Biomedical subjects

D H Smith

Publications and source records attributed to D H Smith.

At least 19 recordsLinked to original sources

PubMed1992

Dependency of arterial compliance on circulating neuroendocrine and metabolic factors in normal subjects.

Reduced arterial compliance is now recognized as a feature of hypertension. Similarly, metabolic factors such as insulin, catecholamines and lipids are also associated with hypertension. This study explores the possibility that these neuroendocrine and metabolic factors may separately influence arterial compliance. Proximal compliance (aorta and large arteries) and distal compliance (small arteries and arterioles) were measured in 57 volunteers (30 hypertensive and 27 normotensive subjects, mean age 45 years). Compliance was quantified by analysis of arterial pulse wave contours obtained intraarterially together with hemodynamic estimates. Proximal compliance correlated with plasma insulin (r = -0.49; p less than 0.001), norepinephrine (r = -0.50; p less than 0.002), triglycerides (r = -0.39; p less than 0.01), total cholesterol (r = -0.33; p = 0.02) and high-density lipoprotein cholesterol (HDL) (r = 0.37; p less than 0.02). Similarly, distal compliance correlated with insulin (r = -0.37; p less than 0.02), triglycerides (r = -0.39; p less than 0.01), total cholesterol (r = -0.38; p less than 0.01) and HDL (r = 0.51, p less than 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1992

Impact of left ventricular hypertrophy on blood pressure responses to exercise.

It is claimed that exaggerated blood pressure (BP) responses to exercise are predictive of future hypertension and may also be indicative of left ventricular (LV) hypertrophy. The relation between LV hypertrophy and maximal exercise BP was examined in 35 normal male volunteers and 65 untreated hypertensive male patients. Multiple stepwise regression analysis revealed that preexercise systolic BP was the major determinant of maximal exercise systolic BP (r = 0.52; p less than or equal to 0.0001), indicating that higher baseline BP predicted higher exercise BP. However, hypertensive patients with LV hypertrophy had the smallest increases in systolic BP with exercise. Accordingly, there was an inverse relation between LV muscle mass and systolic BP responses to exercise in these patients (r = -0.34; p = 0.005). When compared with normotensive subjects, hypertensive patients had lower measures of maximal oxygen uptake and exercise heart rates (p = 0.01). This may indicate lower cardiac performance at maximal exercise and explain the reduced capacity of hypertensive patients with LV hypertrophy to increase systolic BP with exercise. Neither baseline nor exercise BPs correlated with LV mass; instead, the model of regression analysis indicated that body weight was the principal determinant of LV mass. Contrary to previous reports, exaggerated exercise BPs were not associated with LV hypertrophy in hypertensive or normotensive patients.

Adult↗

PubMed1992

Heredity and hypertension: impact on metabolic characteristics.

This study was performed to evaluate the possible role of heredity in the clinical characteristics of hypertension. Metabolic, endocrine, and renal measurements were compared in subjects with normal blood pressure who had a family history of hypertension (n = 60) with those of subjects with normal blood pressure who did not have a family history of hypertension (n = 48). The groups were matched for age (mean, 44 +/- 2 years and 45 +/- 2 years) and blood pressure (127 +/- 1/77 +/- 1 mm Hg and 127 +/- 2/77 +/- 1 mm Hg). The following parameters were higher in the patients with a family history of hypertension than in those without. Plasma insulin concentrations (14.1 +/- 1.1 vs 10.8 +/- 1.0 microU/ml; p less than 0.05), insulin-glucose ratio (0.15 +/- 0.01 vs 0.11 +/- 0.010; p less than 0.05), norepinephrine concentrations (315 +/- 24 pg/ml vs 208 +/- 20 pg/ml; p less than 0.01), plasma renin activity (2.1 +/- 0.2 ng Angl/ml/hr vs 1.6 +/- 0.2 ng Angl/ml/hr; p less than 0.02), total cholesterol levels (217 +/- 8 mg/dl vs 197 +/- 0.3 mg/dl; p less than 0.05), creatinine clearance (125 +/- 9 ml/min vs 96 +/- 8 ml/min; p less than 0.01), and albumin excretion rate (3.2 +/- 0.3 micrograms/min vs 2.6 +/- 0.3 micrograms/min; p = 0.1). Moreover, patients with a family history of hypertension had smaller increases in systolic blood pressure during treadmill exercise (55 +/- 3 mm Hg vs 64 +/- 3 mm Hg; p less than 0.03). There were no differences in echocardiographic left ventricular mass index between the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1992

Circulatory and extracirculatory effects of angiotensin-converting enzyme inhibition.

The antihypertensive effects of angiotensin-converting enzyme (ACE) inhibitors cannot be fully explained by their actions on the circulating renin-angiotensin system (RAS). Agents such as captopril or enalapril maintain efficacy during long-term therapy even when plasma concentrations of converting enzyme or angiotensin II are not fully suppressed. Components of the entire RAS exist at several sites, thereby making it possible for drugs to produce effects at extracirculatory locations. An ACE inhibitor such as quinapril that has a comparatively short plasma concentration half-life binds strongly to plasma ACE as well as to ACE in key tissues including artery wall, heart, and kidney. The effects of ACE inhibition on the tissue RAS are of potential importance in fully explaining the blood pressure-lowering effects of these drugs. ACE inhibitors might also reduce blood pressure by blocking nonhemodynamic actions of angiotensin II. They affect vascular properties by increasing compliance of arteries and they act on baroreceptors and central regulatory mechanisms. Furthermore, ACE inhibitors affect other neuroendocrine systems, including aldosterone, kinins, and prostaglandins; attenuation of sympathetic activity can contribute further to their antihypertensive properties. Actions independent of circulating renin effects do not necessarily require plasma ACE inhibition throughout a 24-hour period. Sustained antihypertensive effects by drugs with short durations of plasma ACE inhibition give credibility to therapeutic targets beyond the circulating RAS.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1992

Evaluation of a novel calcium channel blocker, (S)-emopamil, on regional cerebral edema and neurobehavioral function after experimental brain injury.

The authors investigated the effects of a novel calcium channel blocker, (S)-emopamil, on cerebral edema and neurobehavioral and memory function following experimental fluid-percussion brain injury in the rat. Two independent experiments were performed to evaluate the effects of this compound on cardiovascular variables and postinjury cerebral edema (increases in tissue water content), and on cognitive deficits and neurological motor function following brain injury. Treatment with (S)-emopamil significantly reduced focal brain edema at 48 hours after brain injury. Profound memory dysfunction induced by brain injury was significantly attenuated following (S)-emopamil treatment. In addition, (S)-emopamil also attenuated the deficits in motor function that were observed over a 2-week period following brain injury. These results suggest that changes in calcium homeostasis may play an important role in the pathogenesis of trauma to the central nervous system and that the calcium channel blocker (S)-emopamil might be a useful compound for the treatment of traumatic brain injury.

Animals↗

PubMed1992

The early detection of nonpalpable breast carcinoma with needle localization. Experience with 500 patients in a community hospital.

During a 5-year interval, 500 women underwent 530 needle localizations (NL) for nonpalpable, mammographically suspicious breast lesions. These lesions were localized using the Homer Mammalok Breast Needle/Wire Localizer (Namic; Glens Falls, NY). Almost one half the NL (260/530) were performed for suspicious calcifications; 19 per cent (49/260) proved to be cancerous. Cancer (CA) was identified 90 times in 88 patients (17%); 64 per cent (58/90) were invasive and 36 per cent (32/90) were noninvasive carcinomas. Eighty per cent of the lesions were 1 cm or smaller. Eighty-four axillary dissections were done and only 7 patients (8%) had axillary metastasis. During the same time interval, 277 women underwent axillary dissection, with or without mastectomy, for palpable breast cancer. Ninety-one per cent (252/277) had invasive carcinomas and 38 per cent (104/277) had axillary metastasis. Estrogen receptor assays (ERA) and progesterone receptor assays (PRA) were similar for both patient populations. The authors conclude that NL is an effective, safe method of detecting highly curable, occult breast cancer. It can be done effectively at a community hospital with results very similar to large university studies.

Adult↗

PubMed1992

Selective vulnerability of dentate hilar neurons following traumatic brain injury: a potential mechanistic link between head trauma and disorders of the hippocampus.

Despite intensive study, the neurobiological basis of epilepsy and persistent memory impairment following traumatic head injury remains unknown. Since abnormalities of the hippocampus are known to be associated with temporal lobe seizures and memory dysfunction, we investigated the effects of experimental traumatic brain injury on hippocampal structure and function in the rat. Using a model of fluid-percussion injury, we have discovered that neurons of the dentate hilus are vulnerable to a brief, unilateral impact to the extradural surface of the brain. One week after trauma, there was a dramatic reduction in hilar neurons ipsilateral to the impact, and a milder but significant decrease in neurons on the contralateral side as well. This neuronal loss was highly selective since adjacent dentate granule and pyramidal neurons appeared relatively unaffected. Immunocytochemistry showed that the hilar cell loss included a loss of somatostatin-immunoreactive neurons, and degeneration stains provided evidence that irreversible hilar injury occurred within 4 hr of impact. To assess the functional effects of the hilar damage, dentate granule cell field potentials were measured in response to perforant path stimulation. This revealed abnormal dentate granule cell hyperexcitability at 2.0 Hz stimulation in many of the injured animals. The presence of abnormal hyperexcitability correlated with the loss of hilar neurons. Thus, a momentary impact to the surface of the brain can cause selective, bilateral hippocampal injury with associated abnormalities in dentate gyrus physiology. Furthermore, the pattern of cell loss is similar to that observed in some patients with temporal lobe epilepsy.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Ethical issues in the care of cancer patients.

Nearly all the topics considered by medical ethics generally present themselves to those caring for cancer patients. Although most attention may be given to questions of resource allocation and limiting treatment, other issues are of equal importance. Providing respect and compassion for patients may be even more important. The day-to-day treatment of the patient that recognizes the practical autonomy of the patient and legitimizes the patient's involvement in deciding about his or her own care may do more to preserve the integrity of the patient as a person than anything else that happens to someone who accepts the cancer diagnosis. The physician who can accept the patient's judgment and participation and who can help the patient find positive meaning in what can be a personally and socially devastating disease experience has enacted a highly laudatory ethical standard of patient care.

Beneficence↗

PubMed1991

Protection against endotoxic shock by a tumor necrosis factor receptor immunoadhesin.

Tumor necrosis factors (TNF) alpha and beta are structurally related cytokines that mediate a wide range of immunological, inflammatory, and cytotoxic effects. During bacterial infection of the bloodstream (sepsis), TNF-alpha induction by bacterial endotoxin is thought to be a major factor contributing to the cardiovascular collapse and critical organ failure that can develop. Despite antibiotic therapy, these consequences of sepsis continue to have a high mortality rate in humans. Here we describe a potent TNF antagonist, a TNF receptor (TNFR) immunoadhesin, constructed by gene fusion of the extracellular portion of human type 1 TNFR with the constant domains of human IgG heavy chain (TNFR-IgG). When expressed in transfected human cells, TNFR-IgG is secreted as a disulfide-bonded homodimer. Purified TNFR-IgG binds to both TNF-alpha and TNF-beta and exhibits 6- to 8-fold higher affinity for TNF-alpha than cell surface or soluble TNF receptors. In vitro, TNFR-IgG blocks completely the cytolytic effect of TNF-alpha or TNF-beta on actinomycin D-treated cells and is markedly more efficient than soluble TNFR (24-fold) or monoclonal anti-TNF-alpha antibodies (4-fold) in inhibiting TNF-alpha. In vitro, TNFR-IgG prevents endotoxin-induced lethality in mice when given 0.5 hr prior to endotoxin and provides significant protection when given up to 1 hr after endotoxin challenge. These results confirm the importance of TNF-alpha in the pathogenesis of septic shock and suggest a clinical potential for TNFR-IgG as a preventive and therapeutic treatment in sepsis.

Animals↗

PubMed1991

Serum immunoerythropoietin levels in patients with cancer receiving cisplatin-based chemotherapy.

Serum immunoerythropoietin (SIE) levels were studied of 25 randomly chosen cancer patients undergoing cisplatin-based chemotherapy and ten head and neck cancer patients who were studied prospectively before and during cisplatin-based therapy. The SIE levels were determined by standard radioimmunoassay, and the results were interpreted relative to erythropoietin levels and hematocrits of 17 aplastic or nutritionally anemic patients who were believed to have a normal erythropoietin response. Of the 25 randomly chosen patients, SIE levels were inappropriately low in four patients. In this population, there was a greater likelihood of erythropoietin deficiency in the patients with a hematocrit less than 30% compared with those with higher values (P less than 0.001), although there was no correlation between SIE level and the amount of cisplatin these patients received or their degree of renal impairment. Of the ten head and neck cancer patients, five were found to have inappropriately low SIE levels before therapy, and two additional patients had a decrease of SIE levels during therapy, in one patient to an abnormally low level. The anemia associated with malignancy was concluded to be in part associated with a relative erythropoietin deficiency, and in certain individuals, cisplatin therapy may contribute to that deficiency.

Adult↗

PubMed1991

Resistance of primary isolates of human immunodeficiency virus type 1 to soluble CD4 is independent of CD4-rgp120 binding affinity.

The infection of human cells by laboratory strains of human immunodeficiency virus type 1 (HIV-1) can be blocked readily in vitro by recombinant soluble CD4 and CD4-immunoglobulin hybrid molecules. In contrast, infection by primary isolates of HIV-1 is much less sensitive to blocking in vitro by soluble CD4-based molecules. To investigate the molecular basis for this difference between HIV-1 strains, we isolated the gp120-encoding genes from several CD4-resistant and CD4-sensitive HIV-1 strains and characterized the CD4-binding properties of their recombinant gp120 (rgp120) products. Extensive amino acid sequence variation was found between the gp120 genes of CD4-resistant and CD4-sensitive HIV-1 isolates. However, the CD4-binding affinities of rgp120 from strains with markedly different CD4 sensitivities were essentially the same, and only small differences were observed in the kinetics of CD4 binding. These results suggest that the lower sensitivity of primary HIV-1 isolates to neutralization by CD4-based molecules is not due to lower binding affinity between soluble CD4 and free gp120.

Amino Acid Sequence↗

PubMed1991

Cardiovascular and metabolic characteristics of hypertension.

Hypertension is now seen as a broader condition than high blood pressure alone. Large-scale epidemiologic studies have established that high blood pressure is associated with an increased risk of cardiovascular events, but clinical trials of antihypertensive therapy have shown an inconsistent reduction in major cardiovascular endpoints. Importantly, the incidence of coronary disease has been reduced to only a small extent, suggesting that factors beyond high blood pressure are important in the genesis of atherosclerotic disease in hypertensive patients. It is evident, for example, that patients with hypertension have an exaggerated vulnerability to the consequences of lipid abnormalities. Moreover, it has recently been established that hypertension is characterized by insulin resistance and altered glucose tolerance. As a result, high plasma concentrations of insulin produce proliferative effects on vascular smooth muscle and connective tissue, and they may adversely affect the lipid profile. The left ventricle is also involved in hypertension--independent of blood pressure. There is growing evidence that there are increases in the muscle mass of the left ventricle and changes in its diastolic filling characteristics at the very early stages of hypertension. The arterial circulation is similarly involved, for alterations in structure or function, reflected by diminished arterial compliance, can be demonstrated prior to the appearance of clinical hypertension. Treatment designed to protect hypertensive patients from cardiovascular events must not only be based on blood pressure, but must take into account all the components of the hypertension syndrome.

Blood Glucose↗

PubMed1991

Left ventricular diastolic filling alterations in normotensive young adults with a family history of systemic hypertension.

To characterize the cardiovascular consequences of a history of hypertension in first-degree relatives in normotensive young adults, 72 normotensive (diastolic blood pressure [BP] less than 90 mm Hg) healthy volunteers (age 18 to 30 years) were studied with 2 dimensionally guided M-mode echocardiography, pulsed Doppler echocardiography, and 2-hour automated BP monitoring. Of the 72 subjects, 19 (12 men and 7 women) had a family history of hypertension and were compared with 19 subjects without a family history of hypertension who were matched for systolic BP and gender. There were no detectable differences in 2-hour average BP, left ventricular (LV) mass or wall thickness, or echocardiographic systolic functional indexes between subjects with and without a family history of hypertension. Doppler-derived diastolic functional indexes demonstrated more prominent late diastolic filling in subjects with a family history of hypertension. Late diastolic transmitral flow time and flow velocity integral were greater (132 +/- 24 vs 117 +/- 17 ms, p less than 0.05; and 2.5 +/- 0.7 vs 1.9 +/- 0.5 cm, p less than 0.01, respectively). To measure possible gender-related effects of a family history of hypertension, the men and women were analyzed separately. The 12 men with a family history of hypertension had greater peak late (40 +/- 0.9 vs 31 +/- 0.8 cm/s, p less than 0.02) and ratio of late-to-early (0.64 +/- 0.19 vs 0.46 +/- 0.10, p less than 0.01) transmitral flow velocities and greater late transmitral flow velocity integrals (2.6 +/- 0.8 vs 1.9 +/- 0.5 cm, p less than 0.05) than the matched male control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1991

Identification and comparison of CD34-positive cells and their subpopulations from normal peripheral blood and bone marrow using multicolor flow cytometry.

Four-color flow cytometry was used with a cocktail of antibodies to identify and isolate CD34+ hematopoietic progenitors from normal human peripheral blood (PB) and bone marrow (BM). Mature cells that did not contain colony forming cells were resolved from immature cells using antibodies for T lymphocytes (CD3), B lymphocytes (CD20), monocytes (CD14), and granulocytes (CD11b). Immature cells were subdivided based on the expression of antigens found on hematopoietic progenitors (CD34, HLA-DR, CD33, CD19, CD45, CD71, CD10, and CD7). CD34+ cells were present in the circulation in about one-tenth the concentration of BM (0.2% v 1.8%) and had a different spectrum of antigen expression. A higher proportion of PB-CD34+ cells expressed the CD33 myeloid antigen (84% v 43%) and expressed higher levels of the pan leukocyte antigen CD45 than BM-CD34+ cells. Only a small fraction of PB-CD34+ cells expressed CD71 (transferrin receptors) (17%) while 94% of BM-CD34+ expressed CD71+. The proportion of PB-CD34+ cells expressing the B-cell antigens CD19 (10%) and CD10 (3%) was not significantly different from BM-CD34+ cells (14% and 17%, respectively). Few CD34+ cells in BM (2.7%) or PB (7%) expressed the T-cell antigen CD7. CD34+ cells were found to be predominantly HLA-DR+, with a wide range of intensity. These studies show that CD34+ cells and their subsets can be identified in normal PB and that the relative frequency of these cells and their subpopulations differs in PB versus BM.

Adult↗

PubMed1991

A comparative study of atenolol, nifedipine and their combination in the treatment of hypertension.

The antihypertensive effects, as assessed by clinical and ambulatory blood pressure measurement, of nifedipine slow-release (SR), atenolol and the two in combination were evaluated in 28 known hypertensives in a placebo-controlled, double-blind, randomised cross-over trial. Clinical blood pressure was significantly lower on combination therapy (P less than 0.025) than on either agent alone, although all therapeutic agents reduced blood pressure significantly when compared with placebo (P less than 0.01). All ambulatory blood pressure measurements obtained on any therapeutic agent were significantly lower than those obtained on placebo (P less than 0.01). The mean daytime (08h00-17h00) ambulatory blood pressure measurement as well as the percentage of this monitoring period during which patients were hypertensive were significantly lower (P less than 0.01) on combination therapy than on nifedipine SR. A similar pattern was observed for 24-hour ambulatory blood pressure measurements. Headache was the most significant adverse effect. This was most common with nifedipine SR, less common with combination therapy and least common with atenolol. Combination therapy with nifedipine SR and atenolol is therefore a viable therapeutic alternative in the treatment of patients with benign essential hypertension.

Adult↗

PubMed1991

Response of 7- to 15-month-old infants to sequential immunization with Haemophilus influenzae type b-CRM197 conjugate and polysaccharide vaccines.

OBJECTIVE: To evaluate the immunologic potential of infants 7 to 15 months of age to respond to Haemophilus influenzae type b polysaccharide vaccine following immunization with H influenzae b oligosaccharide-CRM197 conjugate vaccine. STUDY DESIGN: One hundred seventy-one infants, aged 7 to 15 months, were consecutively and alternatively assigned to one of three immunization protocols. Group 1 (n = 71) received three doses of H influenzae b oligosaccharide-CRM197 conjugate vaccine, group 2 (n = 47) received two doses of H influenzae b oligosaccharide-CRM197 conjugate vaccine followed by one dose of H influenzae type b polysaccharide vaccine, and group 3 received one dose of H influenzae b oligosaccharide-CRM197 conjugate vaccine followed by two doses of H influenzae type b polysaccharide vaccine. Immunizations were given on day 0 and at 2 months and 6 months. Anti-H influenzae type b polysaccharide antibody levels were measured on day 0 and 2, 3, 6, 7, and 12 months after the study began. RESULTS: Haemophilus influenzae type b polysaccharide vaccine given as a second dose stimulated an antibody rise but did so less effectively than H influenzae b oligosaccharide-CRM197 conjugate vaccine. Two doses of H influenzae b oligosaccharide-CRM197 conjugate vaccine were highly immunogenic; geometric means were 31 and 35 micrograms/mL in the 7- to 11-month and 12- to 15-month age groups, respectively. Following two doses of H influenzae b oligosaccharide-CRM197 conjugate vaccine, both immunization protocols resulted in (1) equally high geometric mean antibody levels 1 month after immunization and (2) similar geometric mean antibody levels 6 months after immunization. CONCLUSIONS: Haemophilus influenzae b oligosaccharide-CRM197 conjugate vaccine induces antibody levels that would be expected to protect infants from initial invasion and primes the immune system for an anamnestic response. Our data indicate that if a booster immunization is needed, H influenzae type b polysaccharide vaccine could be an alternative to H influenzae b oligosaccharide-CRM197 conjugate vaccine.

Antibodies, Bacterial↗

PubMed1991

Effects of angiotensin II on pressor responses to norepinephrine in humans.

In previous studies in the conscious rabbit and in isolated artery preparations, low doses of angiotensin II synergistically amplified the pressor effects of the sympathetic neurotransmitter, norepinephrine (NE). To determine whether these observations could be replicated in humans, 9 normal adult male volunteers (mean age: 34) each were given 3 i.v. doses of NE (25, 50 and 100 micrograms.kg-1.min-1) during consecutive 10 min infusion periods. On a second study day, the procedure was repeated during infusion of angiotensin II in a subpressor dose (1.25 ng.kg-1.min-1). The angiotensin II didn't alter the BP responses to NE, but it attenuated the heart rate (HR) decreases associated with the NE infusions by 80% (P less than 0.05), 42% (P less than 0.05) and 42% (P less than 0.1). The two study days were then repeated following 2 weeks of oral treatment with the angiotensin converting enzyme inhibitor captopril (which, despite significantly decreasing baseline BP, also tended to decrease HR). In the presence of captopril, the pressor responses to the NE challenges were reduced by 50% (P less than 0.05), 33% (P less than 0.05) and 13% (P less than 0.1) compared with the pre-captopril responses. Thus, angiotensin II in subpressor doses appears to enhance NE pressor effects by attenuating the compensatory HR responses, whereas inhibition of endogenous angiotensin II mechanisms weakens the BP-raising actions of NE. These findings in humans are consistent with earlier observations that the renin-angiotensin system can directly amplify sympathetic pressor effects in two separate ways: by modifying baroreceptor sensitivity and by enhancing the actions of norepinephrine on vascular smooth muscle.

Administration, Oral↗

PubMed1991

Exogenous progesterone and embryo survival in Booroola-cross ewes.

To investigate if exogenous progesterone improves embryo survival, 209 multiparous Booroola Merino x South Australian Merino ewes, heterozygous for the F gene (F+) were allocated to seven treatment groups and inseminated at a synchronized oestrus. Six groups received progesterone from controlled internal drug release G dispensers on the following days after ovulation: 4-7, 4-11, 4-14, 7-11, 7-14 and 11-14. Concentration of peripheral progesterone increased (P less than 0.05) in most supplemented groups, but there were no significant differences in pregnancy rates between treatments. However, the number of fetuses per pregnancy was increased for progesterone treatments starting on Day 4 (Days 4-7, 4-11 and 4-14 combined v. control; P less than 0.05) and for all supplemented treatments compared with the control (P less than 0.05).

Animals↗