Cost-effectiveness of cervical length screening and progesterone treatment to prevent spontaneous preterm delivery in Sweden.

OBJECTIVE: To estimate the cost-effectiveness of strategies to prevent spontaneous preterm delivery (PTD) in asymptomatic singleton pregnancies, using prevalence and healthcare cost data from the Swedish healthcare context. METHODS: We designed a decision analytic model based on the Swedish CERVIX study to estimate the cost-effectiveness of strategies to prevent spontaneous PTD in asymptomatic women with a singleton pregnancy. The model was constructed as a combined decision-tree model and Markov model with a time horizon of 100 years. Four preventive strategies, namely 'Universal screening', 'High-risk-based screening' (i.e. screening of high-risk women only), 'Low-risk-based screening' (i.e. treatment of high-risk population and screening of remaining women) and 'Nullipara screening' (i.e. treatment of high-risk population and screening of nulliparous women only), included second-trimester cervical length (CL) screening by transvaginal ultrasound followed by vaginal progesterone treatment in the case of a short cervix. A fifth preventive strategy involved vaginal progesterone treatment of women with previous spontaneous PTD or late miscarriage but no CL screening ('No screening, treat high-risk group'). For comparison, we used a sixth strategy implying no specific intervention to prevent spontaneous PTD, reflecting the current situation in Sweden ('No screening'). Probabilities for a short cervix (CL ≤ 25 mm; base-case) and for spontaneous PTD at < 33 + 0 weeks and at 33 + 0 to 36 + 6 weeks were derived from the CERVIX study, and probabilities for stillbirth, neonatal mortality and long-term morbidity (cerebral palsy) from Swedish health data registers. Costs were based on Swedish data, except costs for cerebral palsy, which were based on Danish data. We assumed that vaginal progesterone reduces spontaneous PTD before 33 weeks by 30% and spontaneous PTD at 33-36 weeks by 10% (based on the literature). All analyses were from a societal perspective. We expressed the effectiveness of each strategy as gained quality-adjusted life years (QALYs) and presented cost-effectiveness as average (ACER; average cost per gained QALY compared with 'No screening') and incremental (ICER; difference in costs divided by the difference in QALYs for each of two strategies being compared) cost-effectiveness ratios. We performed deterministic and probabilistic sensitivity analysis. The results of the latter are shown as cost-effectiveness acceptability curves. Willingness-to-pay was set at a maximum of 500 000 Swedish krona (56 000 US dollars (USD)), as suggested by the Swedish National Board of Health and Welfare. RESULTS: All interventions had better health outcomes than did 'No screening', with fewer screening-year deaths and more lifetime QALYs. The best strategy in terms of improved health outcomes was 'Low-risk-based screening', irrespective of whether screening was performed at 18 + 0 to 20 + 6 weeks (Cx1) or at 21 + 0 to 23 + 6 weeks (Cx2). 'Low-risk-based screening' at Cx1 was cost-effective, while 'Low-risk-based screening' at Cx2 entailed high costs compared with other alternatives. The ACERs were 2200 USD for 'Low-risk-based screening' at Cx1 and 36 800 USD for 'Low-risk-based screening' at Cx2. Cost-effectiveness was particularly sensitive to progesterone effectiveness and to productivity loss due to sick leave during pregnancy. The probability that 'Low-risk-based screening' at Cx1 is cost-effective compared with 'No screening' was 71%. CONCLUSION: Interventions to prevent spontaneous PTD in asymptomatic women with a singleton pregnancy, including CL screening with progesterone treatment of cases with a short cervix, may be cost-effective in Sweden. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Second-trimester transvaginal ultrasound measurement of cervical length for prediction of preterm birth: a blinded prospective multicentre diagnostic accuracy study.

OBJECTIVE: To estimate the diagnostic performance of sonographic cervical length for the prediction of preterm birth (PTB). DESIGN: Prospective observational multicentre study. SETTING: Seven Swedish ultrasound centres. SAMPLE: A cohort of 11 456 asymptomatic women with a singleton pregnancy. METHODS: Cervical length was measured with transvaginal ultrasound at 18-20 weeks of gestation (C×1) and at 21-23 weeks of gestation (C×2, optional). Staff and participants were blinded to results. MAIN OUTCOME MEASURES: Area under receiver operating characteristic curve (AUC), sensitivity, specificity, positive and negative predictive values (PPV and NPV), positive and negative likelihood ratios (LR+ and LR-), number of false-positive results per true-positive result (FP/TP), number needed to screen to detect one PTB (NNS) and prevalence of 'short' cervix. RESULTS: Spontaneous PTB (sPTB) at <33 weeks of gestation occurred in 56/11 072 (0.5%) women in the C×1 population (89% white) and in 26/6288 (0.4%) in the C×2 population (92% white). The discriminative ability of shortest endocervical length was better the earlier the sPTB occurred and was better at C×2 than at C×1 (AUC to predict sPTB at <33 weeks of gestation 0.76 versus 0.65, difference in AUC 0.11, 95% CI 0.01-0.23). At C×2, the shortest endocervical length of ≤25 mm (prevalence 4.4%) predicted sPTB at <33 weeks of gestation with sensitivity 38.5% (10/26), specificity 95.8% (5998/6262), PPV 3.6% (10/274), NPV 99.7% (5988/6014), LR+ 9.1, LR- 0.64, FP/TP 26 and NNS 629. CONCLUSIONS: Second-trimester sonographic cervical length can identify women at high risk of sPTB. In a population of mainly white women with a low prevalence of sPTB its diagnostic performance is at best moderate. TWEETABLE ABSTRACT: Cervical length screening to predict preterm birth in a white low-risk population has moderate performance.

Streptococcus pneumoniae antimicrobial resistance decreased in the Helsinki Metropolitan Area after routine 10-valent pneumococcal conjugate vaccination of infants in Finland.

Since the introduction of 10-valent pneumococcal conjugate vaccine (PCV10) into the Finnish national vaccination program in September 2010, the incidence of invasive pneumococcal disease in children has decreased steeply in Finland. We studied the antimicrobial susceptibility of invasive and non-invasive Streptococcus pneumoniae (pneumococcus) isolated in the Helsinki Metropolitan Area during 2009-2014. We divided the data into two age groups: isolates from patients <5 years old and ≥5 years old. We also studied the serotype distribution of invasive isolates and of a subset of non-invasive multidrug-resistant isolates. The invasive isolate numbers recovered from patients aged <5 years old declined from 33/228 (15%) in 2009 to 8/208 (4%) in 2014 (p < 0.001) and non-invasive isolate numbers declined during the same time period from 221/595 (37%) to 119/432 (28%) (p < 0.001). At the same time, the proportion of penicillin non-susceptible non-invasive isolates in this age group decreased from 25% (56/220) to 13% (15/119) (p = 0.001) and multidrug-resistant isolates from 22% (49/220) to 6% (7/119) (p < 0.001), respectively. The number of PCV10 serotype isolates also decreased among the serotyped multidrug-resistant non-invasive isolates. Among patients aged ≥5 years old, the isolate numbers did not show a similar decreasing trend compared to the younger group and, further, the number of non-PCV10 serotype isolates increased in invasive cases. To conclude, the antimicrobial non-susceptibility of pneumococcus has decreased markedly, especially among young patients (<5 years old), following PCV10 implementation in Finland.

The heart exhibits right to left communication between the fibres of the muscular part of the interventricular septum.

1900 years ago Galen stated that blood seeps through the perforations in the interventricular septum. However, William Harvey, working 400 years ago, failed to find any. In this study an aqueous solution of a black dye was gently pumped by hand into the right ventricle of 20 porcine hearts. The area in the middle ofthe left muscular part of the interventricular septum in 13 of the hearts was bloodstained under the endocardium at the time the heart stopped beating. The same area of all 20 hearts eventually became stained black. A small amount of black dye seeped through the endocardium of 18 hearts in the middle of the left muscular part of the interventricular septum. In another 20 porcine hearts theinterventricular septa were dissected after boiling. The deep pit under the anterior interventricular sulcus communicated with the right ventricle and with the middle of the left muscular part of the interventricular septum between the fibres of the muscle. The communication closed tight at the very early systole. The communication resembled that reported by Galen 1900 years ago. The communication may be the real foetal route for diastolic circulation through the muscular part of the interventricular septum from right to left. The results suggested that the anatomy, function and embryology of the African monkey, human and porcine heart are not yet fully understood.

Comparison of genotypes of methicillin-resistant and methicillin-sensitive Staphylococcus aureus in Finland.

The frequency of horizontal transfer of the staphylococcal cassette chromosome mec to methicillin-susceptible Staphylococcus aureus is unknown. In order to gain more information regarding this frequency in Finland, the genotypes of 299 clinical methicillin-sensitive Staphylococcus aureus isolates were compared to representatives of 24 epidemic methicillin-resistant Staphylococcus aureus genotypes. Sixty-eight percent of the methicillin-sensitive isolates had a genotype similar to eight of the epidemic methicillin-resistant strains. The remaining isolates (32%) showed 22 different genotypes. The results indicate that, in Finland, several methicillin-sensitive Staphylococcus aureus genotypes may have acquired the staphylococcal cassette chromosome mec.

Predictive value of interleukins 6, 8 and 10, and low HLA-DR expression in acute renal failure.

AIMS: HLA-DR expression and plasma levels of pro- and anti-inflammatory cytokines (IL-6, IL-8 and IL-10) and their predictive value concerning survival of critically ill systemic inflammatory response syndrome (SIRS) patients with and without acute renal failure (ARF) were evaluated. MATERIAL: A total of 103 consecutive adult patients with SIRS from 2 university hospital intensive care units participated in the study. METHOD: Laboratory data for all patients were prospectively collected on the day of admission and 2 days thereafter. Patients with acute renal failure (ARF) and non-ARF patients were compared by Mann-Whitney U-test. Independent predictors of mortality were tested using forward stepwise logistic multiple regression analysis. The discriminative power of different variables was tested using receiver operating characteristic (ROC) curve analysis. RESULTS: ARF developed in 36 patients (35%). ARF patients showed significantly lower HLA-DR expression and higher plasma levels of IL-6, IL-8 and IL-10 than non-ARF patients. In ARF, moderate discriminative power in predicting survival was observed for day 2 IL-6 and IL-10 plasma levels (AUCs 0.703 and 0.749, respectively). CONCLUSIONS: We found no clinically significant discriminative power in predicting survival of ARF patients for monocyte HLA-DR expression or cytokine plasma levels. Therefore, our results do not support the use of HLA-DR expression or cytokine plasma levels for that purpose.

Bacterial plasminogen activators and receptors.

Invasive bacterial pathogens intervene at various stages and by various mechanisms with the mammalian plasminogen/plasmin system. A vast number of pathogens express plasmin(ogen) receptors that immobilize plasmin(ogen) on the bacterial surface, an event that enhances activation of plasminogen by mammalian plasminogen activators. Bacteria also influence secretion of plasminogen activators and their inhibitors from mammalian cells. The prokaryotic plasminogen activators streptokinase and staphylokinase form a complex with plasmin(ogen) and thus enhance plasminogen activation. The Pla surface protease of Yersinia pestis resembles mammalian activators in function and converts plasminogen to plasmin by limited proteolysis. In essence, plasminogen receptors and activators turn bacteria into proteolytic organisms using a host-derived system. In Gram-negative bacteria, the filamentous surface appendages fimbriae and flagella form a major group of plasminogen receptors. In Gram-positive bacteria, surface-bound enzyme molecules as well as M-protein-related structures have been identified as plasminogen receptors, the former receptor type also occurs on mammalian cells. Plasmin is a broad-spectrum serine protease that degrades fibrin and noncollagenous proteins of extracellular matrices and activates latent procollagenases. Consequently, plasmin generated on or activated by Haemophilus influenzae, Salmonella typhimurium, Streptococcus pneumoniae, Y. pestis, and Borrelia burgdorferi has been shown to degrade mammalian extracellular matrices. In a few instances plasminogen activation has been shown to enhance bacterial metastasis in vitro through reconstituted basement membrane or epithelial cell monolayers. In vivo evidence for a role of plasminogen activation in pathogenesis is limited to Y. pestis, Borrelia, and group A streptococci. Bacterial proteases may also directly activate latent procollagenases or inactivate protease inhibitors of human plasma, and thus contribute to tissue damage and bacterial spread across tissue barriers.

Radiographic joint space in rheumatoid elbow joints. A 15-year prospective follow-up study in 74 patients.

OBJECTIVE: To evaluate radiographically the humeroulnar (HU) and humeroradial (HR) joint spaces in patients with long-term rheumatoid arthritis (RA). METHODS: An inception cohort of 74 patients with RA were followed for 15 yr. At the end-point, 148 elbows were radiographed by a standard method. The HU and HR joint spaces were examined from the anteroposterior radiographs by measuring the shortest tangential distance in the middle of the joints. Destruction of the elbow joints, assessed with the Larsen method on a scale of 0-5, was studied in relation to the joint-space measurements. RESULTS: Mean (s.d.) HU joint space (n=148) in RA patients was 2.5 (1.1) mm, range 0-4 mm [2.9 (0.8) mm in men and 2.4 (1.1) mm in women]. Mean (s.d.) HR joint space (n=140) was 2.3 (0.9) mm, range 0-4 mm [2.5 (0.8) mm in men and 2.3 (1.0) mm in women]. HU and HR spaces of the affected joints (Larsen grades 2-5) [1.9 (s.d. 1.1) and 1.8 (0.9) mm respectively] were notably narrower than those of the unaffected (Larsen grades 0-1) joints [3.1 (0.7) and 2.9 (0.6) mm]. All the joints graded as Larsen 4 or 5 (n=13) had a value of 0 mm for both joint spaces. Both the HU and the HR joint-space narrowing was associated with increasing destruction (Larsen grading) of the joint. [r= -0.69 (95% CI -0.77 to -0.60) and r= -0.70 (-0.78 to -0.60)]. The monotonic narrowing was significantly increasing from unaffected (Larsen 0, 1), slightly (2), moderately (3) to severely (4, 5) affected joints (P<0.001). A step in this process occurred between Larsen grades 3 and 4, when the mean joint space diminished from 1.4 and 1.5 respectively to 0 mm. CONCLUSIONS: Joint-space narrowing is a frequent consequence of rheumatoid affection of the elbow joint. HR joint space decreases together with HU joint space; however, the HR joint space is already slightly narrower at the start. The narrowing is a rather late phenomenon, occurring only after erosive destruction. This should be borne in mind when using the Larsen method to evaluate changes in the elbow joint.

Valgus deformity and proximal subluxation of the rheumatoid elbow: a radiographic 15 year follow up study of 148 elbows.

OBJECTIVE: To evaluate the nature of positional changes of humeroulnar (HU) and humeroradial (HR) joints in a cohort of 74 patients with seropositive and erosive rheumatoid arthritis (RA) followed up prospectively. METHODS: At the 15 year follow up standard anteroposterior and lateral radiographs of 148 elbow joints were evaluated. The mediolateral HU angle of the elbow was measured from anteroposterior radiographs. The proximal subluxation of the HU joint was measured from lateral radiographs as the distance between the posterior aspect of the olecranon process and the posterior surface of the humerus. The anteroposterior subluxation of the HR joint was measured from lateral radiographs as the relation of the midpoint of head of the radius to the midpoint of the capitellum of the humerus. Destruction of the elbow joints was assessed with the Larsen method on a scale of 0 to 5 and compared with the measurements. RESULTS: Mean HU angle in 148 elbows of patients with RA was 11.5 degrees (SD 6.1), range -21 degrees (varus) to 34 degrees (valgus); 9.9 degrees (SD 4.3) in men and 12.0 degrees (SD 6.4) in women. The mean HU angle, 14.4 degrees (SD 6.0) of the affected joints (Larsen grades 2-4), showed more valgus than the mean 9.8 degrees (SD 2.5) of the non-affected (Larsen grades 0 to 1) joints; totally destroyed and unstable Larsen 5 joints were excluded. Mean HU and HR subluxations, 2.0 mm (SD 3.8) and 0.8 mm, of the affected joints (Larsen 2-5) were greater than the means, -1.1 mm (SD 1.5) and -0.4 mm (SD 0.9), of the non-affected joints. Both the HU proximal subluxation and the HR anterior subluxation correlated, r(s)=0.64 (95% CI 0.53 to 0.73 ) and r(s)=0.48 (95% CI 0.34 to 0.60), with the destruction of the elbow joint. CONCLUSIONS: The elbow seems to turn into valgus during rheumatoid destruction and excision of the radial head may speed up this process. However, totally unstable Larsen grade 5 joints may also have varus deformity owing to mutilating bone destruction. The ulna subluxates proximally in relation to the humerus, whereas the radius moves slightly anteriorly as a consequence of elbow involvement.

Synthesis and antimicrobial activity of the symmetric dimeric form of Temporin A based on 3-N,N-di(3-aminopropyl)amino propanoic acid as the branching unit.

Dimeric derivative of antimicrobial peptide amide Temporin A (TA) was synthesized by using a new branching unit 3-N,N-di(3-aminopropyl)amino propanoic acid (DAPPA), which allows building of the parallelly symmetric alpha-helical structures. Antimicrobial effect of the original peptide amide, its monomeric carboxy (TAc) and novel dimeric (TAd) analogues were tested against Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative). Both TA and TAd completely inhibited the growth of S. aureus at the concentrations of 5 and 10 microM, respectively, whereas TAc did not show any inhibitory activity. The activities of TAc, TA and TAd correlate directly with the net charges of the molecules, +1, +2 and +4, respectively. Interestingly, TAd displayed antibacterial effect against E. coli at a concentration of 10 microM, where as monomeric TA did not show any activity at concentration as high as 20 microM. The results indicate that the novel structural modification improves the antibacterial properties of Temporin A especially towards Gram-negative bacteria.

Expression of pls, a gene closely associated with the mecA gene of methicillin-resistant Staphylococcus aureus, prevents bacterial adhesion in vitro.

The pls gene, coding for a large surface protein of methicillin-resistant Staphylococcus aureus, was cloned from a strain which adheres poorly to several mammalian proteins. The structure of pls revealed three distinct repeat regions, one of which was a serine-aspartate repeat characteristic of the Clf-Sdr family of surface proteins in staphylococci. The lengths of the repeat regions varied in different clinical strains and could be used as epidemiological markers. pls was found to be closely associated with the mecA gene by pulsed-field gel electrophoresis analysis of SmaI-digested DNA. A pls mutant constructed by allele replacement adhered well to immobilized fibronectin and immunoglobulin G, in contrast to the parental strain, suggesting that Pls could have a role in preventing adhesion at some stages during an infection.

Bone destruction, upward migration, and medialisation of rheumatoid shoulder: a 15 year follow up study.

OBJECTIVE: To evaluate bone destruction, upward migration, and medialisation of the glenohumeral (GH) joint in a cohort of 74 patients with seropositive and erosive rheumatoid arthritis followed up prospectively. METHODS: At the 15 year follow up 148 shoulders were radiographed by a standard method. Bone destruction in the GH joint was examined from the radiographs by four methods, of which three measured the migration and one the remodelling of the humeral head. The distances from the greater tuberosity of the humeral head to the coracoid process (medialisation distance (MD)) and to the articular surface of the humeral head (GA) have been previously developed to evaluate the preoperative offsets of the arthritic GH joint. Medial displacement index (MI) and upward migration index (UI) have been recently developed to evaluate the destructive pattern of the rheumatoid GH joint. Destruction of the GH joints was assessed by the Larsen method on a scale of 0 to 5. The relation between the measurements and the grade of destruction of the GH joints was examined. UI was compared with our previous measurements of the subacromial space. RESULTS: Both the MI and the UI had a negative correlation with the GH joint destruction (Larsen grade), r=-0.49 (95% CI -0.36 to -0.60) and r=-0.58 (95% CI -0.46 to -0.68). The UI correlated significantly with the subacromial space, r=0.90 (95% CI 0.86 to 0.93). The mean MI and UI measurements of the non-affected joints were within the reported normal variation. The mean MD collapsed between Larsen grades 4 (83.0 mm) and 5 (65.5 mm). The morphology of the humeral head began to flatten and erode from the grade 3 onwards and medial head destruction was detected at grade 5. CONCLUSIONS: Medialisation seems to be preceded by upward migration of the humeral head, indicating rotator cuff damage. Symptomatic Larsen grade 3 shoulders should be intensively followed up by clinical and radiological means. If a total shoulder arthroplasty is considered, an orthopaedic consultation is worthwhile at a sufficiently early stage (Larsen 3 and 4), when soft tissue structures responsible for function are still in proper condition and timing of the operative procedure can be well planned.

Incidence of elbow involvement in rheumatoid arthritis. A 15 year endpoint study.

OBJECTIVE: To evaluate the incidence of involvement and cause of destruction of humeroulnar (HU) and humeroradial (HR) joints in a prospectively followed cohort of 74 patients with seropositive and erosive rheumatoid arthritis (RA). METHODS: At the 15 year followup standard anteroposterior and lateral radiographs of 148 elbow joints were evaluated, and the grade of destruction was assessed by the Larsen method. RESULTS: Erosive involvement (Larsen grade 2) was observed in 75/148 (51%) elbows in 45/74 (61%) patients; 30 patients had bilateral and 15 unilateral involvement. The incidence of mild erosions (Larsen grade 2) was 49/148 (33%), and severe erosions (Larsen 3-5) 26/148 (18%). The 13 most severely involved (Larsen grade 4-5) joints were seen in 8 (11%) patients. Erosions were most often observed on the capitellum (64 joints) and the lateral epicondyle (58 joints) of the humerus (AP view) or on the olecranon of the ulna (52 joints). The Larsen score (0-100) for peripheral joints correlated significantly with the elbow joint Larsen grade on both sides: right, r = 0.53 (95% CI 0.34 to 0.68); left, r = 0.53 (95% CI 0.34 to 0.68). CONCLUSION: After 15 years more than half of the elbows and almost 2 of 3 patients with RA showed definite involvement of the elbow joint. Erosions were most often located on the capitellum and the lateral epicondyle of the humerus or the olecranon of the ulna. Severe destruction was most often bilateral.

Functional mapping of the Yersinia enterocolitica adhesin YadA. Identification Of eight NSVAIG - S motifs in the amino-terminal half of the protein involved in collagen binding.

The virulence plasmid-encoded YadA of Yersinia enterocolitica serotype O:3 is a 430-amino-acid outer membrane protein, synthesized with a 25-amino-acid signal peptide. YadA forms homotrimeric surface structures that function as adhesin between bacteria and collagen as well as other host proteins. The structure-function relationships of YadA were studied, and the collagen-binding determinants of YadA were located to its amino-terminal half. Collagen did not bind to any of the overlapping 16-mer YadA peptides, indicating that the collagen binding site of YadA is conformational. Epitope mapping of YadA identified 12 linear antigenic epitopes altogether. Seven epitopes were uniquely recognized by an anti-YadA antiserum able to inhibit collagen binding. Four of these epitopes shared a motif NSVAIG-S that is repeated eight times within the N-terminal half of YadA. Site-directed mutagenesis showed that these motifs are absolutely required for YadA-mediated collagen binding, revealing a novel type of collagen-binding mechanism.

Antibacterial activities of temporin A analogs.

Temporin A (TA) is a small, basic, highly hydrophobic, antimicrobial peptide amide (FLPLIGRVLSGIL-NH2) found in the skin of the European red frog, Rana temporaria. It has variable antibiotic activities against a broad spectrum of microorganisms, including clinically important methicillin-sensitive and -resistant Staphylococcus aureus as well as vancomycin-resistant Enterococcus faecium strains. In this investigation the antimicrobial activity and structural characteristics of TA synthetic analogs were studied. For antibacterial activity against S. aureus and enterococcal strains, the hydrophobicity of the N-terminal amino acid of TA was found to be important as well as a positive charge at amino acid position 7, and bulky hydrophobic side chains at positions 5 and 12. Replacing isoleucine with leucine at amino acid positions 5 and 12 resulted in the greatest enhancement of antibacterial activity. In addition, there was little difference between the activities of TA and its all-D enantiomer, indicating that the peptide probably exerts its effect on bacteria via non-chiral interactions with membrane lipids.

Plasminogen activation in degradation and penetration of extracellular matrices and basement membranes by invasive bacteria.

Methods to assess in vitro the role of plasminogen activation in enterobacterial degradation of extracellular matrices and their protein components as well as in penetration through basement membrane are described. Development of these methods was initiated after the findings that enterobacterial surface structures (fimbriae and the Pla surface protease) function in plasminogen activation as well as in laminin- and/or fibronectin-specific adhesion. Enterobacteria with these properties degrade radiolabeled laminin as well as metabolically labeled extracellular matrix from cultured endothelial or epithelial cells. Plasmin-coated bacteria also penetrate through the reconstituted basement membrane preparation Matrigel. The processes are dependent on plasminogen activation by the invasive bacteria. The results suggest a pathogenic similarity between enterobacteria and tumor cells in cellular metastasis through tissue barriers.

Intramucosal pH and endotoxin and cytokine release in severe acute pancreatitis.

It has been postulated that in severely ill patients splanchnic hypoperfusion may cause endotoxin release from the gut, and this leakage of endotoxin into the circulation can trigger the cascade of inflammatory cytokines. We tested this hypothesis in 9 patients with acute severe pancreatitis by monitoring gastric intramucosal pH (pHi) as measure of splanchnic hypoperfusion at 12-h intervals trying to correlate it to endotoxin and cytokine release. Only 3 of 59 samples, obtained from 3 patients contained circulating endotoxin. Thirteen of 15 plasma samples drawn at pHi <7.20 did not contain endotoxin. The pHi was significantly lower in patients who subsequently developed 3 or more organ failures (P = 0.0017, analysis of variance). Although endotoxemia was only occasionally found, most patients had measurable interleukin 1beta (IL-1beta), interleukin 6 (IL-6), interleukin 8 (IL-8), and interleukin 10 (IL-10) in their plasma. Concentrations of IL-6, IL-8, and IL-10 on admission correlated to degree of organ dysfunction as measured by the multiple organ system failure score (P = 0.035, r = 0.74; P = 0.010, r = 0.91; P = 0.021, r = 0.82, respectively). In conclusion, patients with acute, severe pancreatitis often have splanchnic hypoperfusion and produce a wide array of cytokines despite a rare occurrence of endotoxemia.

Activation of interstitial collagenase, MMP-1, by Staphylococcus aureus cells having surface-bound plasmin: a novel role of plasminogen receptors of bacteria.

Plasmin, the enzymatically active form of plasminogen, can activate several matrix metalloproteinases (MMPs). In this study, we investigated the activation of MMP-1, one of the major interstitial collagenases, by plasmin which was generated on the surface of Staphylococcus aureus cells. Plasmin bound to plasminogen receptors on S. aureus degraded the major (125)I-labeled 55-kDa proMMP-1 into the 42-kDa form corresponding to the size of active MMP-1. MMP-1 formed by S. aureus-bound plasmin was also enzymatically active as judged by digestion of the synthetic collagenase substrate, DNP-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg-NH(2). The finding that, in MMP-1 molecules generated either by soluble plasmin or by S. aureus-bound plasmin, the amino-terminal amino acid sequences were identical indicated that the activation mechanisms of the two plasmin forms do not differ from each other. The present observations emphasise and broaden the physiological importance of bacterial plasminogen receptors. In addition to direct proteolytic effects on components of the extracellular matrix, receptor-bound plasmin is also capable of initiating an MMP-1-dependent matrix-degrading enzymatic cascade.

Interleukin 1 receptor antagonist and E-selectin concentrations: a comparison in patients with severe acute pancreatitis and severe sepsis.

PURPOSE: This prospective clinical study was designed to compare interleukin 1 receptor antagonist (IL-1ra) and E-selectin concentrations in patients with severe acute pancreatitis to those with severe sepsis. MATERIALS AND METHODS: Nine consecutive patients with severe acute pancreatitis and 11 consecutive patients with severe sepsis admitted to a medical/surgical intensive care unit were included in the study. Plasma concentrations of IL-1ra and E-selectin were serially measured daily for 7 days or throughout their stay in the intensive care unit if shorter. RESULTS: The concentrations of IL-1ra were significantly higher on admission in patients with severe sepsis compared with the patients with severe pancreatitis (median levels 10,500 and 2,600 pg/mL, respectively, P = .007). When the data from the first 3 days were analyzed using analysis of variance (ANOVA), the levels of IL-1ra and E-selectin were similar in both groups. The concentrations of IL-1ra and E-selectin correlated to the development of multiorgan dysfunction as assessed by sequential organ failure assessment (SOFA) score (P = .032 and .043, respectively). CONCLUSION: This study shows that IL-1ra and E-selectin are released in acute severe pancreatitis, and the levels seem to be comparable to those in patients with severe sepsis. Concentrations of IL-1ra and E-selectin correlate to the development of multiorgan failure as indicated by high SOFA scores during the first week of disease.