Biomedical subjects

P Zimmermann

Publications and source records attributed to P Zimmermann.

At least 37 records · Page 2Linked to original sources

PubMed2000

The impact of diets with different magnesium contents on magnesium and calcium in serum and tissues of the rat.

The impact of three different magnesium diets (70, 1,000 and 9,000 ppm) on total, ionized and bound magnesium as well as ionized calcium in serum and total calcium and magnesium in femoral bone, skeletal muscle, heart and liver of male Sprague-Dawley rats was investigated. The percentage of ionized serum magnesium was unproportionally high in rats fed a low magnesium (70 ppm) diet. Femoral magnesium was correlated with ionized and total serum magnesium. In contrast, there was generally no correlation between total serum magnesium and the magnesium fractions in skeletal muscle, heart and liver. In rats fed the magnesium deficient diet, total cardiac concentration of magnesium was even significantly increased along with total calcium content, while there were no effects on total muscle and liver magnesium. Within the single groups, ionized serum calcium was never proportional to dietary magnesium, but in all three magnesium diet groups together, it was inversely correlated with dietary magnesium. Moreover, ionized serum calcium was inversely correlated with both ionized and total serum magnesium. In all 3 groups together, the concentrations of total calcium and magnesium in heart and skeletal muscle were correlated, within the single groups correlation existed only in the 1000 ppm group. Magnesium influx via calcium channels during low magnesium intake has been seen in non cardiac tissues [35,36], but nothing similar is known about non selective channels for divalent cations in the heart [33]. Thus, magnesium uptake by cardiac cells along with calcium seems to be possible, especially at low intracellular magnesium concentrations, but is still poorly investigated. We suggest that the calcium-antagonistic effect of magnesium is related to the turnover rate of magnesium rather than to its tissue concentrations.

Animals↗

PubMed2000

Bilayer properties of totally synthetic C16:0-lactosyl-ceramide.

Differential scanning calorimetry (DSC) and x-ray diffraction have been used to study the structural and thermal properties of totally synthetic D-erythro-N-palmitoyl-lactosyl-C(18)-sphingosine (C16:0-LacCer). Over the temperature range 0-90 degrees C, fully hydrated C16:0-LacCer shows complex thermal transitions characteristic of polymorphic behavior of exclusively bilayer phases. On heating at 5 degrees C/min, hydrated C16:0-LacCer undergoes a complex two-peak endothermic transition with maxima at 69 degrees C and 74 degrees C and a total enthalpy of 14.6 kcal/mol C16:0-LacCer. At a slower heating rate (1.5 degrees C/min), two endothermic transitions are observed at 66 degrees C and 78 degrees C. After cooling to 0 degrees C, the subsequent heating run shows three overlapping endothermic transitions at 66 degrees C, 69 degrees C, and 71.5 degrees C, followed by a chain-melting endothermic transition at 78 degrees C. Two thermal protocols were used to completely convert C16:0-LacCer to its stable, high melting temperature (78 degrees C) form. As revealed by x-ray diffraction, over the temperature range 20-78 degrees C this stable phase exhibits a bilayer structure, periodicity d approximately 65 A with an ordered chain packing mode. At the phase transition (78 degrees C) chain melting occurs, and C16:0-LacCer converts to a liquid crystalline bilayer (L(alpha)) phase of reduced periodicity d approximately 59 A. On cooling from the L(alpha) phase, C16:0-LacCer converts to metastable bilayer phases undergoing transitions at 66-72 degrees C. These studies allow comparisons to be made with the behavior of the corresponding C16:0-Cer (. J. Lipid Res. 36:1936-1944) and C16:0-GluCer and C16:0-GalCer (. J. Lipid Res. 40:839-849). Our systematic studies are aimed at understanding the role of oligosaccharide complexity in regulating glycosphingolipid structure and properties.

Antigens, CD↗

PubMed2000

Patterns of attentional impairment following closed head injury: a collaborative European study.

A comprehensive assessment of both selective (focused attention, divided attention) and intensive (alertness and vigilance) attentional processes was performed on 106 patients with closed head injury using a computerised battery for the evaluation of attention. All patients were tested at least five months after their accident. A high percentage of patients were pathological in tests mapping the selective components of attention while only a minority were impaired on tests mapping the intensive components of attention. Three different subgroups of patients with consistent performance patterns were evidenced. The psychometric characteristics of the battery and its possible clinical usefulness are discussed.

Adult↗

PubMed1999

Two modes of sulfite oxidation in the extremely thermophilic and acidophilic archaeon acidianus ambivalens

Sulfite-oxidizing enzyme activities were analyzed in cell-free extracts of aerobically grown cells of Acidianus ambivalens, an extremely thermophilic and chemolithoautotrophic archaeon. In the membrane and cytoplasmic fractions, two distinct enzyme activities were found. In the membrane fraction, a sulfite:acceptor oxidoreductase activity was found [530 mU (mg protein)(-1); apparent K(m) for sulfite, 3.6 mM]. In the cytoplasmic fraction the following enzyme activities were found and are indicative of an oxidative adenylylsulfate pathway: adenylylsulfate reductase [138 mU (mg protein)(-1)], adenylylsulfate:phosphate adenyltransferase ["ADP sulfurylase"; 86 mU (mg protein)(-1)], adenylate kinase [650 mU (mg protein)(-1)], and rhodanese [thiosulfate sulfur transferase, 9.2 mU (mg protein)(-1)]. In addition, 5',5"'-P(1),P(4)-di(adenosine-5') tetraphosphate (Ap(4)A) synthase and Ap(4)A pyrophosphohydrolase activities were detected.

Journal Article↗

PubMed1999

Differential sensitivity of the caudal and rostral nucleus accumbens to the rewarding effects of a H1-histaminergic receptor blocker as measured with place-preference and self-stimulation behavior.

A recent series of studies in rats has demonstrated positively reinforcing and memory enhancing effects following lesions of the nucleus tuberomammillaris, which is the only known source of neuronal histamine. The aim of the present experiments was to assess whether inhibition of histaminergic neurotransmission in the ventral striatum has positively reinforcing effects. In Experiment 1 rats with chronically-implanted cannulae were injected with the H1 receptor blocker d-( + )-chlorpheniramine at doses of 0.1, 1.0 and 10.0 microg into the rostral or caudal parts of the nucleus accumbens, a brain region known to be involved in reward-related processes. Immediately after the treatment the animals were placed into one of four restricted quadrants of a circular open field (closed corral) for a single conditioning trial. During the drug-free test for conditioned place preference, when a choice among the four quadrants was provided, those rats injected with 10.0 microg chlorpheniramine in the caudal nucleus accumbens spent more time in the treatment corral, indicative of a positively rewarding drug action. In Experiment 2 the question was posed whether injection of chlorpheniramine into the nucleus accumbens influences electrical self-stimulation of the lateral hypothalamus. For this purpose rats were chronically implanted with two bipolar electrodes aimed at the lateral-hypothalami and with two additional guide cannulae aimed either at the rostral or caudal nucleus accumbens. After having established reliable self-stimulation behavior at one of the two electrode sites the animals were allowed to self-stimulate for one hour (baseline). Then they were unilaterally injected with 10.0 microg chlorpheniramine or vehicle and allowed to self-stimulate for another hour (test). On the next day the same procedure took place, except for the difference that the animals received an injection aimed at the hemisphere not treated so far. Animals treated with chlorpheniramine in the caudal and in the rostral nucleus accumbens displayed higher rates of ipsihemispheric self-stimulation behavior. Moreover, the animals treated with the H1 receptor blocker in the caudal nucleus accumbens displayed higher rates of ipsihemispheric self-stimulation than those having received an injection in the rostral pole. Upon completion of this part of the experiment all animals received an additional intraperitoneal treatment with chlorpheniramine (20 mg/kg) or vehicle, respectively, and were tested in the same way described above. This treatment also resulted in an amplification of intracranial self-stimulation behavior. These results support the hypothesis that histaminergic neurotransmission is involved in the inhibitory control of a central system subserving reward-related processes. The present data also further highlight the nucleus accumbens as functionally heterogenous along its rostrocaudal axis, with the caudal-shell subregion being more sensitive to antihistaminic induced reward than the rostral entity.

Animals↗

PubMed1999

Left ventricular assist system support is associated with persistent inflammation and temporary immunosuppression.

BACKGROUND: In patients undergoing left-ventricular assist system support, it has not been elucidated to which extent mechanical circulatory support itself as opposed to the underlying condition of endstage heart-failure contributes to perturbation of immune homeostasis. METHODS: In eleven heart transplant candidates who had to undergo Novacor left-ventricular assist device bridging, we prospectively sampled interleukin-6, T-cell and monocyte subsets and compared them to fifteen UNOS status II patients awaiting cardiac transplantation on medical heart failure treatment as outpatients at the time of LVAS implantation/listing decision as well as 2.0+/-1.2 months and 4.5+/-2.3 months later. In order to assess deviations in both groups from normal values, thirty-two healthy subjects served as reference group. RESULTS: Patients undergoing Novacor bridging had higher C-reactive protein, leukocyte, neutrophil, and monocyte levels at all three times, and exhibited lower CD3 +, CD4+, CD3+/CD45 RO T-cell and natural killer cell counts than medically treated patients awaiting transplantation 2 months after the LVAS implantation/listing decision. In comparison to controls, both groups had higher levels of inflammatory activation and lower levels of immunocompetence at all three times. CONCLUSIONS: While both groups of endstage heart failure patients show immunological alterations compared to controls, patients who have to be bridged by the Novacor LVAS exhibit a more pronounced activation of inflammatory markers. This may be due to more advanced heart failure but the device itself also may contribute to more pronounced inflammation and a temporary suppression of immunocompetent cells.

Adult↗

PubMed1999

Attachment representation and emotion regulation in adolescents: a psychobiological perspective on internal working models.

Attachment theory claims that inner working models of attachment substantially control behavioral and emotional regulation. There are different levels of organization of the attachment system following a developmental sequence from basic attachment behaviors at newborn age to a procedural organization in terms of behavioral strategies at the end of the first year to a representational organization later on. Also, the organismic systems underlying emotions and emotional regulation may occur and may be described on different organizational levels. Inner working models are seen as regulatory mechanisms for the interplay between the different organismic systems underlying emotions and emotional regulation. This paper will concentrate on biobehavioral organization. Combining assumptions of attachment theory with assumptions about biobehavioral function may provide the possibility of validating theoretically derived interpretations of the attachment system. Including the physiological processes in addition to the psychological processes enables us to test assumptions about the function of the inner working model with respect to processes that are not accessible by verbal communication and that are not expressed through overt behavior. The paper will provide theoretical and empirical evidence for the contribution of the inner working model of attachment to emotional perception, emotional expression and the coherence of inter-modal organization. The empirical findings suggest that from a developmental perspective the inclusion of different levels of regulation may provide possibilities of studying continuity and stability of individual differences of the attachment system during the life-course both within and across levels.

Adaptation, Psychological↗

PubMed1999

Structure and functions of internal working models of attachment and their role for emotion regulation.

The concept of organization in the service of adaptation has been applied to attachment theory (Sroufe & Waters, 1977) as well as to a variety of life sciences (Ryan, Kuhi & Deci, 1997). Internal working models (IWMs) are postulated as providing organizing structure to the attachment behavior system controlling attachment behaviors toward caregivers and, with increasing age, autonomous individual adaptation. While many theoretical specifications have been suggested on that topic (e.g. Bretherton, 1987, 1990; Bretherton & Munholland, 1999; Main, Kaplan & Cassidy, 1985; Sroufe & Fleeson, 1986), empirical studies focusing directly on the structure or functions of internal working models are rare. Knowledge about the structure and functioning of IWMs could add to the understanding of the developmental influences of the attachment organization across the life-span. In this paper two topics will be addressed shortly and related to an empirical investigation concerning the relationship between attachment representations during late adolescence and emotion regulation patterns: (1) structure and functions of IWMs in terms of information-processing and emotion and behavior regulation; and (2) the transfer from IWMs of self-with-attachment figures to adaptive personality structures based on autonomous self-regulation.

Adaptation, Psychological↗

PubMed1999

The syndecans, tuners of transmembrane signaling.

Syndecans, a family of transmembrane proteoglycans, are putative integrators of extracellular signals. The interaction of syndecans with extracellular ligands via particular motifs in their heparan sulfate chains, their clustering, association with particular cytoskeletal structures, binding to cytoplasmic effectors, and intracellular phosphorylation represent as many means to bring this role to a successful conclusion. In this review, we will briefly address the characteristics of syndecans as heparan sulfate proteoglycans (HSPGs) and focus mainly on the properties, binding interactions, and potential signaling functions of the cytoplasmic domains of these molecules.

Amino Acid Sequence↗

PubMed1999

Alexithymia and attachment representation in idiopathic spasmodic torticollis.

We investigated alexithymia and the mental representation of attachment in idiopathic spasmodic torticollis (IST). It was hypothesized a) that alexithymia in IST is more prevalent than in a nonclinical control group and b) that significant correlations emerge between alexithymia and a dismissing attachment representation. Twenty patients with IST and 20 healthy controls matched for age and sex were administered the Toronto Alexithymia Scale (TAS-20) and the Adult Attachment Interview (AAI). Attachment was classified using the Attachment Interview Q-sort. IST patients scored significantly higher on the measure of alexithymia than subjects in the comparison group. In IST a dismissing attachment representation was significantly more frequent than in the control group. Across the total sample, externally oriented thinking correlated positively with dismissing attachment, and both externally oriented thinking and difficulty communicating feelings (two of the three subscales of the TAS-20) correlated inversely with secure attachment. Alexithymia is more prevalent in IST than in normals. As was hypothesized, alexithymia in adults is significantly interrelated with the mental representation of attachment.

Adult↗

PubMed1999

Structure and properties of totally synthetic galacto- and gluco-cerebrosides.

The structural and thermal properties of aqueous dispersions of the totally synthetic cerebrosides, D-erythro-N-palmitoyl galactosyl- and glucosyl-C18-sphingosine (C16:0-GalCer and C16:0-GluCer, respectively) have been studied using differential scanning calorimetry (DSC) and X-ray diffraction. Over the temperature range 0-100 degrees C, both C16:0-GalCer and C16:0-GluCer show complex thermal transitions characteristic of polymorphic behavior of exclusively bilayer phases. On heating, hydrated C16:0-GalCer undergoes an exothermic bilayer-bilayer transition at 59 degrees C to produce a stable bilayer crystal form. X-ray diffraction at 70 degrees C reveals a bilayer structure with an ordered hydrocarbon chain-packing arrangement. This ordered bilayer phase undergoes an endothermic chain-melting transition at 85 degrees C to the bilayer liquid crystalline state. Similar behavior is exhibited by hydrated C16:0-GluCer which undergoes the exothermic transition at 49 degrees C and a chain-melting transition at 87 degrees C. The exothermic transitions observed on heating hydrated C16:0-GalCer and C16:0-GluCer are irreversible and dependent upon previous chain melting, prior cooling rate, and time of incubation at low temperatures. Thus, the structure and properties of totally synthetic C16:0-GalCer and C16:0-GluCer with identical sphingosine (C18:1) and fatty acid (C16:0) chains are quite similar, suggesting that the precise isomeric structure of the linked sugar plays only a minor role in regulating the properties of hydrated cerebrosides. Further, these studies indicate that the complex thermal behavior and bilayer phase formation exhibited by these single-sugar cerebrosides are intrinsic properties and not due to the heterogeneity of the sphingosine base found in natural and partially synthetic cerebrosides.

Calorimetry, Differential Scanning↗

PubMed1998

Doppler assessment of the maternal interlobar renal and uterine arteries in mid-pregnancy in women at low and high risk for pregnancy-induced hypertension.

PURPOSE: The purpose of this study was to examine the relationship between vascular resistance of the maternal intrarenal arteries and the main uterine arteries in pregnant women at low and high risk for pregnancy-induced hypertension. METHODS: The resistance indices (RIs) in the main uterine arteries and the interlobar branches of the right renal artery were measured by duplex Doppler sonography in 338 pregnant women at 21-24 weeks of gestation, including 175 women at high risk for pregnancy-induced hypertension. Of those, 54 patients had repeat Doppler measurements during pregnancy. RESULTS: Cross-sectional data showed no correlation between the RIs in the right interlobar renal arteries and either uterine artery. Furthermore, no relationship existed between persistent diastolic notching in the uterine arteries and the RI in the renal circulation. The mean renal artery RI was 0.62. Compared to that in patients with a normal outcome, the renal artery RI was not significantly different in patients who developed proteinuric pregnancy-induced hypertension (PPIH) or severe pregnancy-induced hypertension (PIH) later during pregnancy. Multiple analysis of variance for longitudinal data showed no correlation between the RI in the maternal renal arteries and gestational age, severe PIH, or PPIH. CONCLUSIONS: The RIs in the maternal intrarenal arteries and the main uterine arteries are not related to each other in pregnant women, even in patients with abnormal uterine artery Doppler findings, severe PIH, or PPIH.

Arteries↗

PubMed1998

Changes in pulmonary mechanics after fiberoptic bronchoalveolar lavage in mechanically ventilated patients.

OBJECTIVE: We prospectively assessed the impact of bronchoalveolar lavage (BAL) on respiratory mechanics in critically ill, mechanically ventilated patients. STUDY DESIGN: Mechanically ventilated patients underwent BAL of one lung segment using 5 x 20 ml of sterile, physiologic saline with a temperature of 25-28 degrees C. The fractional inspired oxygen was increased to 1.0, but ventilator settings were otherwise left unchanged. Static pulmonary compliance, pulmonary resistance, alveolar ventilation, and serial dead space were measured 60 min and 2 min before and 8, 60, and 180 min after BAL to assess the consequences of the procedure. In addition, blood gases [partial pressure of carbon dioxide in arterial blood (PaCO2) and arterial oxygen tension (PaO2)], hemodynamic variables (heart rate, systolic and diastolic blood pressure), and body temperature were recorded at the same time points. SETTING: Intensive care unit of a university hospital. PATIENTS: 18 consecutive critically ill, mechanically ventilated patients. RESULTS: Pulmonary compliance decreased by 23% (p < 0.05) and pulmonary resistance increased by 22% (p < 0.05) shortly after BAL. The changes in pulmonary compliance and resistance were more than 30% in one third of the patient population. One hour after the procedure, PaO2 was significantly lower and PaCO2 significantly higher than before the procedure. Three hours after the procedure, pulmonary resistance returned to pre-BAL values but compliance remained 10% below baseline values (p < 0.05). CONCLUSION: BAL in mechanically ventilated patients is associated with deterioration of pulmonary mechanics and function.

Adult↗

PubMed1997

Monoaryl- and bisaryldihydroxytropolones as potent inhibitors of inositol monophosphatase.

The first successful preparation of mono- and disubstituted 3,7-dihydroxytropolone involves a four-step synthetic scheme. Thus, bromination of 3,7-dihydroxytropolone (8) followed by permethylation of the resultant products furnished gram quantities of intermediates 13-18. Single or double Suzuki coupling reactions between these permethylated monobromo- and dibromodihydroxytropolone derivatives and a variety of boronic acids delivered the expected products whose deprotection yielded the desired compounds 1a-u and 26a-n, usually in fair to good yields. Tropolones 1 and 26 were found to be potent inhibitors of inositol monophosphatase with IC50 values in the low-micromolar range. The results are discussed in the context of the recently described novel mode of inhibition of the enzyme by 3,7-dihydroxytropolones.

Binding Sites↗

PubMed1997

Syntenin, a PDZ protein that binds syndecan cytoplasmic domains.

The syndecans are transmembrane proteoglycans that place structurally heterogeneous heparan sulfate chains at the cell surface and a highly conserved polypeptide in the cytoplasm. Their versatile heparan sulfate moieties support various processes of molecular recognition, signaling, and trafficking. Here we report the identification of a protein that binds to the cytoplasmic domains of the syndecans in yeast two-hybrid screens, surface plasmon resonance experiments, and ligand-overlay assays. This protein, syntenin, contains a tandem repeat of PDZ domains that reacts with the FYA C-terminal amino acid sequence of the syndecans. Recombinant enhanced green fluorescent protein (eGFP)-syntenin fusion proteins decorate the plasmamembrane and intracellular vesicles, where they colocalize and cosegregate with syndecans. Cells that overexpress eGFP-syntenin show numerous cell surface extensions, suggesting effects of syntenin on cytoskeleton-membrane organization. We propose that syntenin may function as an adaptor that couples syndecans to cytoskeletal proteins or cytosolic downstream signal-effectors.

Amino Acid Sequence↗

PubMed1997

Doppler assessment of the uterine and uteroplacental circulation in the second trimester in pregnancies at high risk for pre-eclampsia and/or intrauterine growth retardation: comparison and correlation between different Doppler parameters.

During a 20-month period we studied 175 pregnant women at high risk for hypertensive disorders of pregnancy or intrauterine growth retardation, and 172 patients at low risk, in a prospectively designed cross-sectional trial. Using duplex pulsed wave Doppler ultrasound, we recorded blood velocity waveforms from both main uterine arteries, the uteroplacental arteries in the region of placental implantation and the umbilical artery at 21-24 weeks of gestation. Persistent notches in the main stem uterine arteries and elevated resistance indices of > 0.68 in the uterine arteries and > 0.38 in the uteroplacental arteries were defined as abnormal waveforms. The incidence of proteinuric pregnancy-induced hypertension (PPIH) and intrauterine growth retardation (IUGR) were recorded as main outcome measures. Doppler proved to be more efficient at predicting a complicated pregnancy in those patients who were at high risk: a positive medical history alone was associated with a three-fold greater risk of developing PPIH and/or IUGR. In the high-risk group a single pathological Doppler sign accounted for an additional three- to four-fold increased risk, and the combination of all three pathological signs, a seven-fold additional risk for later disease. In this group PPIH and/or IUGR was found in 58.3%, compared to 8.3% if Doppler results were normal. The criterion for the definition of pathological Doppler results, whether persistent notching, the resistance index (RI) of the main stem uterine artery, or the RI in the arteries of the uteroplacental bed, was of minor importance, as all Doppler parameters were strongly correlated. However, the combination of all parameters was superior to a single parameter, and a bilateral notch was superior to a unilateral notch in terms of minimizing false-positive results. However, Doppler was less powerful in the population at low risk. Here PPIH and/or IUGR was seen in 6.1-6.4% in the group with abnormal Doppler findings compared to 5.2% in pregnancies with normal findings. None of the patients showed bilateral notching. In conclusion, pathological Doppler velocimetry of the uterine and uteroplacental circulation was a powerful predictor of PPIH and/or IUGR in high-risk pregnancies, identifying a group in which 58.3% would suffer from disease later in pregnancy. A combination of several Doppler parameters was superior to a single parameter, although the parameters were strongly correlated with each other.

Blood Flow Velocity↗

PubMed1997

[Risks and side effects of diagnostic bronchoalveolar lavage in ventilated patients].

Bronchoalveolar lavage is used increasingly often as a diagnostic tool in critically ill patients undergoing mechanical ventilation. Most patients, even those with haemodynamic instability or respiratory failure, tolerate the procedure without marked adverse effects. A relatively small proportion of patients, however, will experience potentially deleterious side effects like prolonged deterioration of pulmonary mechanics, oxygen desaturation or sepsis-like symptoms. Despite all precautions, it is not possible to date to identify increased-risk patients beforehand. The potential benefits, namely, early diagnosis of an aetiological agent who is responsible for infection, must therefore be carefully weighted against the risks.

Bronchoalveolar Lavage Fluid↗

PubMed1996

Interleukin-6 correlates with hemodynamic impairment during dobutamine administration in chronic heart failure.

Proinflammatory cytokines have been implicated in the pathophysiology of chronic heart failure. We determined mixed venous levels of interleukin-6 (IL6) in 18 heart transplant candidates before, 1, 4, and 24 h after initiation of dobutamine infusion (3 micrograms/kg/min) during hemodynamic evaluation. During the first 4 h of dobutamine, systemic vascular resistance decreased (1358 to 1024 dyn x s x cm-5, P = 0.01) while cardiac index (2.3 to 2.9 l/min/m2, P = 0.008) increased. Both returned to baseline after 24 h. IL6 was elevated at baseline compared to age-matched controls (1.5 (0/4.3) vs. 0 (0/0.5) P = 0.003). There was an increase in IL6 from 1.5 (0/4.3) to 3.6 (0.3/5.3) pg/ml after 24 h (P = 0.04). We found higher IL6 levels in the sicker half of patients as defined by pulmonary capillary wedge pressure > 24 mmHg (P = 0.005), mean pulmonary arterial pressure > or = 35 mmHg (P = 0.01), right atrial pressure > 13 mmHg (P = 0.02), and heart rate > or = 87/min (P = 0.02) as well as mean arterial pressure < 82 mmHg (P = 0.005). In conclusion, in this pilot study IL6 correlates with the severity of chronic heart failure during low dose dobutamine infusion.

Adult↗