Nitric oxide (NO) is an important physiological mediator of vascular tone and is thought to be involved in the pathogenesis of septic shock. Plasma nitrate is the stable end product of NO oxidation and in part reflects endogenous NO production. We measured plasma nitrate levels in 47 episodes of suspected septicaemia in 43 in-patients (16 male and 27 female, age 15-63 years). Nitrate concentrations were significantly higher (P < 0.01) compared to healthy controls. Further analysis revealed that significantly elevated levels occurred only in the septic patients who had normal or elevated numbers of neutrophils in the peripheral blood and were hypotensive on presentation. Failure of plasma nitrate concentrations to rise significantly in patients with neutropenia suggests that this cell type may be important in the activation of the arginine-NO system in severe sepsis in man.

In septic patients capable of normal white cell responses, high plasma levels of PAI-I, t-PA antigen and t-PA-PAI-I complex were observed. The ratios of t-PA and PAI-I were such that free PA activity was almost never observed. In patients severely leucopenic prior to becoming septic the changes were significantly less marked, so presence of leucocytes enhances the fibrinolytic inhibition occurring in sepsis. The non-leucopenic septic group showed greater evidence of thrombin generation in that FPA levels were higher but fibrinogen levels were only slightly less and antithrombin levels not different from those in the leucopenic group. A greater tendency to fibrin deposition and the striking fibrinolytic inhibition noted in patients with normal white cell responses may contribute to the development of some of the complications of sepsis in which fibrin deposition participates and may explain their relative rarity in leucopenic patients. When shock supervened, levels of PAI-I were high in both leucopenic and non-leucopenic groups, indicating that a source of PAI-I outwith the leucocytes themselves contributes to the phenomena observed.

SummaryLeucocytes, both polymorphs and mononuclear cells, play a variety of roles in the evolution of human response to sepsis, both local and generalised. In this study, inhibitors of plasminogen activator were measured in leucocytes from normal and septic patients. Plasminogen activator inhibitor-1 (PAI-1) was identified in polymorphs from normal individuals and levels rose significantly in polymorphs from septic patients: neutrophils from normal subjects did not contain PAI-2 but this protein was detectable in significant quantities in polymorph preparations from septic patients. In contrast, mononuclear cells from normal and septic patients contained no detectable quantities of PAI-1. Significant amounts of PAI-2 were present in normal mononuclear cells, and the levels rose significantly in monocytes from septic patients. PAI-2 is thus here identified in human subjects, distinct from those with pregnancy or malignancy, as playing a role in a pathological process. The increased levels of both inhibitors produced by leucocytes may clearly contribute directly to the persistence of fibrin, a characteristic feature of the response to infection, local or general; they may thus participate in successful localisation of infections (abscess formation etc.) and in the evolution of the major systemic complications of disseminated sepsis characterised by microvascular occlusion by fibrin such as renal failure, shock lung or digital ischaemia.

Despite the sustained presence of active u-PA in the circulation and of t-PA antigen at the onset of symptoms, plasmin-alpha 2-antiplasmin generation was largely suppressed by high levels of PAI-1. The suppression of plasmin generation by u-PA and t-PA may ensure the persistence of fibrin in the microcirculation and so contribute to organ failure.

The quality of care for patients with cleft lip and palate is extremely variable across the world. Treatment protocols differ and methods of data registration are not uniform. Improving this care by means of comparative research is challenging. The best treatment programmes can be identified by uniformly registering patient-orientated outcomes and comparing the outcomes with those of other treatment centres. That knowledge can be used to improve one's own care. An international team consisting of specialists and cleft lip and palate patients has developed a set of outcome measures that are considered by patients to be most important. This team is coordinated by the International Consortium of Health Outcomes Measurement (ICHOM). The cleft lip and palate outcome set can be used by all centres worldwide in following up on cleft lip and palate patients. In the Erasmus Medical Centre in Rotterdam, the 'Zorgmonitor Schisis' (Care Monitor Cleft Lip and Palate) has been built, an application in which these outcome measures are collected at fixed times. Implementing this set of outcome measures in other cleft lip and palate treatment centres and using the outcomes as (inter)national benchmarks will result in transparency and the improvement of the treatment of cleft lip and palate worldwide.