Reactive multiple keratoacanthoma in a patient with chronic renal insufficiency.
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Biopsy↗
Biomedical subjects
N Conrad
Publications and source records attributed to N Conrad.
Expression of endomyocardial nitric oxide synthase and coronary endothelial function in human cardiac allografts.
BACKGROUND: Inducible nitric oxide synthase (iNOS) is expressed and is functionally active in the presence of transplant arteriosclerosis. However, the early involvement of iNOS in alterations of microvascular endothelial function in the absence of preexisting lesions remains unclear; this information would be of prognostic value. We studied the course of iNOS mRNA expression, transcardiac nitric oxide production, and their potential association with microvascular coronary endothelial dysfunction in human cardiac allografts. METHODS AND RESULTS: A total of 42 patients were studied at 1, 6, and 12 months after heart transplantation. Microvascular coronary flow velocity reserve (CFVR) was tested in an endothelium-dependent (acetylcholine) and -independent manner (adenosine) using a Doppler flow wire. Endomyocardial iNOS expression was determined by reverse transcription polymerase chain reaction. iNOS protein and nitrotyrosine levels were detected by immunohistochemistry. Transcardiac plasma nitrite/nitrate (NOx) levels were measured by the Griess reaction. CFVR was impaired in 26.1% of patients (n=11) at 1 month and in 31% of patients (n=13) at 12 months after heart transplantation. Patients who developed impaired CFVR in the first year showed a significant increase in iNOS gene expression. Patients with impairment of CFVR 1 month after heart transplantation had higher levels of iNOS mRNA than patients with a normal CFVR. Patients with an initial impairment of CFVR who did not improve over time presented with significantly higher iNOS mRNA levels. iNOS protein and nitrotyrosine were expressed in the endomyocardial vessels of patients with impaired CFVR. Transcardiac NOx release was higher in patients with impaired CFVR. CONCLUSIONS: In human cardiac allografts, microvascular endothelial dysfunction is associated with an enhanced endomyocardial iNOS mRNA expression and higher transcardiac NOx production and is accompanied by the expression of nitrotyrosine protein, suggesting peroxynitrite plays a role in the disease process. The data from the present study suggest an important role for the iNOS/nitric oxide pathway in the regulation of microvascular function in the absence of preexisting atherosclerotic lesions.
Acetylcholine↗
Coronary flow reserve and nitric oxide synthases after cardiac transplantation in humans.
OBJECTIVE: Coronary endothelial dysfunction may precede morphological changes in both the epicardial conduit and microvascular resistance vessels in heart transplant recipients. Since the development of transplant atherosclerosis is the major limiting factor for long-term survival, the identification of early mediators of vasomotor dysfunction may be of therapeutic interest. We therefore investigated the potential relationship between the expression of nitric oxide synthases (NOS) and coronary endothelial function in human cardiac transplant recipients over time. METHODS: Forty-two human cardiac transplant recipients were studied at 1 and 12 months after heart transplantation (HTx). The microvascular coronary flow velocity reserve (CFVR) was tested for endothelium-dependent (acetylcholine) and -independent (adenosine) stimuli by intravascular Doppler flow-wire. Epicardial diameter changes were evaluated by quantitative coronary angiography. Endomyocardial inducible (iNOS) and endothelial constitutive nitric oxide synthase were determined by RT-PCR. Nitric oxide production (nitrite and nitrate (NOx)) and TNF-alpha were measured in plasma samples from the aorta and coronary sinus. RESULTS: CFVR was impaired in 26.1% (n=11) of patients at 1 month and in 31% (n=13) 12 months after HTx. iNOS-mRNA levels were significantly higher in patients with impaired endothelium-dependent CFVR. In addition, only in these patients were TNF-alpha levels higher and these correlated with plasma NOx levels at 1 and 12 months post-HTx (1 month: r=0.81, P=0.001; 12 months: r=0.62, P=0.04). CONCLUSIONS: Coronary microcirculatory dysfunction in response to acetylcholine is present in nearly 30% of patients during the first year following transplantation. These patients present with higher iNOS-mRNA expression and TNF-alpha plasma levels. Selective modulation of the TNF-alpha/iNOS-pathway may be of therapeutic value to improve coronary endothelial dysfunction in cardiac transplant recipients.
Adult↗
Reduced myocardial cellular damage and lipid peroxidation in off-pump versus conventional coronary artery bypass grafting.
BACKGROUND: The development of new surgical devices and techniques allows off pump coronary artery bypass grafting (OPCAB) without the use of CPB and cardioplegia. This study tested whether OPCAB reduces myocardial cell damage, lipid peroxidation and systemic endothelin release when compared to conventional coronary artery bypass grafting. METHODS: Twenty-six patients were assigned to either the OPCAB procedure using a suction device and regular sternotomy (n = 13) or were treated conventionally using extracorporeal circulation, blood cardioplegia and hypothermic arrest (29-31 degrees C; n = 13). Troponin I and creatine kinase - MB were determined for cardiac specific cell damage. Myocardial and systemic malondialdhyde levels were measured to account for oxyradical mediated lipid peroxidation. Systemic big-endothelin levels were determined as a marker for endothelial cell activation. RESULTS: A significant reduction of the cardiac specific cell damage was observed in the OPCAB group vs. the CABG group over time in the absence of acute myocardial ischemia or infarction. In addition, systemic and myocardial lipid peroxidation as measured by the malondialdehyde (MDA) levels were lower in the OPCAB group when compared to CABG. Finally, plasma levels of big-Endothelin (big-ET) significantly rose in the CABG but not in the OPCAB group. CONCLUSIONS: The data of the present study indicate that OPCAB revascularization without the use of CPB and cardioplegic arrest reduces myocardial cell damage and lipid peroxidation. It is also associated with a reduced activation of the potent vasoconstrictor peptide endothelin. All of this may contribute to improved myocardial function and faster postoperative recovery from surgical revascularization procedures, particularly in critically ill patients.
Aged↗
Effects of Celsior and University of Wisconsin preservation solutions on hemodynamics and endothelial function after cardiac transplantation in humans: a single-center, prospective, randomized trial.
Optimal preservation of the myocardium remains a major concern in clinical and experimental heart transplantation. The present study compared the efficacy of University of Wisconsin (UW) and Celsior preservation solution with respect to myocardial performance, epicardial and microvascular endothelial vasomotor function and myocardial expression of endothelin and nitric oxide synthases in humans. Forty-one cardiac transplant recipients received either UW (n = 20) or Celsior (n = 21) preserved hearts. Catecholamine and vasodilator requirements were assessed within the first 5 postoperative days. Left ventricular performance and endothelial function was assessed 1 month after transplantation. Endothelin and nitric oxide synthase gene expression were detected in myocardial biopsy samples. Celsior preserved hearts required significantly more catecholamines and vasodilators within the first 5 postoperative days. Myocardial performance and endothelial function were comparable 1 month after transplantation. Total ischemic time correlated with impaired endothelial function in the Celsior but not in the UW group. Endothelin and inducible nitric oxide synthase gene expression were significantly higher in the Celsior group. The results of the study show that both solutions provide myocardial protection with regard to left ventricular performance and endothelial function 1 month after cardiac transplantation. The necessity for higher vasodilator and catecholamine therapy in Celsior preserved hearts suggests post-ischemic myocardial stunning within the first 5 postoperative days. The positive correlation between impaired endothelial function and total ischemic time in the Celsior group requires longitudinal investigation in particular with regard to the development of allograft vasculopathy.
Adenosine↗
An association between microvascular endothelial dysfunction, transcardiac nitric oxide production and pro-inflammatory cytokines after heart transplantation in humans.
Endothelial dysfunction anticipates the development of transplant coronary artery disease (TxCAD) observed more than 1 year after transplantation (HTx). We investigated whether in patients early after HTx myocardial inducible and constitutive nitric oxide synthases (iNOS; cNOS) are expressed and cardiac nitric oxide production occurs. Moreover, a possible relationship to alterations in endothelium dependent and independent vasomotor function was assessed. Forty-two transplant recipients were studied 37 +/- 5 days after HTx. Microvascular coronary flow velocity reserve (CFVR) was tested endothelium dependent (acetylcholine; 30 microg/min x 5 min/i.c.) and independent (adenosine; 160 microg/min x 5 min/i.c.) by Doppler flow wire. Flow velocity increase by a factor greater than 2 was considered normal. Quantitative coronary angiography was used to assess epicardial vasomotor function in response to the same stimuli. Myocardial iNOS and cNOS gene expression were detected by semiquantitative reversed transcriptase polymerase chain reaction. Plasma nitrite levels (microM) were measured by spectrophotometry. Cytokines (TNF-alpha, IL-6; pg/ml) were measured by enzyme linked immunosorbent assay. In 26.1% of patients (n = 11; group A) an impaired endothelium dependent CFVR (1.65 +/- 0.23 increase) was observed; in 73.9% (n = 31, group B) a normal endothelium dependent CFVR (3.0 +/- 0.7 increase; P = 0.003) was observed. Myocardial iNOS and cNOS gene expression did not differ between the two groups. Transcardiac cytokine production was noted in 58.8% of patients for IL-6 and in 53.3% for TNF-alpha. Coronary sinus (CS) levels of TNF-alpha, IL-6 and nitrite were higher in group A. A significant increase in nitrite production was found only in patients with impaired endothelium dependent CFVR (aorta: 43.9 +/- 3.7 vs CS: 52.8 +/- 5.6, P = 0.05), suggesting transcardiac nitric oxide production. In addition, CS nitrite levels correlated with CS TNF-alpha levels in patients with impaired CFVR (r = 0.44, P = 0.003). Microvascular endothelium dependent CFVR is impaired in 26% of patients early after HTx. Activation of cytokines and the NO pathway seem to be involved in this vasomotor dysfunction The association between cardiac nitric oxide production and TNF-alpha in this group indicates a chronic high immunologic process, which may represent an early and important target for therapy and prevention of TxCAD.
Adenosine↗
Delivery of dermatopathologic health care in the twenty-first century.
Dermatology and dermatopathology has experienced significant growth over the last century and continues to burgeon. Upheavals as a consequence of the advent of managed care have threatened both specialties, especially with regard to direct access and choice of consultant. The demand for dermatology and dermatopathology services continues to increase, and for patients to be served appropriately, these issues must be addressed.
Cost-Benefit Analysis↗
An investigation into the neuroprotective properties of ibuprofen.
There is increasing evidence suggesting a protective role for anti-inflammatory medications in neurological disorders such as Alzheimer's disease (AD). While there has not been any direct evidence for this, a number of clinical studies indicate that those patients who have had a history of nonsteroidal anti-inflammatory use, have a lower incidence of AD. Since there is currently no evidence on the mechanism by which these agents offer possible neuroprotection, we investigated the potential neuroprotective properties of the nonsteroidal anti-inflammatory drug, ibuprofen, by examining whether this agent could reduce lipid peroxidation and superoxide radical generation. Quinolinic acid and cyanide, known neurotoxins, were used to induce lipid peroxidation and superoxide anion formation respectively, in rat brain homogenate. The results show that ibuprofen significantly (p<0.05) reduced quinolinic acid-induced lipid peroxidation and cyanide-induced superoxide production. The results of the present report therefore suggest a possible mechanism for the neuroprotective effect of ibuprofen.
Animals↗
Reduced expression of systemic proinflammatory cytokines after off-pump versus conventional coronary artery bypass grafting.
BACKGROUND: Both cardiopulmonary bypass (CPB) and operative trauma are associated with increased expression of proinflammatory cytokines. We assessed the relative contribution of CPB on activation of various proinflammatory cytokines in patients undergoing coronary revascularization by comparing them with patients receiving coronary artery bypass grafts using off-pump (OPCAB) techniques. METHODS: Twenty-six patients were assigned to either the OPCAB procedure using a suction device and regular sternotomy (n = 13) or were treated conventionally using extracorporeal circulation, blood cardioplegia and hypothermic arrest (29-31 degrees C; n = 13). C-reactive protein and systemic levels of TNF-alpha, TNF specific receptors Rp1 and Rp2, Interleukin-6 (IL-6) and soluble IL-2 receptors (sIL-2r) were assayed by ELISA or EIA. To account for systemic nitric oxide production, total nitrate/nitrite (NOx) was measured using the Griess reaction. RESULTS: Coronary revascularization with CPB was associated with a significant expression increase in the TNF-system and sIL-2r when compared to the OPCAB patients. Although IL-6 expression did not differ between both groups, C-reactive protein levels were significantly lower in the OPCAB group. Moreover, systemic NOx levels as the stable end-product of nitric oxide were lower in the OPCAB group. CONCLUSIONS: The data of the present study indicate that, despite comparable surgical trauma, the OPCAB revascularization procedure without the use of CPB and cardioplegic arrest significantly reduces the systemic inflammatory response syndrome and early catecholamine requirement. This may contribute to improved organ function, subsequently resulting in improved postoperative recovery from surgical revascularization procedures, particularly in critically ill patients.
Aged↗
Inducible nitric oxide synthase activation after ischemia/reperfusion contributes to myocardial dysfunction and extent of infarct size in rabbits: evidence for a late phase of nitric oxide-mediated reperfusion injury.
BACKGROUND: Ischemia/reperfusion (I/R) leads to the induction of inducible nitric oxide synthase. The present study investigated the effects of selective and continuous inhibition of iNOS on myocardial performance, infarct size and histomorphological changes after I/R in rabbits. METHODS AND RESULTS: Ischemia/reperfusion (I/R) was induced by occlusion of the circumflex coronary artery for 30 min followed by 48 h of reperfusion. Sham animals (group A) served as control. Three groups were subjected to I/R: (B) placebo; (C) aminoguanidine (AMG; 10 mg/kg bolus) given prior to and 48 h after I/R to test its acute effects; (D) AMG (300 mg/kg/day s.c.) to test effects of continuous treatment. Hemodynamics, myocardial blood flow, infarct size, iNOS activity, cGMP levels, immunohistochemical analysis of iNOS expression and AMG tissue levels were determined. Continuous AMG treatment improved myocardial performance (hemodynamics and blood flow) compared to placebo group. iNOS was highest in placebo-treated animals. AMG tissue levels were highest in tissues affected by I/R. Infarct size (% of the circumflex region) was significantly smaller in group D when compared to group B. CONCLUSIONS: This is the first study showing that activation of myocardial iNOS isozyme during 48 h of reperfusion contributes to a late phase of I/R-induced injury in rabbits. Selective and continuous modulation of iNOS by AMG over this time period exerts protective effects with respect to myocardial performance, coronary blood flow, cellular infiltration and reduction of infarct size; this may be a novel therapeutic approach in the clinical situation to limit irreversible myocardial injury associated with ischemia and reperfusion.
Adrenergic beta-Agonists↗
Incipient intraepidermal cutaneous squamous cell carcinoma: a proposal for reclassifying and grading solar (actinic) keratoses.
Actinic keratoses (AKs) are primarily induced by ultraviolet (UV) radiation and are often identified as premalignant lesions. In our opinion, AKs are proliferations of transformed, neoplastic keratinocytes confined to the epidermis that may eventually extend into the dermis, at which point they are termed squamous cell carcinoma (SCC). In contrast to AKs, SCCs have the potential to metastasize and kill. This process is analogous to that of evolving carcinoma of the uterine cervix that has been termed cervical intraepithelial neoplasia (CIN), a time-tested and reliable classification that provides clinicians with accurate information on which to base treatment decisions regarding cervical neoplasms following biopsy testing. A similar classification scheme could provide guidance to clinicians for the diagnosis and treatment of evolving SCC of the skin and as such, we propose a similar classification using the terminology keratinocytic intraepidermal neoplasia (KIN). This system is more reflective of the histology and natural history of SCC and eliminates ambiguity in the terminology of lesions currently referred to as AKs. The KIN classification defines features by which individual specimens can be objectively graded and specific treatment recommendations are made based on the grade of the lesion. We propose that the term keratinocytic intraepidermal neoplasia (KIN) be used to define and describe evolving SCC of the skin and that the term actinic (solar) keratosis be eliminated.
Carcinoma, Squamous Cell↗
High levels of expression of p27KIP1 and cyclin E in invasive primary malignant melanomas.
Cancer cells have abnormal cell cycle regulation which favors accelerated proliferation, chromosomal instability, and resistance to the senescence response. Although the p16INK4a locus is the most prominent susceptibility locus for familial melanomas, the low frequency of p16 mutations in sporadic melanomas suggests additional alterations in other cell cycle regulatory genes. Here we used primary melanoma tumors to reveal early cell cycle alterations that could be masked in advanced metastatic lesions due to their inherently high genetic instability. Unexpectedly, the cyclin-dependent kinase inhibitors p27KIP1 and/or p21Waf-1/SDI-1 were found to be expressed in 13 of 18 (72%) of the primary melanomas with a Breslow thickness greater than 0.076 mm. In general, p27 and/or p21 staining in the primary tumors correlated with low Ki-67 index. Importantly, most of the p21- and p27-positive tumors expressed high levels of cyclin D1 and cyclin E. In proliferating cells p27 is predominantly associated with cyclin D-CDK4 complexes, but does not inhibit the kinase activity, whereas in quiescent cells p27 is found associated with inactive CDK2 complexes. p27 was also expressed at high levels in proliferating primary melanomas in culture, and found to be associated with active cyclin E-CDK2 complexes containing high levels of cyclin E. It is thus likely that accumulation of cyclin E overcomes the potent inhibitory activity of p27 and p21 in CDK2 complexes. Of the primary melanomas with no indication of invasiveness, only three of 15 (20%) were positive for p27 and/or p21. We propose that high levels of p27 and p21 may confer upon melanoma tumors their characteristic resistance to conventional therapies. In turn, high levels of cyclins E and D1 may contribute to unlimited proliferation in primary melanomas that express the tumor suppressor p16INK4. J Invest Dermatol 113:1039-1046 1999
CDC2-CDC28 Kinases↗
Amelanotic lentigo maligna melanoma: a unique case presentation.
Amelanotic melanomas comprise only 2% of melanomas and are commonly a difficult clinical diagnosis, due to the lack of melanin pigment typically found in melanomas. Even rarer is the amelanotic lentigo maligna, which may have an unusual clinical presentation, such as erythema, pruritus, or edema. Biopsy is the key to diagnosis. Multiple therapies for amelanotic lentigo malignas have been tried, but excision, with margin control (Mohs micrographic surgery-frozen or paraffin sections), remains the treatment of choice.
Aged↗
Multiple primary melanoma.
BACKGROUND: Incidence rates of cutaneous malignant melanoma (CMM) have been increasing for decades among Caucasian populations worldwide. Multiple factors identify persons at increased risk of CMM, including those with a family history of melanoma and those with atypical moles. Approximately 6-12% of melanomas are familial and approximately 12% of patients with familial melanoma have multiple primary melanomas. OBJECTIVE: To report a case of a patient with atypical moles and with 17 multiple primary melanomas. To review the literature on multiple primary melanomas as well as to review the genetics and treatment of melanoma. CONCLUSION: Patients with numerous atypical moles and a family or personal history of melanoma are at greatest risk for developing CMM. Patients from this population tend to develop CMM approximately 10 years earlier than the general population and have an increased risk for developing multiple primary melanomas. Since genetic tests capable of detecting individuals with an inherited susceptibility to CMM are not available, it is important to identify those patients with an increased risk and monitor them closely with regular total-body examinations.
Biopsy↗
Aminoguanidine inhibits inducible NOS and reverses cardiac dysfunction late after ischemia and reperfusion--implications for iNOS-mediated myocardial stunning.
BACKGROUND: The functional significance of inducible nitric oxide synthase (iNOS) activation in response to myocardial ischemia and reperfusion (I/R) was investigated. METHODS: New Zealand rabbits were randomly treated with either placebo, aminoguanidine (AMG; selective iNOS inhibitor), or L-arginine. Left-ventricular hemodynamics and myocardial blood flow were measured before coronary occlusion and 30 minutes and 48 h after initiation of reperfusion. RESULTS: I/R resulted in left-ventricular dysfunction and increased myocardial iNOS activity. Placebo treatment had no effects on myocardial function. However, AMG significantly inhibited iNOS activity, significantly improved left-ventricular maximum + dP/dt and decreased LVEDP, whereas administration of L-arginine reduced + dP/dt and slightly increased LVEDP, compared to AMG-treated animals. Myocardial blood flow in the affected myocardium significantly increased after both AMG and L-arginine. CONCLUSIONS: The present data indicate that induction of myocardial iNOS after 48 h I/R contributes to the development of reversible left-ventricular dysfunction, suggesting the involvement of iNOS in myocardial stunning. Whereas L-arginine is associated with further reduction of left-ventricular contractility, continuous inhibition of iNOS activation by AMG improves left-ventricular performance; this may be a novel and clinically important therapeutic modality in certain disease states associated with I/R, including cardiac operations using extracorporeal circulation and coronary angioplastic procedures.
Animals↗
Genital ulcer caused by human bite to the penis.
BACKGROUND AND OBJECTIVES: Human bite injuries, while less frequent than cat or dog bites, usually stem from aggressive behavior, sports, or sexual activity. It has been thought that human bites have a higher rate of infection than animal bites, but this view is likely skewed because of the frequency of closed fist injuries presenting to emergency rooms. Human bites to the genitalia also occur, but are not often reported because of embarrassment. GOAL OF THE STUDY: We report a genital ulceration after a human bite to the penis and review appropriate diagnostic and therapeutic maneuvers. STUDY DESIGN: This article reports the development of a severe genital ulcer associated with a human bite to the penis secondarily infected, as verified by culture, with an oral flora organism Eikenella corrodens. RESULTS: The genital ulceration healed after appropriate antibiotic therapy. CONCLUSIONS: Treatment of human bites focuses on obtaining an accurate history and performing a salient physical examination, as well as early irrigation and debridement. Transmission of communicable disease should be considered as a possible consequence. Prophylactic antibiotic treatment and primary closure of wounds continue to be areas of controversy.
Aged↗
Antibody raised to AKAAAKAAAKA sequence on tropoelastin recognizes tropoelastin but not mature crosslinked elastin: A new tool in metabolic and structural studies of elastogenesis.
Tropoelastin, which is secreted from the cell in a soluble form, contains specific alanine rich repeat domains that are destined to form covalent desmosine and isodesmosine crosslinks in mature insoluble elastin. We raised a monospecific polyclonal antibody to a AKAAAKAAAKA synthetic peptide (AKA) which represents this alanine rich region of tropoelastin. The antibody was reactive with the original peptide antigen and purified tropoelastin, but not with mature crosslinked elastin isolated from several animal species. Conditioned media from chick aorta smooth muscle cells in culture reacted in an ELISA with the AKA antibody, but only in the presence of BAPN to block the conversion of the epsilon-amino groups to aldehydes. Immunofluorescence demonstrated that the AKA antibody decorated newly deposited tropoelastin assembled in fine fibrils in matrix produced by cultured human skin fibroblasts. EM-immunogold specifically localized this antibody to the immature elastic fibers present in fetal sheep ductus arteriosus. Moreover, immunohistochemistry demonstrated that the antibody recognized nonpolymerized tropoelastin assembled on the periphery of elastic fibers in the aorta of chicks raised on copper deficient and BAPN containing diets. These studies demonstrate that this new anti-tropoelastin antibody can be used as a useful tool to investigate elastin metabolism where it is important to distinguish between tropoelastin and mature crosslinked elastin.
Animals↗
Nitric oxide and endothelin in the development of cardiac allograft vasculopathy. Potential targets for therapeutic interventions.
Extensive research has been carried out in recent years to discover the potential risk factors contributing to cardiac allograft atherogenesis. Injury to endothelial cells has been regarded as an important early mechanism in the development of transplant atherosclerosis; it leads to the manifestation of epicardial and microvascular endothelial dysfunction and development of intimal hyperplasia. Moreover, continuous minor endothelial cell damage contributes to endothelial dysfunction which reflects one of the first measurable steps in the cascade of atherogenesis without macroscopic evidence of vascular lesions. The discovery of two important vasoactive substances nitric oxide (NO) and endothelin (ET) has brought new insights but also new unsolved questions regarding the mechanisms leading to atherosclerosis. To date it is known that both substances play a major role in both prevention and development of atherosclerosis. NO appears to be protective in low concentrations by inhibiting leukocyte and platelet activation/adherence and smooth muscle cell proliferation. Impaired endothelial NO production, as one cause of endothelial dysfunction may occur in early stages of atherosclerosis before macroscopic lesions are evident. In addition, increased endothelin release also results in endothelial dysfunction by inducing vasoconstriction; it promotes vascular lesion formation due to endothelial- and vascular smooth muscle cell proliferation. Direct and indirect manipulation of both the NO and ET signal transduction systems may provide novel preventive and therapeutic approaches for limiting transplant atherogenesis and to treat native atherosclerosis. This review summarizes important experimental and clinical evidence which points to nitric oxide and endothelin as potential therapeutic targets in the process of cardiac allograft vasculopathy.
Animals↗