluation of residual tumor. Extension of the cyst into the CP angle cisterns usually precludes complete surgical resection.

Adult↗
PubMed2001

Penetration of dacarbazine and its active metabolite 5-aminoimidazole-4-carboxamide into cutaneous metastases of human malignant melanoma.

BACKGROUND: Dacarbazine has been on the market for approximately 3 decades but remains the most effective single agent available for the therapy of metastatic malignant melanoma (MMM). Most MMMs, however, respond poorly to dacarbazine therapy. Apart from tumor resistance at a molecular level, several studies support the notion that therapeutic failure in tumor therapy also might be attributed to an impaired transcapillary drug transfer. METHODS: On the basis of this hypothesis, the authors measured intratumor transcapillary transfer rates of dacarbazine and its active metabolite 5-aminoimidazole-4-carboxamide (AIC) by in vivo microdialysis after intravenous administration of dacarbazine at doses of 200 mg/m(2) to 1000 mg/m(2) (n = 7) in patients suffering from MMM. RESULTS: For all doses, area under the concentration curve (AUC) values for dacarbazine and AIC were not significantly different between plasma and tumor interstitium with AUC(tumor)/AUC(plasma) ratios of 0.97 +/- 0.08 (mean +/- standard error of the mean) for dacarbazine and 0.76 +/- 0.22 for AIC. AUC(0-240) values for dacarbazine and AIC measured in plasma correlated closely with corresponding AUC(0-240)values measured in the interstitium of MMMs with values of r(s) = 0.82 (P = 0.042) and r(s) = 0.90 (P = 0.037), respectively. CONCLUSIONS: The results of this study indicate favorable tumor penetration characteristics of dacarbazine and its active metabolite AIC. The relative lack of response to antineoplastic therapy with dacarbazine, thus might be explained by resistance of melanoma cells at a molecular level rather than by an inability of dacarbazine and AIC to penetrate into the interstitium of MMM.

Aged↗
PubMed2001

Ischemic preconditioning prevents endothelial injury and systemic neutrophil activation during ischemia-reperfusion in humans in vivo.

BACKGROUND: Endothelial dysfunction leading to neutrophil infiltration of tissues has been implicated in tissue injury caused by ischemia-reperfusion (IR). Tissue injury during IR can be reduced by prior ischemic preconditioning (IPC). In humans, it is unclear whether endothelial dysfunction occurs during IR or whether IPC offers protection against endothelial dysfunction and inflammatory cell activation. We studied the effects of experimental IR on endothelial and neutrophil function in the human forearm in vivo and examined the protection afforded by IPC. METHOD AND RESULTS: The forearm was made ischemic for 20 minutes by inflating a blood pressure cuff to 200 mm Hg. We assessed endothelial function of conduit (radial artery flow-mediated dilation) and resistance vessels (blood flow responses to intra-arterial infusion of the endothelium-dependent dilator acetylcholine) in healthy volunteers before and after IR. IR reduced flow-mediated dilation of the radial artery at 15 minutes of reperfusion (7.7+/-1.5% to 3.5+/-0.9%) and the dilator response of resistance vessels to acetylcholine at 15, 30, and 60 minutes of reperfusion. IR did not reduce the dilator response of the radial artery to glyceryltrinitrate and only caused a small reduction of glyceryltrinitrate-induced dilation of resistance vessels at 60 minutes of reperfusion. IR caused an increase in neutrophil CD11b expression and platelet-neutrophil complexes in the circulating blood. IPC (three 5-minute episodes of ischemia) before IR prevented endothelial dysfunction and neutrophil activation. CONCLUSIONS: A clinically relevant period of ischemia-reperfusion causes profound and sustained endothelial dysfunction and systemic neutrophil activation. IPC attenuates both of these effects in humans.

Acetylcholine↗
PubMed2001

Long-term family outcomes for children with very low birth weights.

OBJECTIVE: To examine long-term outcomes in families of children with very low birth weights (<1500 g) in relation to the extent of low birth weight and neonatal medical risk. DESIGN: Concurrent/cohort prospective study. SETTING: Regional follow-up program. PARTICIPANTS: Families of 60 children of school age with birth weights less than 750 g, 55 with birth weights between 750 and 1499 g, and 49 normal birth weight full-term controls. MAIN OUTCOME MEASURES: Parent ratings of psychological distress, family function, and child-related stress. RESULTS: Families with children with birth weights less than 750 g experienced greater stress than did families of controls (born at full term), and families who were sociodemographically advantaged experienced greater stress than did those who were disadvantaged. Higher neonatal medical risk also predicted a more negative impact on the family, but only in advantaged families. Regression analyses suggested that adverse family outcomes were mediated by ongoing problems in child functioning. CONCLUSIONS: Families of children with birth weights less than 750 g experience more long-term adversity than families of full-term children. Family sequelae are also present for children with very low birth weight at high neonatal medical risk. Ongoing child health and behavior problems may be the major source of these sequelae, and sociodemographic status is an important consideration in identifying family adversity. Although many families appear unaffected, results support the need to monitor family outcomes and develop interventions for both the child and family.

Child Behavior Disorders↗
PubMed2001

Pharmacokinetics of emedastine difumarate, a new anti-histaminic agent in patients with renal impairment.

OBJECTIVE: Emedastine difumarate is a new H1 receptor antagonist with well defined pharmacokinetic and pharmacodynamic profiles in healthy volunteers. However, to date it is not known whether impaired renal function in patients with chronic renal insufficiency affects its pharmacokinetics and probably also its tolerability. Therefore, we here set out to compare the pharmacokinetics of emedastine difumarate in patients suffering from different degrees of renal failure with a control group of healthy volunteers. METHODS AND RESULTS: For this purpose we conducted an open, single-centre, comparative parallel group study in patients and healthy volunteers. Emedastine difumarate 2 mg was administered orally to the study population in single and seven repetitive doses twice daily (b.i.d.). Pharmacokinetics differed markedly between volunteers (n = 6) and patients (n = 17). The maximum serum concentration of emedastine (Cmax), area under the serum concentration-time curve, mean residence time and terminal disposition half-life were significantly higher in patients (P < 0.05), while time to reach Cmax and apparent volume of disposition were not statistically different after single and repeated (steady-state) oral administrations. Blood pressure and heart rate were also not affected by the study medication. CONCLUSION: The present study shows that impaired renal function alters the pharmacokinetics of emedastine in plasma. Thus, dose adjustment of emedastine difumarate is advisable in patients with impaired renal function.

Administration, Oral↗
PubMed2001

Characterization of four CD18 mutants in leucocyte adhesion deficient (LAD) patients with differential capacities to support expression and function of the CD11/CD18 integrins LFA-1, Mac-1 and p150,95.

Leucocyte adhesion deficiency (LAD) is a hereditary disorder caused by mutations in the CD18 (beta2 integrin) gene. Four missense mutations have been identified in three patients. CD18(A270V) supports, at a diminished level, CD11b/CD18 (Mac-1, alphaMbeta2 integrin) and CD11c/CD18 (p150,95, alphaXbeta2 integrin) expression and function but not CD11a/CD18 (LFA-1, alphaLbeta2 integrin) expression. Conversely, CD18(A341P) supports a limited level of expression and function of CD11a/CD18, but not of the other two CD11/CD18 antigens. CD18(C590R) and CD18(R593C) show a decreasing capacity to associate with the CD11a, CD11c and CD11b subunits. Transfectants expressing the CD11a/CD18 with the C590R and R593C mutations are more adhesive than transfectants expressing wild-type LFA-1, and express the reporter epitope of the monoclonal antibody 24 constitutively. Thus, the four mutations affect CD18 differently in its capacities to support CD11/CD18 expression and adhesion. These results not only provide a biochemical account for the clinical diversity of patients with leucocyte adhesion deficiency, but also offer novel insights into the structural basis of interaction between the alpha and beta subunits, which is an integral component in our understanding of integrin-mediated adhesion and its regulation.

Alleles↗
PubMed2001

Conversion of amino acids into aroma compounds by cell-free extracts of Lactobacillus helveticus.

AIMS: Lactobacillus helveticus is an essential starter in Swiss-type cheeses such as Emmental. This study was to determine whether cell-free extracts of Lact. helveticus were able to convert free amino acids into neutral volatile aroma compounds at the pH and temperature occurring in cheese. METHODS AND RESULTS: A mix of branched-chain (Leu, Ile, Val), aromatic (Tyr, Phe) and sulphur (Met) amino acids was incubated for 7 days, at pH 5.7 and 24 degrees C, with cell-free extracts of six strains. The amino acids were all transaminated into the corresponding keto acids when an amino group acceptor (alpha-ketoglutaric acid) was provided. Phe and Tyr were transaminated the most efficiently, followed by Leu, Met, Ile and Val. Three major volatile compounds were detected by GC-MS: benzaldehyde, dimethyl disulphide and 2-methyl propanol. Whatever the strain, benzaldehyde was produced in the highest quantity (0.25-1 micromol l(-1) mg(-1) protein). CONCLUSIONS, SIGNIFICANCE AND IMPACT OF THE STUDY: Lactobacillus helveticus intracellular enzymes could significantly contribute to the production of aroma compounds from amino acid catabolism.

Amino Acids↗
PubMed2001

The role of the collectin system in pulmonary defence.

The human collectin system comprises the serum protein, mannose- binding lectin and the hydrophilic surfactant proteins A and D. The three proteins possess structural and functional similarities and are important components of innate immunity. Through a variety of mechanisms, including direct opsonisation and complement activation, they assist in host defence against a wide array of micro-organisms. Investigation of the roles of the surfactant proteins in pulmonary disease has been assisted recently by the development of transgenic knockout mice. Animals deficient in these proteins display susceptibility to certain bacterial and viral pathogens, stimulating research into the role of polymorphisms in these genes in human respiratory disease. The role of MBL in human pulmonary disease is less well established, although accumulating evidence suggests that it is a modifier for lung disease in tuberculosis and cystic fibrosis.

Adult↗
PubMed2001

Angioplasty increases target site concentrations of ciprofloxacin in patients with peripheral arterial occlusive disease.

OBJECTIVE: Patients with peripheral arterial occlusive disease are prone to soft tissue infections and frequently require antibiotics. To date, however, it is not known whether improvement of arterial blood flow by angioplasty of stenosis increases antibiotic concentrations in ischemic lesions. PATIENTS AND METHODS: All patients were scheduled to undergo elective percutaneous transluminal angioplasty (n = 10). Following a single, 400-mg dose of ciprofloxacin, drug concentrations in plasma, ischemic and healthy soft tissue; arterial peak systolic velocity; and ankle-brachial pressure index were assessed before and after angioplasty. Unbound ciprofloxacin concentrations were measured at the site of infection with use of in vivo microdialysis. RESULTS: Angioplasty increased peak systolic velocity and ankle-brachial pressure index compared with baseline (P <.002). Before angioplasty area under concentration-time curve (AUC(0-300)) values for ciprofloxacin were lower in ischemic tissue than in healthy tissue, with median values of 7.1 mg.h/L (range, 3.5-13.0) and 11.3 mg.h/L (range, 3.4-19.0), respectively (P =.03). After angioplasty AUC(0-300) values were identical in ischemic and healthy adipose tissue; median AUC(0-300) values were 8.0 mg.h/L (range, 4.0-20.7) and 8.5 mg.h/L (range, 4.4-22.9), respectively (P =.7). A combined in vivo pharmacokinetic/in vitro pharmacodynamic simulation based on tissue concentration data indicates that this difference in pharmacokinetics is also reflected in antimicrobial effect. CONCLUSION: Antibiotic concentrations are reduced significantly in ischemic lesions compared to those of healthy adipose tissue in patients with peripheral arterial occlusive disease. From the present data it might be speculated that improvement of arterial blood flow at the affected extremity is associated with increased cure rates of soft tissue infections in these patients.

Adipose Tissue↗
PubMed2001

Impaired target site penetration of beta-lactams may account for therapeutic failure in patients with septic shock.

OBJECTIVE: Current guidelines for adjusting antimicrobial therapy regimens commonly are based on drug concentrations measured in plasma. In septic patients, however, the interstitial space of soft tissues in addition to the central compartment represents the target site of infection. We thus hypothesized that one explanation for therapeutic failure during antibiotic treatment might be the inability to achieve effective antimicrobial concentrations in the interstitial space fluid of soft tissues. This is corroborated by the fact that piperacillin, a frequently administered beta-lactam antibiotic, often fails to be effective despite documented susceptibility of the causative pathogen in vitro. DESIGN: Prospective comparative study of two groups. SETTING: The intensive care unit and research ward of an university hospital. SUBJECTS: Six patients with septic shock and a control group of six gender- and age-matched healthy volunteers. INTERVENTIONS: To measure piperacillin penetration into the interstitial space fluid of skeletal muscle and subcutaneous adipose tissue, we employed microdialysis after a single intravenous administration of 4.0 g of piperacillin to patients and healthy volunteers. Piperacillin concentrations were assayed by using reversed-phase high-pressure liquid chromatography. MEASUREMENTS AND MAIN RESULTS: In septic shock patients, interstitial piperacillin concentrations in skeletal muscle and subcutaneous adipose tissue were five- to ten-fold lower than corresponding free plasma concentrations (p <.03). Mean piperacillin concentrations in subcutaneous adipose tissue never exceeded 11 microg/mL, which is below the minimal inhibitory concentration for a range of relevant pathogens in patients with septic shock. CONCLUSION: The results of the present study demonstrate that in septic shock patients, piperacillin concentrations in the interstitial space may be subinhibitory, even though effective concentrations are attained in plasma. The lack of success of antimicrobial therapy in these patients thus might be attributable to inadequate target site penetration of antibiotics.

Adipose Tissue↗
PubMed2001

Dendritic cell activation and cytokine production induced by group B Neisseria meningitidis: interleukin-12 production depends on lipopolysaccharide expression in intact bacteria.

Interactions between dendritic cells (DCs) and microbial pathogens are fundamental to the generation of innate and adaptive immune responses. Upon stimulation with bacteria or bacterial components such as lipopolysaccharide (LPS), immature DCs undergo a maturation process that involves expression of costimulatory molecules, HLA molecules, and cytokines and chemokines, thus providing critical signals for lymphocyte development and differentiation. In this study, we investigated the response of in vitro-generated human DCs to a serogroup B strain of Neisseria meningitidis compared to an isogenic mutant lpxA strain totally deficient in LPS and purified LPS from the same strain. We show that the parent strain, lpxA mutant, and meningococcal LPS all induce DC maturation as measured by increased surface expression of costimulatory molecules and HLA class I and II molecules. Both the parent and lpxA strains induced production of tumor necrosis factor alpha (TNF-alpha), interleukin-1alpha (IL-1alpha), and IL-6 in DCs, although the parent was the more potent stimulus. In contrast, high-level IL-12 production was only seen with the parent strain. Compared to intact bacteria, purified LPS was a very poor inducer of IL-1alpha, IL-6, and TNF-alpha production and induced no detectable IL-12. Addition of exogenous LPS to the lpxA strain only partially restored cytokine production and did not restore IL-12 production. These data show that non-LPS components of N. meningitidis induce DC maturation, but that LPS in the context of the intact bacterium is required for high-level cytokine production, especially that of IL-12. These findings may be useful in assessing components of N. meningitidis as potential vaccine candidates.

Acyltransferases↗
PubMed2001

Demystified...adhesion molecule deficiencies.

The basic physiology of leucocyte emigration from the intravascular space into the tissues is now known to be dependent on a class of cell surface molecules that have come to be known as adhesion molecules. Many cell-cell interactions are dependent on adhesion and signal transduction via the various adhesion molecules, particularly the integrins. The study of the functions of these molecules has been enhanced by the development of blocking and activating monoclonal antibodies, knockout mice, and by the rare "experiments of nature" in the human population, in whom there is absence or dysfunction of one of the adhesion molecules. This review describes these leucocyte adhesion defects and discusses how they have provided important insights into the function of these molecules.

Cell Adhesion Molecules↗
PubMed2001

Similar effects of atorvastatin, simvastatin and pravastatin on thrombogenic and inflammatory parameters in patients with hypercholesterolemia.

BACKGROUND: Previous studies have suggested that statins exert beneficial effects beyond their favorable lipid lowering effect. Particularly, the modification of thrombus formation and degradation, alteration in inflammatory response, plaque stabilization and improved endothelial function are thought to be responsible for additional reduction of morbidity and mortality due to cardiovascular events. To date, however, it is still unclear whether these effects are elicited by all statins. METHODS AND RESULTS: We set out to compare in a controlled, randomized, double-blind study design the effects of almost equieffective cholesterol lowering doses of three chemically and pharmacokinetically different statins (atorvastatin, simvastatin, pravastatin) on hemostatic and inflammatory markers in 99 hypercholesterolemic patients. At entry and 3 months after onset of statin therapy plasma cholesterol and von Willebrand factor antigen (vWf-Ag), fibrinogen, d-dimer, prothrombin fragment 1+2 (F1.2) and C-reactive protein (CRP) were measured. The effect on plasma values of F1.2, vWf-Ag, d-dimer and CRP was not significantly different between the three treatment groups. The effect of simvastatin on fibrinogen (p = 0.005) was more pronounced than the effects of atorvastatin (p = 0.48 n.s.) and pravastatin (p = 0.15 n.s.). Plasma levels of F1.2 and vWf-Ag (when data of all statins were pooled) were significantly reduced by 7% and 10% versus baseline, respectively. No significant reduction was observed for d-dimer (p = 0.26) and CRP (p = 0.5). Total plasma cholesterol levels decreased significantly (p < 0.0001 in all groups) between 22% and 29% compared to baseline. CONCLUSION: The present study shows similar short-term (3 months) effects of atorvastatin, simvastatin and pravastatin on selected hemostatic and inflammatory parameters in plasma in patients with hypercholesterolemia. Thus, chemical and pharmacological differences between statins appear to exert no major influence on these parameters.

Adult↗
PubMed2001

Contributions of Neisseria meningitidis LPS and non-LPS to proinflammatory cytokine response.

To determine the relative contribution of lipopolysaccharide (LPS) and non-LPS components of Neisseria meningitidis to the pathogenesis of meningococcal sepsis, this study quantitatively compared cytokine induction by isolated LPS, wild-type serogroup B meningococci (strain H44/76), and LPS-deficient mutant meningococci (strain H44/76[pLAK33]). Stimulation of human peripheral-blood mononuclear cells with wild-type and LPS-deficient meningococci showed that non-LPS components of meningococci are responsible for a substantial part of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta production and virtually all interferon (IFN)-gamma production. Based on tricine sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of LPS in proteinase K-treated lysates of N. meningitidis H44/76, a quantitative comparison was made between the cytokine-inducing capacity of isolated and purified LPS and LPS-containing meningococci. At concentrations of >10(7) bacteria/mL, intact bacteria were more potent cytokine inductors than equivalent amounts of isolated LPS, and cytokine induction by non-LPS components was additive to that by LPS. Experiments with mice showed that non-LPS components of meningococci were able to induce cytokine production and mortality. The principal conclusion is that non-LPS parts of N. meningitidis may play a role in the pathogenesis of meningococcal sepsis by inducing substantial TNF-alpha, IL-1beta, and IFN-gamma production.

Animals↗
PubMed2000

Mental stress induces transient endothelial dysfunction in humans.

BACKGROUND: Mental stress has been linked to increased morbidity and mortality in coronary artery disease and to atherosclerosis progression. Experimental studies have suggested that damage to the endothelium may be an important mechanism. METHODS AND RESULTS: Endothelial function was studied in 10 healthy men (aged 50. 4+/-9.6 years) and in 8 non-insulin-dependent diabetic men (aged 52. 0+/-7.2 years). Brachial artery flow-mediated dilation (FMD, endothelium dependent) and response to 50 microg of sublingual glyceryl trinitrate (GTN, endothelium independent) were measured noninvasively by use of high-resolution ultrasound before and after (30, 90, and 240 minutes) a standardized mental stress test. The same protocol without mental stress was repeated on a separate occasion in the healthy men. In healthy subjects, FMD (5.0+/-2.1%) was significantly (P:<0.01) reduced at 30 and 90 minutes after mental stress (2.8+/-2.3% and 2.3+/-2.4%, respectively) and returned toward normal after 4 hours (4.1+/-2.0%). Mental stress had no effect on the response to GTN. In the repeated studies without mental stress, FMD did not change. The diabetic subjects had lower FMD than did the control subjects (3.0+/-1.5% versus 5.0+/-2.1%, respectively; P:=0.02) but showed no changes in FMD (2.7+/-1.1% after 30 minutes, 2.8+/-1.9% after 90 minutes, and 3.1+/-2.3% after 240 minutes) or GTN responses after mental stress. CONCLUSIONS: These findings suggest that brief episodes of mental stress, similar to those encountered in everyday life, may cause transient (up to 4 hours) endothelial dysfunction in healthy young individuals. This might represent a mechanistic link between mental stress and atherogenesis.

Adult↗