Growth hormone and insulin-like growth factor-I stimulate hormonal function and proliferation of thymic epithelial cells.

We have investigated the role of GH and insulin-like growth factor-I (IGF-I) in controlling the secretion of thymulin, a hormone produced by thymic epithelial cells (TEC). Thymulin plasma concentrations (mean +/- SD) were increased in 21 patients with acromegaly compared to those in 30 controls, as assessed by bioassay (4.24 +/- 0.97 vs. 2.67 +/- 0.87; P less than 0.001) and RIA (561 +/- 241 vs. 315 +/- 113 pg/L; P less than 0.01). Good correlations were observed between plasma levels of thymulin and IGF-I (P less than 0.001). In vitro experiments demonstrated that both recombinant human GH and IGF-I significantly increased thymulin production in culture supernatants of normal human TEC and a rat TEC line. In parallel, IGF-I also significantly stimulated the proliferation of human TEC, as measured by bromodeoxyuridine incorporation. Additionally, the stimulatory effect of GH on thymulin production was abrogated by both an anti-IGF-I antibody and an anti-IGF-I receptor antibody. These results support a role for GH and IGF-I in the control of thymic hormonal function in man and suggest that the effect of GH may be mediated by local secretion of IGF-I within the thymus.     

Type 1 diabetes mellitus, autoimmune disease: physiopathologic aspects and practical applications

Type 1 (insulin-dependent) diabetes mellitus results from an autoimmune disease which is directed to insulin-secreting islet cells. In man, it is closely associated to definite major histocompatibility complex alleles. The islets are infiltrated by inflammatory cells (insulitis). Anti-islet cell autoantibodies are present in most patients and represent a valuable marker for the autoimmune reaction. The major role of autoreactive T lymphocytes has been demonstrated in animal models of spontaneous insulin-dependent diabetes (the BB rat and the NOD mouse). Such pathophysiological concepts already have clinical applications. The presence of anti-islet cell antibodies identifies patients with type 1 diabetes of slow onset who initially present with non-insulin dependent diabetes. In the same respect it is now feasible to predict the possible occurrence of diabetes in 'at risk' subjects (such as siblings of a diabetic patient) on the basis of HLA typing and the presence of markers of anti-beta cell immunity. Lastly, both in animal models and in human diabetes, it has been demonstrated that immune intervention can alter the course of anti-islet autoimmunity. From these results one may hope in the future to get preventive treatment of type 1 diabetes before the onset of metabolic disturbances.     

Complications of intravascular catheters in ICU: definitions,incidence and severity. A randomized controlled trial comparing usual transparent dressings versus new-generation dressings (the ADVANCED study)

Purpose

To describe all post-insertion complications involving most used intravascular access, and to determine whether the use of a new-generation transparent dressing (3M? IV Advanced) might reduce their number and impact on ICU patient outcomes.

Methods

Patients older than 18, with an expected length of stay ≥48 h and requiring at least one central venous catheter (CVC), arterial catheter (AC), haemodialysis catheter (HDC), pulmonary arterial catheters (PAC) or peripheral venous catheter (PVC) were randomized into two groups: a new-generation transparent dressing, or the hospital’s classical transparent dressing, and were followed daily for any infectious and non-infectious complications. Complications were graduated for severity by an independent international multicentre multidisciplinary panel of practitioners using a Delphi process.

Results

We included 628 patients, 2214 catheters (873 PVCs, 630 CVCs, 512 ACs and 199 HDCs and PACs) and 4836 dressings. Overall incidence rate was of 60.9/1000 catheter-days. The most common complication was dysfunction (34.6/1000 catheter-days), mainly for PVCs (16/1000 catheter-days) and ACs (12.9/1000 catheter-days). Infectious complications incidence rate in CVCs and ACs was of 14.5/1000, mostly due to colonization (14.2/1000 catheter-days). Thrombosis incidence was of 3.8/1000 catheter-days with severe and very severe complications in 16 cases (1.8/1000 catheter-days) and one thrombosis-related death. 3M? IV Advanced dressing did not decrease the rate of catheters with at least a minor complication [57.37/1000 vs. 57.52/1000 catheter-days, HR 1.03, CI (0.84–1.27), p = 0.81]. Incidence rates for each single complication remained equivalent: infectious [HR 0.93 (0.62–1.40), p = 0.72], deep thrombosis [HR 0.90 (0.39–2.06), p = 0.80], extravasation and phlebitis [HR 1.40 (0.69–2.82), p = 0.35], accidental removal [1.07 (0.56–2.04), p = 0.84] and dysfunction [HR 1.04 (0.80–1.35), p = 0.79].

Conclusion

The ADVANCED study showed the overall risk of complications to intravascular catheters in ICU patients being dysfunction, infection and thrombosis. The 3M? IV Advanced dressing did not decrease complication rates as compared to standard dressings.

     

Usefulness of a strategy based on bronchoscopy with direct examination of bronchoalveolar lavage fluid in the initial antibiotic therapy of suspected ventilator-associated pneumonia

OBJECTIVES: To evaluate (a) the routine accuracy of bronchoalveolar lavage by direct examination (BAL-D) in diagnosing ventilator-associated pneumonia (VAP), and (b) the impact of a diagnostic strategy including clinical judgment, bronchoscopy, and BAL-D on the initial diagnosis and appropriateness of treatment when VAP is suspected. DESIGN AND SETTING: Prospective cohort study in two academic ICUs in Paris, France. PATIENTS AND PARTICIPANTS: Mechanically ventilated patients with suspected VAP underwent bronchoscopy with BAL and protected specimen brush (PSB). BAL-D results were available within 2 h, BAL on culture and PSB results after 24 h, and antibiotic susceptibility after 48 h. At each step in the strategy the senior and the resident in charge of the patient were asked their diagnosis and their therapeutic plan on the basis of presently available data. Definite diagnosis of suspected VAP was based on histology, appearance of cavitation, positive pleural fluid culture, results of PSB and BAL culture, and follow-up. MEASUREMENT AND RESULTS: A total of 110 episodes of suspected VAP were studied; 94 definite diagnoses were made (47 VAP, 47 no VAP). Using a threshold 1% of infected cells, BAL-D discriminated well between patients with and those without VAP (sensitivity 93.6%, specificity 91.5%, area under the receiver-operating characteristic curve 0.953). The senior clinical judgment was correct in 71% cases. It was correct in 78% and 94% of cases after airway visualization and BAL-D findings, respectively. After BAL-D the positive and negative predictive values in diagnosing VAP were 90% and 98%, respectively. However, the therapeutic plan was correct in only 65% using clinical judgment (15 untreated patients, 3 ineffective treatment, 15 useless treatment), 66% using airway visualization (14 untreated VAP, 4 ineffective treatment, 14 useless treatment), and 88% using BAL-D results (1 untreated patients, 6 ineffective, 4 useless), according to definite diagnosis and final antibiotic susceptibility testings. CONCLUSIONS: A strategy based on bronchoscopy and BAL-D generally leads to a rapid and appropriate treatment of nosocomial pneumonia in ventilated patients.     

Practices in non-neutropenic ICU patients with<Emphasis Type="Italic"> Candida</Emphasis>-positive airway specimens

Objective: To examine practices of French intensivists regarding the management of mechanically ventilated patients with Candida-positive airway specimens but no major risk factors for immunodepression. Design: Closed-item questionnaire with a clinical vignette. Setting: 564 French intensive care units (ICUs). Participants: 198 intensivists who have a special interest in infectious diseases and who answered the questionnaire (response rate, 35.1%). Intervention: None. Measurements and results: The respondents recommended bronchoalveolar lavage (62.6% of respondents), protected distal sampling and protected specimen brush (59.1%), transbronchial biopsy (38.9%), and tracheal aspiration (12.1%) for the diagnosis of candidal pneumonia. A positive airway specimen was felt by most respondents (83.3%) to indicate colonisation; 66.7% of respondents recommended tests for systemic candidiasis in this situation, and 56.5% serial sampling to compute the colonisation index. Azole derivatives were the preferred antifungal medications. The clinical vignette described a patient with chronic obstructive lung disease who required mechanical ventilation for an acute exacerbation and who had a tracheal aspirate positive for Candida. Responses varied widely, with 37.8% of respondents diagnosing clinically insignificant colonisation but 24.2% recommending antifungal treatment and 61.6% serial testing to assess the Candida colonisation index. Intensivists with greater experience with severely immunocompromised patients were more aggressive in their diagnostic management. Conclusions: Wide variations occur among practices of French intensivists regarding Candida-positive airway specimens in patients without major risk factors for immunodepression. Additional studies are needed to improve our understanding of the links between Candida colonisation and infection and to determine the indications for pre-emptive antifungal treatment in non-neutropenic critically ill patients.Presented in January 2002 at the congress of the French Society of Critical Care Medicine     

Decrease in internal jugular endothelin levels after carotid cross-clamping during human carotid revascularization procedures

Endothelin-1 (ETL-1), a peptide recently isolated from vascular endothelial cells, acts in cerebral arteries in vitro as a potent and long-lasting vasoconstrictor and has been implicated in the development of cerebral vasospasm. To ascertain whether this new vasoconstrictor has any effect on regulation of the cerebral circulation, we measured plasma ETL-1 concentrations in patients undergoing carotid revascularization and attempted to correlate the variations of venous and arterial plasma ETL-1 with the characteristics of the procedure, including cerebral vasospasm. We prospectively studied 11 patients undergoing a total of 14 carotid surgical revascularization procedures (12 endarterectomies, 2 polytetrafluoroethylene bypass grafts from the common to the internal carotid arteries). Before carotid cross-clamping, blood samples were drawn from the internal jugular vein and the healthy common carotid artery proximal to the occlusive lesion to be treated. After endarterectomy, blood samples were withdrawn from the internal, external, and common carotid arteries. After the release of the last clamp, a final aliquot of blood was withdrawn from the internal jugular vein. After plasma extraction on a C2-ethyl microcolumn, plasma endothelin-like immunoreactivity was measured by means of radioimmunoassay with a polyclonal antibody. In 9 of the 11 patients, internal jugular vein ETL-1 concentration decreased statistically significantly after carotid artery cross-clamping (4.2±1.4 pg/ml vs. 3.9±1.1 pg/ml;p<0.05). In the 2 patients in whom ETL-1 levels failed to drop, a shunt was used during the procedure in 1, and the other was the only patient who had an ipsilateral ischemic postoperative stroke. The decrease in internal jugular vein ETL-1 concentration failed to correlate with any of the cross-clamping times. The level of arterial blood ETL-1 remained steady in the common carotid artery before and after cross-clamping (4.5±1.5 pg/ml vs. 4.6±0.9 pg/ml). A small, nonsignificant decrease in ETL-1 level was noted in the external and internal carotid arteries after cross-clamping. The decrease in internal jugular vein ETL-1 levels may in part reflect a compensatory response to carotid artery cross-clamping, which could limit the reduction of local cerebral blood flow.     

Rat primary hepatocytes show enhanced performance and sensitivity to acetaminophen during three-dimensional culture on a polystyrene scaffold designed for routine use

The in vitro evaluation of hepatotoxicity is an essential stage in the research and development of new pharmaceuticals as the liver is one of the most commonly impacted organs during preclinical toxicity studies. Fresh primary hepatocytes in monolayer culture are the most commonly used in vitro model of the liver but often exhibit limited viability and/or reduction or loss of important liver-specific functions. These limitations could potentially be overcome using three-dimensional (3D) culture systems, but their experimental nature and limited use in liver toxicity screening and drug metabolism has impaired their uptake into commercial screening programs. In this study we use a commercially available polystyrene scaffold developed for routine 3D cell culture to maintain primary rat hepatocytes for use in metabolism and toxicity studies over 72?h. We show that primary hepatocytes retain their natural cuboidal morphology with significantly higher viability (>74%) than cells grown in monolayer culture (maximum of 57%). Hepatocytes in the 3D scaffolds exhibit differential expression of genes associated with phase I, II, and III drug metabolism under basal conditions compared with monolayer culture and can be induced to stably express significantly higher levels of the cytochrome-P450 enzymes 1A2, 2B1, and 3A2 over 48?h. In toxicity studies the hepatocytes in the 3D scaffolds also show increased sensitivity to the model toxicant acetaminophen. These improvements over monolayer culture and the availability of this new easy to use 3D scaffold system could facilitate the uptake of 3D technologies into routine drug screening programs.     

Transfer of take-home messages in graduate ICU education

Purpose

Teaching by lecture (lecture format) is widely used at congresses and in medical educational programmes. The process involves the transfer of take-home messages. The aim of this study was to assess the number of take-home messages identified by postgraduate critical care junior doctors (juniors) during lectures.

Methods

This was a prospective observational study of 13 lectures. Lecturers were not informed in advance of the study. At the end of the lecture (30 or 50?min), the lecturer (senior doctor) and juniors listed the three main take-home messages on a form. Subjective elements of the juniors?? appraisal (quality of the presentation, explanation of the topic??s relevance, enthusiasm of the lecturer, background, case-based, delivery and personality, comprehensibility, practical applicability of information given, prioritization, presence of raw data, references, overall satisfaction) and objective elements (length of lecture, number of take-home messages written on the slides) of the lectures were recorded. Successful knowledge transfer was assessed by matching lecturers?? and juniors?? take-home messages.

Results

In total, 367 forms completed by 367 juniors were analysed. A match equal to 3 (highest match), 2, 1 or 0 was observed in 3.8, 26.7, 48.2 and 21.2% of the forms, respectively. No single subjective or objective element of the lecture was associated with the number of identified take-home messages.

Conclusions

Two-thirds of critical care junior doctors identified at best only one of the three main take-home messages of a lecture, suggesting that knowledge transfer is poor during passive format learning. These results suggest that there is a need to develop strategies to improve the performance of lecture-based learning.