Unfavorable mechanical effects of heat and moisture exchangers in ventilated patients

OBJECTIVE: To investigate the mechanical effects of artificial noses. SETTING: A general intensive care unit of a university hospital. PATIENTS: 10 patients in pressure support ventilation for acute respiratory failure. INTERVENTIONS: The following three conditions were randomly tested on each patient: the use of a heated humidifier (control condition), the use of a heat and moisture exchanger without filtering function (HME), and the use of a combined heat and moisture exchanger and mechanical filter (HMEF). The pressure support level was automatically adapted by means of a closed-loop control in order to obtain constancy, throughout the study, of patient inspiratory effort as evaluated from airway occlusion pressure at 0.1 s (P0.1). Patient's ventilatory pattern, P0.1, work of breathing, and blood gases were recorded. MEASUREMENTS AND MAIN RESULTS: The artificial noses increased different components of the inspiratory load: inspiratory resistance, ventilation requirements (due to increased dead space ventilation), and dynamic intrinsic positive end-expiratory pressure (PEEP). The additional load imposed by the artificial noses was entirely undertaken by the ventilator, being the closed-loop control of P0.1 effective to maintain constancy of patient inspiratory work by means of adequate increases in pressure support level. CONCLUSIONS: The artificial noses cause unfavorable mechanical effects by increasing inspiratory resistance, ventilation requirements, and dynamic intrinsic PEEP. Clinicians should consider these effects when setting mechanical ventilation and when assessing patients' ability to breathe spontaneously.     

The beta 1 integrin, very late activation antigen-4 on human neutrophils can contribute to neutrophil migration through connective tissue fibroblast barriers

Polymorphonuclear leucocyte (PMNL) accumulation in extravascular tissues and inflammatory exudates is dependent on their migration through blood vessel endothelium and then through connective tissue. Previously we utilized a barrier of human synovial and dermal fibroblasts (HSF or HDF) grown on microporous filters, as a model of PMNL migration through connective tissue. Those studies showed that beta 2 (CD18) and the beta 1 integrins, very late activation antigen-5 (VLA-5) and VLA-6, in part mediate this PMNL migration. Here we report that VLA-4, which can also be expressed at low levels on activated PMNL, is also involved in PMNL migration induced by C5a through fibroblast (HSF and HDF) barriers, because monoclonal antibody (mAb) to VLA-4 significantly inhibited (by 20-30%) PMNL migration. Blocking the function of CD18, VLA-5 or VLA-6 was not required for detection of the VLA-4-mediated migration. Combination treatment with mAb to VLA-4 and with mAb to VLA-5 or to VLA-6 further inhibited PMNL migration, irrespective of whether CD11/CD18 mechanisms were blocked with anti-CD18 mAb or not. Treatment of PMNL with a peptide based on the VLA-4-binding domain in the CS-1 fragment of fibronectin, but not a control peptide, inhibited PMNL migration to a comparable extent to treatment with mAb to VLA-4. A low level of VLA-4 was expressed on C5a-activated PMNL, detected by immunofluorescence flow cytometry. These results suggest that VLA-4 can be mobilized by human peripheral blood PMNL and can, in addition to VLA-5, VLA-6 and CD11/CD18 integrins, mediate PMNL migration through connective tissue. This is in marked contrast to PMNL transendothelial migration, where beta 1 integrins appear to play no significant role.     

Sensory-specific satiety: comparison of taste and texture effects

The respective contributions of taste (saltiness and sweetness) and texture (the hardness dimension) to sensory-specific satiety (SSS) were compared. Sixteen male and 16 female, young, normal-weight adults rated the pleasantness of taste, pleasantness of texture and desire to eat on visual analog scales for eight test foods, were then given one of the foods to eat ad libitum for lunch, and re-rated the same parameters for the eight foods 2 and 20 min after the end of the meal. The experimental sets of eight test foods and four lunch foods were balanced for taste quality (salty vs. sweet) and texture quality (hard vs. soft). Lunch foods were the hard and soft versions of a salty food (ham and cheese sandwich on baguette vs. white bread) or of a sweet food (apples vs. applesauce). Sensory-specific satiety was observed for both saltiness and sweetness (e.g. pleasantness of the taste of, and desire to eat sweet test foods decreased significantly after eating a sweet lunch food and similarly for salty foods), and to a lesser extent for texture (e.g. pleasantness of the texture of, and desire to eat hard test foods decreased after eating a hard lunch food and similarly for one of the soft foods). The authors conclude texture-specific satiety may be a significant component of satiety.     

Kinetics of modification of the mitochondrial succinate-ubiquinone reductase by 5,5''-dithiobis-(2-nitro-benzoic acid)

In the present study, we examined the effect of the thromboxane/prostaglandin endoperoxide analogue U46619 on proliferation and hypertrophy in cultured rat vascular smooth muscle cells and the roles of protein kinase C and transforming growth factor-beta (TGF-beta) in the mediation of the hypertrophic response to U46619. Since an increase in basic fibroblast growth factor (bFGF) was previously shown to mediate the hypertrophic response to U46619, we also assessed the relationship between bFGF and TGF-beta in the expression of U46619 actions. U46619 increased [35S]methionine incorporation into protein and protein content of vascular smooth muscle cells but had no effect on cell number. A role for TGF-beta was supported by the following observations: (1) exogenous human TGF-beta 1 increased protein synthesis; (2) antibody to TGF-beta blocked both TGF-beta- and U46619-induced increases in protein content; (3) U46619 increased active and total TGF-beta bioactivities; and (4) the actions of U46619 on protein content and TGF-beta bioactivity were blocked by the thromboxane/prostaglandin endoperoxide receptor antagonist SQ 29,548. Previous observations had demonstrated a role for bFGF in the expression of U46619 actions on protein synthesis. Results of the present study suggest that TGF-beta and bFGF interact in mediating the protein synthetic response to U46619. First, the concentration of exogenous TGF-beta (10 pmol/L) alone required to produce a protein synthetic response equivalent to that induced by U46619 was much higher than the concentration of endogenous active TGF-beta that accumulated in the media in response to U46619 (0.7 pmol/L). Second, bFGF (20 ng/mL) increased total TGF-beta bioactivity and stimulated protein synthesis. The hyper-trophic response to bFGF was blocked by anti-TGF-beta. The ability of U46619 and bFGF to increase protein synthesis and protein content in vascular smooth muscle cells was associated with TGF-beta-induced suppression of proliferation, as evidenced by the ability of antibody to TGF-beta to enhance U46619- and bFGF-induced increases in [3H]thymidine incorporation into DNA. Results of the present study also supported a role for protein kinase C in the expression of U46619 and bFGF actions. U46619 increased protein kinase C activity in the particulate fraction of vascular smooth muscle cells. Moreover, the protein kinase C inhibitors GF109203X and staurosporine blocked U46619- and bFGF-induced increases in protein synthesis as well as active and total TGF-beta bioactivities. By contrast, the protein kinase C inhibitors did not prevent the increases in protein synthesis induced by exogenous TGF-beta. The results demonstrate that thromboxane/prostaglandin endoperoxide signals increased TGF-beta bioactivity via protein kinase C. Increases in both bFGF and TGF-beta are required for an optimal hypertrophic response to U46619. The hypertrophic response to TGF-beta occurs through a protein kinase C-independent pathway.     

Protein phosphorylation: technologies for the identification of phosphoamino acids

Protein phosphorylation plays a central role in many biological and biomedical phenomena. In this review, while a brief overview of the occurrence and function of protein phosphorylation is given, the primary focus is on studies related to the detection and analysis of phosphorylation both in vivo and in vitro. We focus on phosphorylation of serine, threonine and tyrosine, the most commonly phosphorylated amino acids in eukaryotes. Technologies such as radiolabelling, antibody recognition, chromatographic methods (HPLC, TLC), electrophoresis, Edman sequencing and mass spectrometry are reviewed. We consider the speed, simplicity and sensitivity of tools for detection and identification of protein phosphorylation, as well as quantitation and site characterisation. The limitations of currently available methods are summarised.     

Potent and selective bicyclic lactam inhibitors of thrombin: Part 2: P1 modifications

The synthesis and antithrombotic activity of a series of nonpeptide bicyclic thrombin inhibitors is described. We have explored the SAR with modifications to the P1 site. The introduction of arginine mimetics at the P1 site led to potent and selective thrombin inhibitors.     

Clinical and histopathological aspects of 113 necrotizing malignant melanomas of the choroid. 1. Clinical and histological features of necrotizing choroidal melanomas

BACKGROUND: Tumor necrosis may reflect a destructive immune reaction. Systematic and statistically significant comparative clinico-histopathologic studies have not yet been reported. PATIENTS AND METHODS: 113 necrotizing choroidal melanomas (NCM) recruited from 701 enucleated globes 1967-1988 were resectioned, stained and compared to 100 choroidal melanomas without necrosis (CM), and data of 74 patients with a follow-up of more than 10 years were evaluated. RESULTS: Statistically significant characteristics of NCM were: patient age < 60 yrs. for NCM 27.4%, CM 46%; patient age in men for NCM was 64 yrs on average (CM: 58 yrs.), in women for NCM 67 yrs. (CM: 59 yrs.). Time elapsed between first symptoms and enucleation was < 12 months in 15.9% of NCM (89% for CM), and > 12 months in 23.9% of NCM (11% in CM). Mixed or epitheloid cell tumors was seen in 54.9% of NCM and 49% of CM, spindle cell tumors in 36.3% of NCM and 51% in CM. Advanced tumor stages T3 and T4 were present in 45.1% resp. 36.3% of NCM compared to 37% resp. 16% in CM. Scleral invasion was documented in 67.3% of NCM and 37% of CM, extrascleral dissemination in 43% of NCM and 16% of CM. Secondary glaucomas were seen in 62.2% of NCM and 6% CM, a penetration through Bruch's membrane in 61.0% of NCM and 46% of CM. Intratumoral hemorrhage was noted in 68.14% of NCM and 24% of CM, extratumoral bleeding in 23.9% of NCM and 0% CM. Inflammatory reactions in tumors were observed in 96.7% of NCM harboring > 30% necrosis compared to 5% in CM, and extratumoral in 94.5% of NCM and 0% of CM. Intraocular extratumoral necrosis was seen in 23.9% of NCM and 0% of CM. There were no significant differences in the degree of pigmentation of the 90.3% pigmented NCM or of the 94% pigmented CM, neither in the tumor localization, being constantly behind the equator in 87% of cases. Survival of patients with NCM patients was 5 years and 9 months on average (5-year mortality rate 41.9%), and 74.3% were deceased from metastatic spread. CONCLUSIONS: Significant clinical and histopathological differences between necrotizing and non-necrotizing malignant melanomas of the choroid can be identified. The inflammatory reaction of NCM must be further elucidated, particularly with respect to the nature of tumor-infiltrating lymphocytes.     

Treatment of chronic allodynia in spinally injured rats: effects of intrathecal selective opioid receptor agonists

We examined the effects of intrathecal (i.t.) selective opioid receptor agonists in alleviating mechanical and cold allodynia in spinally injured rats. Both DAMGO ([D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin, a mu-opioid receptor agonist) and DPDPE ([D-Phe2,D-Phe5]-enkephalin, a delta-opioid receptor agonist) dose-dependently relieved the chronic allodynia-like behavior at doses selective for their respective receptors. The anti-allodynic effect of DAMGO and DPDPE was reversed by the selective mu- and delta-opioid receptor antagonists CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2) and naltrindole, respectively. In contrast, the selective kappa-opioid receptor agonist U50488H did not alleviate the allodynia-like behavior, but rather enhanced it. The anti-nociceptive and anti-allodynic effect of i.t. DAMGO was blocked by U50488H. Thus, activation of spinal mu- and delta-, but not kappa-opioid receptors produced anti-allodynic effect in this model of central pain. Drugs which act selectively on opioid receptor subtypes may be useful in managing chronic central pain of spinal cord origin.