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Practical aspects of differential ventilation with selective peep in acute respiratory failure.

Hypoxaemia in association with acute respiratory failure continues to be a severe problem in some intensive care patients. Among strategies proposed, we want to focus attention on differential ventilation with selective PEEP, administered in the lateral position. This ventilation technique has proved successful in the treatment of refractory hypoxaemia due to severe bilateral lung disease. The rationale of this concept is briefly presented in this paper, where the main emphasis is laid on the practical aspects of its clinical application. Two case reports are included as examples of our experiences.

Acute Disease↗

Differentiation of an immature T cell line: a model of thymic positive selection.

Thymocyte differentiation is dependent upon recognition of major histocompatibility complex (MHC) molecules on thymic stroma, a process called positive selection. Here we describe an immature CD4+8+ T cell line derived from a TCR transgenic mouse that differentiates into CD4+8- cells in response to antigen and nonthymic antigen-presenting cells. When injected intrathymically, these cells differentiate in the absence of antigen. The ability of immature T cells to recognize MHC molecules in the absence of foreign antigen in the thymus can thus be attributed to a unique property of thymic antigen-presenting cells. These studies also demonstrate the phenotypic and functional changes associated with TCR-mediated T cell maturation and establish an in vitro model system of positive selection.

Animals↗

Histology, protein clearances, and response to treatment in the nephrotic syndrome.

In a group of 400 nephrotic patients, both adults and children, the histological picture seen on renal biopsy, the selectivity of differential protein clearances, and the response to corticosteroid therapy where applied were studied. The only discernible difference was that of the relative incidence of underlying renal disease; in particular, the much greater incidence of "minimal change" lesions and the near absence of glomerular disease secondary to systemic disorders in children. Highly selective differential protein clearances were strongly associated with response to steroids within eight weeks, and this depended on the relation between this type of protein clearance and the minimal change lesion, which was the only histological appearance associated with complete response to corticosteroid therapy within eight weeks. Neither renal biopsy nor studies of proteinuria allowed prediction of which responding patients would subsequently relapse.Studies of differential protein clearances allow the paediatrician to avoid renal biopsy with safety in nephrotic children aged 1 to 5 years, but cannot distinguish any given renal disease with certainty. Generalized diseases affecting the kidney are usually associated with poorly selective differential protein clearances. Within all groups the most severe changes were usually associated with the least selective differential protein clearances, and vice versa.

Adolescent↗

Transfer of stimulus differentiation and perceptual selection rules.

Three experiments examined the conditions under which transfer of stimulus differentiation occurs. Two experiments involved transfer in paired associate lists having identical stimuli and re-paired response terms compared with lists having different stimuli. In one experiment, transfer was determined for lists of three-word stimuli in which various elements were shared among the stimuli. The pattern of redundancy was such that the spatial position of a discriminative element was either consistent or not consistent in different items, or there was no discriminative element. Transfer of differentiation was obtained only when position was constant. In the second experiment, stimuli were single words and were either unrelated, rhymed, or were instances of common concepts. No evidence of transfer of differentiation was obtained with either rhymes or concepts. In the third experiment, subjects learned pairs in which the stimuli were single letters; then subjects transferred to a list in which either rhyming or unrelated stimuli began with the same letters. Transfer was not differential.

Discrimination Learning↗

GABA enhancement of flunitrazepam binding in mice selectively bred for differential sensitivity to ethanol.

The binding of the benzodiazepine [3H]flunitrazepam (FNZ) and the allosteric enhancement of FNZ binding by gamma-aminobutyric acid (GABA) were investigated in brain tissue from short-sleep (SS) and long-sleep (LS) mice, lines selectively bred for differential sensitivity to ethanol. GABA enhanced FNZ binding in a dose-dependent manner in both lines. This enhancement was greater in SS than in LS cortical and cerebellar regions, but did not differ between lines in midbrain or hindbrain regions. In whole brain, no difference was observed between the two lines in the number or affinity of benzodiazepine receptors, as determined by FNZ binding. These results suggest that the nature of allosteric interactions within the GABA-benzodiazepine receptor complex is different for LS and SS mice.

Animals↗

Chondrocytes provide morphogenic signals that selectively induce osteogenic differentiation of mesenchymal stem cells.

During endochondral bone development cartilage formation always precedes that of bone, leading to the hypothesis that chondrocytes provide inductive signals for osteogenesis. To test this hypothesis, C3H10T1/2 mesenchymal stem cells were cocultured in membrane separated trans-well culture chambers with nonhypertrophic chondrocytes, hypertrophic chondrocytes, calvaria osteoblasts, or tendon fibroblasts derived from embryonic chickens to assess if individual cell types would selectively promote osteogenic differentiation. Then, differentiation of C3H10T1/2 mesenchymal stem cells in coculture were compared with that induced by bone morphogenetic protein 7 or osteogenic protein-1 (BMP-7; OP-1) treatment. Osteogenesis, as determined by the expression of Cbfa1 and osteocalcin (OC) messenger RNAs (mRNAs), was induced strongly in C3H10T1/2 cells cocultured with both chondrocyte cell populations but was not induced by coculture with either osteoblasts or skin fibroblasts. Interestingly, treatment of C3H10T1/2 cells with BMP-7 induced both chondrogenesis and osteogenesis, and only osteogenic differentiation was observed in the C3H10T1/2 cells cocultured with chondrocytes. No alterations in the expression of mRNAs for BMP-1 to -8 were observed in the C3H10T1/2 cells under any of the coculture conditions. This shows that the induction of endogenous BMPs by coculture does not regulate osteogenesis in an autocrine manner. These results show that chondrocytes express soluble morphogenetic factors that selectively promote osteogenesis, and this selective effect is not mimicked by an exogenously added BMP.

Alkaline Phosphatase↗

Collinsia sparsiflora in serpentine and nonserpentine habitats: using F2 hybrids to detect the potential role of selection in ecotypic differentiation.

Here we document phenotypic differences between serpentine and nonserpentine ecotypes of Collinsia sparsiflora, as well as patterns of selection in these contrasting soil habitats. We transplanted the two parental ecotypes and experimental F2 hybrids into six field sites, and collected morphological, phenological and fitness data on emergent plants. To focus on edaphically mediated selection, rather than on pollinator-mediated selection, we used pollinator-exclusion cages. Transplanted parentals of the two ecotypes showed genetic differentiation for floral traits, but not for phenological traits or cotyledon size. For the F2 hybrids growing on serpentine soils, there was significant directional selection on cotyledon size, flower size and flower shape. However, the pattern of selection did not differ significantly between serpentine and nonserpentine sites. Overall, we did not see evidence for divergent selection on the two soil types. We conclude that differences in floral traits between the ecotypes do not reflect adaptation to physical conditions associated with soil type, and that there are unmeasured traits that must be contributing to ecotypic differentiation.

Asbestos, Serpentine↗

Behavioral responses to repeated cocaine exposure in mice selectively bred for differential sensitivity to pentobarbital.

Mice from the 20th generation of three lines divergently selected for response to pentobarbital-induced sedation times [long-sedation time (LST), short sedation time (SST), and randomly bred control (RBC)] were used to study cocaine-induced behavioral sensitization. These lines showed variable degrees of locomotor activities in response to cocaine. At a low cocaine dose and long withdrawal period (10 mg/kg, twice a day for 5 days followed by a 14-day withdrawal), the LST mice showed tolerance development. In response to cocaine, the locomotor activities of the SST were not significantly different from the RBC group. At a higher dose and a shorter withdrawal period (20 mg/kg, daily for 7 days followed by a 3-day withdrawal), the SST mice showed behavioral sensitization similar to the RBC mice, but the LST mice did not develop sensitization. The different responses in locomotor activity induced by cocaine suggest that genetic factors may play a role in determining the magnitude of response to this drug. Dopamine (DA) levels did not differ significantly in either striatum (STR) or nucleus accumbens (NAC) for the cocaine-treated animals to their corresponding saline-treated controls. The affinity (Kd) of D2 in the NAC decreased significantly, without changes in density (Bmax), in the cocaine-treated SST and RBC mice. On the other hand, the density of D2 binding sites in the SST and the RBC mice in the STR was significantly increased in cocaine-treated groups without change in Kd. The LST mice did not show any changes in the Kd and Bmax in either the STR or the NAC. Taken together, these findings suggest that the changes in the Kd of D2 in the NAC and the Bmax of D2 in the STR may contribute to the differences in locomotor responses to cocaine exposure in these mouse lines.

Analysis of Variance↗

Ventilation and perfusion of each lung during differential ventilation with selective PEEP.

Lung perfusion was studied in 10 patients (mean age 58 yr) in the lateral position during enflurane anesthesia. They were ventilated through a double-lumen endotracheal catheter: 1) by one ventilator with free distribution of ventilation between the lungs, with no (zero) end-respiratory pressure (ZEEP); 2) as above but with a general positive end-expiratory pressure (PEEP) of 9 cmH2O; or 3) by two ventilators with equal distribution of ventilation between the lungs and with a selective PEEP of 8 cmH2O to the dependent lung only. Total ventilation was on average 8 l/min (BTPS) throughout the study. During the first method, 34% of ventilation was distributed to the dependent and 66% to the nondependent lung. Cardiac output (thermodilution) was 4.5 l/min, 57% being distributed to the dependent lung as assessed by iv boli of Xenon 133. During the second method, ventilation was assumed to be distributed equally between the lungs. Cardiac output was decreased to 3.8 l/min, and the dependent lung received 81% of lung blood flow. During the third method, cardiac output was significantly greater than during the second method (4.1 l/min), 51% passing to the dependent lung. Peak and end-inspiratory airway pressures were 5-18 cm H2O lower during selective than during general PEEP. Arterial oxygen tension was significantly greater during the third method than during either of the other ventilator settings and the alveolar-arterial oxygen tension difference was almost halved compared with the first method. It is concluded that differential ventilation with selective PEEP improves ventilation-perfusion matching and thus oxygenation.

Adult↗

Chemical synthesis of a peptide fragment of thymopoietin II that induces selective T cell differentiation.

Thymopoietin is a polypeptide hormone of the thymus that consists of a 49 amino acid polypeptide chain of 5562 daltons. A peptide corresponding to positions 29-41 of bovine thymopoietin II was synthesized by the Merrifield solid-phase technique. This peptide was shown to have a purity (correct sequence) of 96% by amino acid and C terminal analyses and by a complete determination of the amino acid sequence by manual Edman degradations. It displayed a selectivity of action similar to that of thymopoietin itself, inducing the differentiation of T lymphocytes but not of complement receptor (CR+) B lymphocytes. Although a number of substances induce the differentiation of both T cells and CR+B cells under the conditions of assay in vitro, only thymopoietin and the synthetic peptide described in this report have been shown to induce the differentiation of T cells selectively. Our data establish that the key residues involved in the active site of thymopoietin are present within a synthetic polypeptide which constitutes a minor portion of the amino acid sequence of thymopoietin. Since this peptide had 3% activity by comparison with thymopoietin, the tertiary structure of thymopoietin may be required for optimal configuration of the active site to produce full biological activity.

Amino Acid Sequence↗

Reexamining the functions of zinc sulfate as a selective depressant in differential sulfide flotation--the role of coagulation.

Zinc sulfate is a well-known selective depressant for zinc sulfide minerals such as sphalerite during the flotation of complex Cu-Pb-Zn sulfide ores. It deactivates sphalerite flotation by substituting the activating metal ions, and depresses sphalerite flotation by forming hydrophilic coatings of zinc hydroxyl species on sphalerite surfaces. However, we recently observed that zinc sulfate could also induce coagulation of fine sphalerite particles and such coagulation significantly reduced the mechanical entrainment of the fine sphalerite. Therefore, it seems that the effectiveness of zinc sulfate as a selective sphalerite depressant is not only due to its ability to make mineral surface hydrophilic, which reduces genuine flotation, but also due to its ability to coagulate the mineral, which reduces mechanical entrainment. Zinc sulfate is a "dual function" selective flotation depressant.

Journal Article↗

Differential analysis of selected prompts and neurological variables in motor assessment of moderately mentally retarded children.

The purpose of this study was to elevate the specificity of gross-motor assessment strategies presently used with moderately mentally retarded children by measuring voluntary motor performance as a function of level of reflex development, level of orthopedic functioning, and type of prompts used in test instructions. After clinically assessing subjects' levels of reflex and orthopedic functioning, we randomly assigned subjects to multisensory-, physical-, modeling-, and verbal-prompt treatment groups. Multisensory prompts and differential use of selected prompts were effective with younger and older children, respectively. A significant interrelationship was found between subjects' levels of reflex development and voluntary motor performance.

Adolescent↗

Differential response to selection on the two sexes in Drosophila melanogaster.

Artificial selection for short wing was performed in two Drosophila melanogaster populations with partially different gene pools: the C populations were derived from a Canton stock while the H lines were derived from a cross between Canton and a b, cn, vg strain. It is shown that in both populations selection on females (CF, HF) was more effective than selection on males (CM, HM). This difference cannot be explained in terms of differences in additive genetic variability between the two sexes because: (1) both sexes contribute to the genetic variability utilized by selection applied to one sex only, and (2) switching selection pressure on females in the M lines does not result in a response comparable to that obtained in the F populations; this rules out almost completely recombination as the responsible agent for the differences between the selection limits reached by M and F selections.-These results, together with several additional observations concerning sexual dimorphism, fitness and the effect of natural selection, suggest that a complex interaction should be involved in the differential response of M and F lines, controlling the wing length phenotype.

Animals↗

Differential effect of selected antiarrhythmic drugs on coronary artery ligation-induced ventricular arrhythmias on the right or left sides.

The differential effect of the antiarrhythmic agents quinidine, propranolol, verapamil and sotalol was studied on right and left sided ventricular arrhythmias induced by ligation of the right coronary artery or anterior descending branch of the left coronary artery, respectively. Quinidine (0.30 mg/kg/min), propranolol (0.30 mg/kg/min), sotalol (0.25 mg/kg/min) and verapamil (0.018 mg/kg/min) were injected in unanesthetized dogs 18-24 h after coronary artery ligation. The doses of test drugs required for suppression of the ventricular arrhythmias were higher in the case of quinidine, sotalol and verapamil, but not in case of propranolol. The potency of the selected drugs in abolishing ventricular ectopics was, in descending order: verapamil, sotalol, propranolol and quinidine. The differential antiarrhythmic effect of these drugs in ventricular arrhythmias is discussed.

Animals↗

Evidence for a selective and multi-step model of T cell differentiation: CD4+CD8low thymocytes selected by a transgenic T cell receptor on major histocompatibility complex class I molecules.

We have characterized a prominent (15-20%) thymocyte population expressing CD4 at a high and CD8 at a low level (CD4+8lo) in mice transgenic for a T cell receptor (TCR) restricted by major histocompatibility complex (MHC) class I molecules. The results demonstrate that the CD4+8lo population is an intermediate stage between immature CD4+8+ and end-stage CD4+8- thymocytes and that the survival of these cells crucially depends on the successful interaction of the transgenic TCR with self MHC class I molecules. In addition we demonstrate that the avidity of the interaction between TCR and self MHC class I molecules determines whether CD4+8lo thymocytes are found in significant numbers in this transgenic model. Our findings support a selective and multi-step model of T cell differentiation in the thymus.

Animals↗

A novel role of fibrin in epidermal healing: plasminogen-mediated migration and selective detachment of differentiated keratinocytes.

Recent studies have shown that fibrin promotes epidermal regeneration in vitro and maintains the stem cell population after transplantation of keratinocytes in vivo. As epidermal keratinocytes do not express integrin alpha(v)beta3, the receptor for fibrin and fibrinogen, the mechanism through which fibrin affects epidermal cells remains elusive. To investigate the role of fibrin in epidermal wound healing, we developed an in vitro model in which fibrin was added to the top of wounded keratinocyte monolayers grown on collagen. With this matrix topology, keratinocytes migrate between the collagen on their basal side and fibrin on their apical side mimicking migration of the epidermis in vivo. Using this model, we found that fibrin promoted keratinocyte migration in low and high calcium concentrations by exposing the cells to plasminogen. The migration rate depended strongly on the concentration of fibrinogen and the rate of plasmin-mediated fibrin degradation. Surprisingly, fibrin and fibrinogen caused significant detachment of keratinocytes which was prevented by the addition of calcium. Further examination using flow cytometry revealed that the detached cells were larger, more granular, and had very low levels of beta1 integrin, which are all signs of differentiated keratinocytes. Our results suggest a novel dual role of fibrin in epidermal healing. First, fibrin promotes keratinocyte migration indirectly by exposing plasminogen to migrating cells, and second, fibrin selectively disrupts adhesion of differentiated keratinocytes. Our data are novel and may have important implications in understanding wound healing and in the use of fibrin as a biomaterial for protein and gene delivery.

Calcium↗

A role for c-myc in the regulation of thymocyte differentiation and possibly positive selection.

The purpose of thymocyte differentiation is to establish the T cell repertoire and eliminate nonfunctional and autoreactive T cells. In an analysis of potential regulators of this process, we have found that c-myc expression is down-regulated dramatically during early thymocyte differentiation and subsequently up-regulated along with TCR/CD3 in CD4+8+ cells. Transgenic E beta-myc mice that constitutively express c-myc in thymocytes have a larger proportion of thymocytes with high TCR/CD3 and low heat-stable antigen-1 expression than controls, and an increase in the number of transitional cells with a CD4+CD8low phenotype. Mature E beta-myc T cells respond less vigorously than controls to activation through their TCR/CD3 complex, as measured by proliferation and induction of the activation marker CD69. These results are consistent with a hypothesis in which activation of immature T cells through TCR/CD3 induces c-myc up-regulation and drives thymocytes through the initial stage of positive selection.

Animals↗

The effect of halothane on mice selectively bred for differential sensitivity to alcohol.

We have investigated the response of mice to halothane that have been selectively bred for either sensitivity (long sleep, LS) or resistance (short sleep, SS) to the anesthetic effects of ethanol. While large differences in the response of the animals to ethanol were observed in sleep time, blood anesthetic concentration at time of awakening, and body temperature, the SS and LS lines did not differ in their response to halothane. We conclude that the mechanism of action of ethanol and halothane differ in a significant way from each other.

Animals↗