Biomedical subjects

K Heeg

Publications and source records attributed to K Heeg.

At least 91 records · Page 5Linked to original sources

PubMed1990

[Routine throat swabs in artificially ventilated patients: meaningful bacteriologic monitoring or a needless procedure?].

UNLABELLED: Organisms colonizing the oropharynx of patients in the intensive care unit (ICU) play an important role in the development of nosocomial infection. Thus, routine throat swab specimens of ICU patients are recommended to screen for potential pathogens [20]. This investigation was designed to clarify the value of throat swabs taken in addition to tracheal aspirates, urine cultures, and wound swabs with regard to antibiotic therapy in patients with pneumonia and other infections. MATERIALS AND METHODS. A total 627 intubated patients were examined in a surgical ICU during a 12 month period. Pharyngeal swabs, tracheal aspirates, urine cultures, and-if necessary-swabs from wounds and drains were taken immediately after admission to the ICU and routinely thereafter three times each week. DEFINITIONS: Early onset pneumonia: pneumonia occurring within 4 days; late onset pneumonia: pneumonia occurring after the 4th day. Intra-abdominal infection: diffuse or localized peritonitis or abdominal abscess. Wound infection: soft-tissue or bone infection. Corresponding organisms: the same species of bacteria with the same sensitivity pattern (Table 1). RESULTS. Sixty-eight of the patients developed pneumonia. 37 had early onset pneumonia. In 22 of these patients, throat and tracheal specimens had been obtained 2-3 days before the pneumonia was diagnosed. In these specimens, the causative organisms for the subsequent pneumonia were isolated in the throat in 60% of cases and in tracheal secretions in 40% (Table 3). In 35 patients with late onset pneumonia, the causative bacteria were found in 66% of the cases in the throat swabs obtained 2-3 days before the diagnosis was made, in tracheal aspirates in 74% (Table 4). Throat swabs obtained at admission to the ICU from already infected patients or from patients who developed an infection were significantly more colonized with potentially pathogenic micro-organisms (Fig. 1). In 4 patients with early onset pneumonia the results of the throat swab cultures influenced antibiotic therapy, but none of the throat culture results influenced the therapy of the patients with late onset pneumonia or other infections (intra-abdominal infection, wound infection, urinary tract infection). CONCLUSIONS. The throat swab taken at admission may indicate patients at risk for infection. However, throat cultures taken routinely thereafter, parallel with tracheal aspirate cultures, do not provide additional information that is diagnostically or therapeutically helpful. Therefore, throat swab cultures are not necessary for routine bacteriological monitoring. For the prevention of colonization by local administration of antimicrobial agents, regular throat cultures are mandatory.

Adolescent↗

PubMed1990

[Bacterial pneumonia in ventilated patients. The role of bronchoalveolar lavage in diagnosis and therapy].

In the diagnosis and treatment of bacterial pneumonia, the isolation and resistance pattern of the causative organisms are very relevant. Bronchoalveolar lavage (BAL) with quantitative culture is the best technique to obtain material for bacteriological investigations in nonintubated medical patients and in a baboon model. The present study was designed to clarify the following questions: What is the value of BAL compared to tracheal secretion (TS) in ventilated patients with regard to antibiotic therapy? Is it possible to distinguish colonization and infection by investigation of BAL? MATERIAL AND METHODS. In 34 ventilated patients, we studied the diagnostic and therapeutic value of BAL in comparison to TS. Thirteen patients suffered from pneumonia, 9 patients were colonized, and in 12 pneumonia was uncertain. These terms are defined as follows: 1. Pneumonia: temperature over 38.5 degrees C, leukocyte count over 12,000/mm3, infiltrate in the x-ray compatible with pneumonia, purulent tracheal secretion, positive bacteriological findings. All criteria must be fulfilled. 2. Colonized patients: mechanical ventilation more than 7 days, no signs of infection, isolation of the same bacteria species in two previously obtained tracheal secretions. 3. Uncertain pneumonia: not all criteria mentioned above were fulfilled. BAL was performed in the usual manner. The bronchoscope was wedged into a distal airway and 6 x 20 ml of sterile, nonbacteriostatic saline (0.9% NaCl) was instilled through the suction channel and subsequently aspirated. All investigation materials were immediately processed in the bacteriological laboratory. From the BAL specimen Giemsa and Gram preparations were performed to look for contamination from the throat and intracellular bacteria. RESULTS. Patients with pneumonia: In all patients the TS and BAL were positive. Cultures from BAL and TS were in agreement in 77% of the cases. In 10 patients intracellular bacteria (BAL) were present, in two patients the Gram preparation was nonapplicable because of destroyed cells. In one patient Haemophilus spp. could be isolated in the BAL (10(5)/ml BAL), but not in TS, which definitely influenced therapy. Colonized patients: In all patients TS and BAL were positive, with exact agreement in 33% of the cases. The concentration of isolated bacteria (BAL) was not as high in these patients as in the patients with pneumonia (median: 8 X 10(3) vs 6 X 10(4]. However BAL allowed no differentiation between colonization and infection in individual cases. Uncertain pneumonia: TS was positive in 8 patients, no TS could be obtained in 4. BAL was sterile in 4. Only in 2 bacteria greater than or equal to 10(4)/ml were isolated and both patients had intracellular bacteria. The results (BAL) influenced therapy in 5 cases (4 patients received no antibiotics; in 1 patient the antibiotics were modified). CONCLUSION. BAL is very helpful in patients suspected of having pneumonia and in sepsis of unknown origin when pneumonia should be excluded...

Adult↗

PubMed1989

Synergy between interleukin 4 and interleukin 2 conveys resistance to cyclosporin A during primary in vitro activation of murine CD8 cytotoxic T cell precursors.

Even though cyclosporin A (CsA) suppresses in vitro production of lymphokines such as interleukin 2 (IL 2) and responsiveness of cytotoxic T cell (CTL) precursors to IL 2, thereby inhibiting the in vitro generation of CTL, in vivo CsA does not affect the induction of alloreactive CTL. This paradox suggests that CsA-resistant signals are operating in vivo. Using an in vitro model system in which the requirement for antigen-presenting cells during primary activation of resting murine CD8 T cells is bypassed by immobilized anti-CD3 monoclonal antibodies, we here describe conditions in which IL 4 conveys CsA resistance to murine CD8 T cells triggered by immobilized anti-CD3 monoclonal antibodies to respond to IL 2. CsA resistance of IL 4 and IL 2-responsive CD8 T cell parallels conditions in which signals provided by IL 4 and IL 2 synergize with each other. CsA dissociates in vitro proliferative and differentiative events by suppressing the former while enhancing the latter. In addition to the known pleiotropic effects of IL 4, our results define an IL 4-dependent, CsA-resistant signal pathway which allows CTL differentiation in the absence of significant cell proliferation.

Animals↗

PubMed1989

Adoptive transfer of human peripheral blood lymphocytes (PBL) in scid mice.

Two protocols were examined for the ability to transfer a human T cell system into SCID mice. Upon intraperitoneal injection (i.p.) of human peripheral blood lymphocytes (PBL) into SCID mice the injected cells could be recovered over weeks from the peritoneal cavity, yet human T cells did not seed into secondary lymphoid organs such as the spleen, lymph nodes or bone marrow. In contrast, SCID mice grafted with human embryonal thymus tissue contained high numbers of CD4+CD8- and CD8+CD4- human T cells in their lymph nodes and spleen when they had been injected i.p. with human PBL.

Animals↗

PubMed1989

Cyclosporine A prevents the generation of single positive (Lyt2+ L3T4-, Lyt2- L3T4+) mature T cells, but not single positive (Lyt2+ T3-) Immature thymocytes, in newborn mice.

The influence of cyclosporine A (CsA) on T-cell maturation was investigated in newborn mice. CsA treatment during the pre- and postnatal periods resulted in a hypoplasia of peripheral lymphatic organs, and absence of mature T3+ T cells in lymph nodes and spleens; no functional T-cell reactivity was observed. In thymuses of CsA-treated mice, no T3+ single positive Lyt2+ or T3+L3T4+ thymocytes could be found, but double positive (DP) cells were readily detected. A thymocyte subset with the phenotype Lyt2+L3T4-T3- was still discernible; this population was non-functional in vitro. The data show that the maturation of single positive (SP) T cells is critically influenced by CsA; under the conditions used here we found no evidence that 'leaky' autoreactive SP T cells develop in CsA-treated newborn mice.

Animals↗

PubMed1989

Cyclosporine A prevents the generation of single positive mature T cells in newborn mice.

The effect of Cyclosporin A (CsA) during T cell development was investigated in newborn mice. CsA treatment completely blocked the generation of peripheral single positive (SP) mature T cells: the lymphatic tissues were hypoplastic. However, double negative (DN) T3 expressing lymphocytes were still detectable. Thymuses from CsA-treated mice lacked the SP L3T4(CD4)+ subset, DN and double positive (DP) thymocytes were still present. We further defined a SP Lyt2(CD8)+ thymic subpopulation which lacked CD3 expression and displayed no functional activity in vitro. Thus, CsA critically interferes with the maturation of SP T lymphocytes; we found no evidence for 'leaky' autoreactive peripheral SP T cells in CsA-treated newborn mice.

Animals↗

PubMed1989

[Frequency of colonization and pneumonia and development of resistance in long-term ventilated intensive-care patients subjected to selective decontamination of the digestive tract].

Colonization of the oropharynx with potentially pathogenic microorganisms (PPM) is a highly significant factor in the pathogenesis of bacterial pneumonia in intensive care patients. Via colonization of the oropharynx, bacteria pass into the tracheobronchial tree, where they can give rise to pneumonia after overcoming pulmonary resistance mechanisms. By a new, prophylactic antibiotic treatment schedule consisting in selective decontamination of the digestive tract (SDD) with locally applied nonabsorbable antibiotics, Stoutenbeek achieved drastic lowering of the colonization and infection rate in trauma patients. In the present study, we wanted to check whether this new prophylactic antibiotic schedule can be applied on a surgical intensive care ward in all patients with long-term ventilation, irrespective of the diagnosis, and whether it affords advantages over a conventional antibiotic schedule. MATERIALS AND METHODS. All patients on a surgical intensive care ward in whom it was expected that mechanical ventilation would be necessary for more than 4 days were included in the study. During the first 6 months 83 patients were investigated, in whom antibiotics were only administered when the presence of infection had been confirmed, in accordance with generally accepted guidelines (control group). In the second 6-month period, 82 patients were selectively decontaminated with 4 x 100 mg polymyxin E, 4 x 80 mg tobramycin and 4 x 500 mg amphotericin B, administered through the gastric tube and in an antimicrobial paste in the oropharynx (SDD group). The SDD schedule entailed systemic administration of cefotaxime in the first 3-4 days. RESULTS. In the control group, enterobacteria/Pseudomonas spp. were isolated significantly more frequently than in the SDD group (P less than 0.001): in the pharyngeal smear in up to 53%, in the tracheal secretion up to 36%, and in the rectal smear in up to 93% of the patients In the SDD group in the 1 week the frequency of gram-negative aerobic bacteria in the pharynx decreased from 33% to 5%, in the tracheal secretion from 23% to 14% and in the rectum from 86% to 52% (24% in the second week). However, the decrease in gram-negative microorganisms was accompanied by significant increase in the frequency of Staphylococcus epidermidis and enterococci. The SDD schedule proved to be effective with regard to the rate of infection. In the control group, 35 patients developed pneumonia (42%) as against 5 patients receiving SDD prophylaxis (6%). The duration of mechanical ventilation in the patients with pneumonia was 5 days longer than in patients without pneumonia.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

PubMed1988

IL-4 bypasses the immune suppressive effect of cyclosporin A during the in vitro induction of murine cytotoxic T lymphocytes.

We have analyzed at the clonal level the effect of IL-4 on the immune suppressive action of cyclosporin A (CsA) during the in vitro primary activation of anti-MHC alloantigen-reactive murine CD8+ CTL. Although neither IL-4 nor IL-2 alone were able to overcome the CsA-mediated suppression, the addition of IL-4 in the presence of IL-2 restored in a dose-dependent manner the induction of cytolytic activity. On the other hand, CsA greatly impaired proliferative responses of alloantigen-reactive CD8 T cells, thereby operationally dissecting proliferative responsiveness from acquisition of cytolytic activity during primary activation of alloantigen-reactive CD8+ T cells. The existence of a CsA-resistant induction pathway for Ag-specific CD8+ T cell-mediated cytolytic activity may be of relevance for experimental and clinical organ transplantation.

Animals↗

PubMed1988

High-dose irradiated splenic stimulator cells show no endogenous interleukin-2 production but stimulate clonally developing helper T cells to produce interleukin-2.

The effect of various physical or chemical treatments of splenic stimulator cells on their endogenous, mitogen-inducible IL-2 production and on their ability to induce IL-2 production in clonally developing helper T lymphocytes was investigated. While most methods (T cell depletion by monoclonal antibodies plus complement, glutaraldehyde fixation, heat inactivation and high-dose irradiation) effectively suppressed the endogenous IL-2 production of splenic stimulator cells, only T cell depletion and high-dose (6000-10,000 R) irradiation sustained their stimulatory capacity. High-dose irradiated stimulator cells induced high numbers of clonally developing helper T lymphocytes to secrete IL-2. Moreover, this induction was found to be antigen-specific. Hence, high-dose irradiation is a simple, rapid and reliable method for the treatment of stimulator cells, especially when large numbers of cultures are to be screened.

Animals↗

PubMed1988

Primary activation of murine CD8 T cells via cross-linking of T3 cell surface structures: two signals regulate induction of interleukin 2 responsiveness.

In the model system used here to study the minimal signal requirements for the activation of murine resting CD8 T cells, cross-linking of T cell receptor structures by antigen-presenting cells is substituted for by the use of anti-CD3 monoclonal antibodies immobilized in Sepharose beads. We show that cross-linking of CD3 structures, even in combination with CD8 structures, is necessary but insufficient to induce responsiveness to the growth-promoting effect of interleukin 2 (IL2), i.e. fails to induce expression of functional IL2 receptors. A macrophage cell line product termed IL2 receptor-inducing factor (RIF), but not IL1, IL3, IL4 or tumor necrosis factor, efficiently functions as costimulator. Once activated, growth of CD8 T cells is entirely driven by IL2. We conclude that two restriction points control the activation of resting CD8 T cells. While cross-linking of CD3 structures is essential as a first step, RIF is required as competence factor to induce IL2 responsiveness. We consider the possibility that the ability of antigen-presenting cells to produce RIF determines the immunogenicity of presented antigen towards antigen-reactive resting CD8 T cells.

Animals↗

PubMed1988

Reactivity of Ly-2+ T cells against 2,4,6-trinitrophenyl (TNP)-modified syngeneic stimulator cells: specificity, frequency of interleukin 2-producing Ly-2+ helper T cells and clonal segregation from Ly-2+ cytotoxic T lymphocytes.

The in vitro reactivity of purified murine Ly-2+ and L3T4+ T cells towards 2,4,6-trinitrophenyl (TNP)-modified syngeneic stimulator cells was analyzed. Both T cell subpopulations autonomously proliferated and produced interleukin 2. In either the Ly-2+ or L3T4+ T cell subset the frequencies of TNP-specific interleukin 2 (IL 2)-producing T lymphocyte precursors (IL 2 TL-p) were equally high (f = 1/400-1/1000). Clonally developing IL 2 TL of either T cell subset showed an exquisite antigen (TNP) specificity as shown by the split culture approach. TNP-specific Ly-2+ IL-2 TL used class I MHC (H-2Kk) gene products as major histocompatibility complex (MHC) restriction elements, while L3T4+ IL 2 TL proved to be class II MHC (H-2I-AkI-Ek) restricted. Clonal segregation analyses revealed that the majority of clonally developing TNP-reactive Ly-2+ TL segregated into either IL 2 TL-p or cytotoxic T lymphocyte presursors, i.e. both functions appear to be mutually exclusive. Less than 10% of the responding Ly-2+ T cells seemed to be bifunctional. These findings provide compelling evidence for the L3T4+ T cell-independent, autonomous reactivity of Ly-2+ T cells in MHC-restricted antigen-specific responses and suggest T-T cell interactions within the functional heterogenous Ly-2+ T cell population.

Animals↗

PubMed1988

Interleukin 4 (BSF-1) induces growth in resting murine CD8 T cells triggered via cross-linking of T3 cell surface structures.

To analyze the role of interleukin 4 (IL4, BSF-1) during primary activation of resting (high-density) murine CD8 T cells, a model system was used which bypasses antigen-presenting cells by the use of anti-T3 monoclonal antibodies immobilized on Sepharose beads. In high, but not in low cell density cultures, IL4 alone induced cell growth. In low cell density cultures, further to T3 cross-linking a soluble macrophage product was required as co-stimulator to induce sensitivity to IL4. This co-stimulator activity was unrelated to recombinant (r)IL1, rIL6 and rTNF-alpha (tumor necrosis factor alpha). In primary CD8 T cell responses rIL4-driven growth was about half of that induced by rIL2, and not inhibitable by anti-IL2 receptor antibodies. Higher concentrations of IL4 down-regulated cell proliferation. In the course of IL4-driven growth, the proliferating cells acquired sensitivity to the growth-promoting effect of IL2. Activated CD4 or CD8 T cells were found to be equally sensitive to the IL4 and IL2-driven growth pathway. Taken together, these results define a physiologic role of IL4 as growth factor during primary activation of resting CD8 T cells and thus extend the spectrum of target cells for IL4.

Animals↗

PubMed1988

L3T4+ T-cell-independent reactivity of Lyt2+ T cells in vivo.

The aim of this study was to analyze in vivo the L3T4+ T-cell-subset-independent reactivity of Lyt2+ T cells toward transplantation alloantigens. To this end, we depleted normal mice of L3T4+ T cells by injection of monoclonal antibodies to the L3T4 antigen. This procedure not only led phenotypically to a disappearance of L3T4+ T cells, but also effectively abolished reactivity toward class II MHC antigens in vitro and in vivo. However, L3T4+ T-cell-depleted mice still reacted to class I MHC alloantigens in vivo: after immunization with class I MHC alloantigens Il-2 receptor-bearing T cells appeared in the draining lymph nodes, and developed antigen-specific cytolytic activity. Moreover, upon in vivo priming the frequencies of class I MHC-specific precursors of Il-2-producing and cytolytic Lyt2+ T lymphocytes increased up to 20-fold. L3T4+ T-cell-depleted mice rejected class I MHC-bearing skin grafts promptly. We conclude that not only in vitro but also in vivo Lyt2+ T cells remain reactive toward class I MHC antigens in the absence of L3T4+ T helper cells.

Animals↗

PubMed1988

Cross-linking of T-cell receptors is insufficient to induce IL-2 responsiveness (activation) in resting Lyt-2+ T cells. IL-4 or RIF are essential as second signal.

High-density (resting) murine Lyt-2+ T cells exposed in vitro to the ligand concanavalin A (Con A), or immobilized F23.1 monoclonal antibody (mAb) recognizing an allotypic determinant on the T-cell receptor (TCR), or high-density (resting) allogeneic B stimulator cells remain IL-2-unresponsive; such cells do not express functional IL-2 receptors unless reconstituted with accessory cells. We conclude that cross-linking of TCR is insufficient as signal to induce IL-2 responsiveness, that is, activation. Both the macrophage product RIF and the T-cell product interleukin-4 efficiently induce the IL-2 responsiveness in resting Lyt-2+ T cells exposed in vitro either to the ligand Con A, or to immobilized F23 mAb, or to nonimmunogenic allogeneic stimulator cells. We conclude that two restricting points control the induction of IL-2 responsiveness (activation) in antigen-driven Lyt-2+ T-cell responses, that is, cross-linking of TCR by way of presented antigen and "costimulator" activity expressed by accessory cells. Both RIF and IL-4 express costimulator activity, therefore replacing the requirement for accessory cells.

Animals↗

PubMed1988

Two distinct signals regulate induction of IL-2 responsiveness in CD8+ murine T cells.

In the model system used here, cross-linking of T-cell receptor structures (TCR) by antigen-presenting cells (APCs) is substituted by the use of anti-F23.1 anti-T-cell receptor monoclonal antibody immobilized on Sepharose beads. We show that CR cross-linking of resting murine CD8+ T cells seeded at low cell densities is insufficient to induce responsiveness to the growth-promoting effect of interleukin-2 (IL-2), i.e. fails to induce expression of functional IL-2 receptors. The macrophage cell-line product, IL-2 receptor-inducing factor (RIF), but not IL-1, IL-3, IL-4 and interferon-gamma (IFN-gamma) functions efficiently as a co-stimulator. Once activated, growth of CD8+ T cells is driven entirely by IL-2. We conclude that two restriction points control the activation of resting CD8+ T cells. While cross-linking of TCR is essential as the first step, RIF is required as the competence factor to induce IL-2 responsiveness. We consider the possibility that the ability of APCs to produce RIF determines the immunogenicity of APCs towards antigen-reactive resting CD8+ T cells.

Animals↗

PubMed1987

Frequency of herpes simplex virus-specific murine cytotoxic T lymphocyte precursors in mitogen- and antigen-driven primary in vitro T cell responses.

The aim of this study was to assess and to compare the frequencies and specificities of herpes simplex virus (HSV)-specific cytotoxic T lymphocyte precursors (CTL-p) in mitogen (concanavalin A)-activated splenic T cells, as well as in antigen-activated splenic T cells of normal nonimmunized mice. In the mitogen-driven system one of 130 T cell blasts developed clonal progenies able to lyse specifically HSV-infected syngeneic targets. In the antigen-driven system HSV-specific CTL-p could be detected in normal lymphocytes provided the stimulator cells used were enriched for dendritic cells and pulsed with high concentrations of heat-inactivated HSV. Depending on the mouse strain used, the frequencies of HSV-specific CTL-p ranged from 1/500 to 1/10,000 in normal mice. Upon antigen priming within local lymph node cells, an increase of frequencies from 1/500 to 1/170 was observed in CBA/Ca mice.

Animals↗

PubMed1987

Frequency analysis of class I MHC-reactive Lyt-2+ and class II MHC-reactive L3T4+ IL 2-secreting T lymphocytes.

The reactivity of Lyt-2+ or L3T4+ T cells stimulated with either mutant class I or class II MHC alloantigens was studied. Whereas stimulation with class I MHC antigens induced only Lyt-2+ T cells to proliferate and to secrete IL 2, stimulation with class II MHC alloantigens induced L3T4+ but not Lyt-2+ T cells. When the frequencies of precursors of IL 2-secreting T lymphocytes (IL 2TL-p) were determined by limiting dilution analyses, class I MHC-reactive Lyt-2+ T cells displayed frequencies (f = 1/200) as high in magnitude as those within class II MHC-reactive L3T4+ (f = 1/100). Clonally developing IL 2TL of either T cell subset were antigen-specific, as shown in split-culture experiments. Whereas L3T4+ helper TL could be induced to specific IL 2 secretion over a long time period (days 3 to 9), Lyt-2+ TL showed a marked time optimal on day 4; thereafter, the number of TL colonies inducible to secrete IL 2 decreased steadily. IL 2 production and IL 2TL-p frequencies of unseparated T responder cells were not the numerical superposition of the two individual T cell subsets (Lyt-2+ + L3T4+); the latter finding is likely to reflect regulatory influences of Lyt-2+ T cells on IL 2-secreting L3T4+ T cells.

Animals↗

PubMed1987

Identification of interleukin 2-producing T helper cells within murine Lyt-2+ T lymphocytes: frequency, specificity and clonal segregation from Lyt-2+ precursors of cytotoxic T lymphocytes.

The prime aim of this study was to assess whether the autonomous primary mixed lymphocyte culture response of Lyt-2+ T cells towards class I major histocompatibility complex (MHC) antigens reflects in terms of interleukin 2 (IL2) production and cytotoxicity the activation of multifunctional Lyt-2+ T cells, or the activation of functionally distinct T cell subsets. The results demonstrate that highly purified Lyt-2+ T cells proliferate in response to class I MHC antigens, as opposed to L3T4+ T cells which react towards class II MHC antigens. In both responder cell types proliferative responses are associated with IL2 secretion, while only Lyt-2+ T cells develop measurable cytotoxic effector cells. The precursor frequency of IL2-producing helper cells in MHC class I-reactive Lyt-2+ T cells equals that in MHC class II-reactive L3T4+ T cells (f = 1/500-1/1000). In clonal segregation analysis greater than 90% of Lyt-2+ colonies secreting IL2 do not develop cytotoxic activity, while greater than 90% of Lyt-2+ cytotoxic T cells fail to produce detectable IL2. A minority of less than 10% of Lyt-2+ T cells appears to be bifunctional. As such the results point out the existence of functionally committed T cells within class I MHC-reactive Lyt-2+ T cells able to produce either IL2 or to develop into cytotoxic effector cells.

Animals↗