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D Klingmüller

Publications and source records attributed to D Klingmüller.

At least 19 recordsLinked to original sources
PubMed2000

Hyperproliferative hepatocellular alterations after intraportal transplantation of thyroid follicles.

The thyroid hormone 3,5,3'-triiodo-L-thyronine (T3) is a strong direct hepatocyte mitogen in vivo. The effects of T3 resemble those of peroxisome proliferators, which are known to induce hepatocellular tumors in rats. With the aim of studying long-term local effects of thyroid hormones on liver parenchyma, small pieces of thyroid tissue were transplanted via the portal veins into the livers of thyroidectomized male Lewis rats. At 1 week, 3 weeks, 3 months, and 18 months after transplantation, the transplants were found to proliferate, to synthesize thyroglobulin, and to release thyroxine and T3. At 3 and 18 months after transplantation, the hepatocytes of the liver acini downstream of the transplanted follicles showed an increase in cytoplasmic basophilia, a loss of glycogen, an enlargement and hyperchromasia of their nuclei, and a strong increase in cell turnover compared with unaltered liver acini. The altered hepatocytes exhibited an increase in the activities of glucose-6-phosphate dehydrogenase, glucose-6-phosphatase, malic enzyme, mitochondrial glycerol-3-phosphate dehydrogenase, cytochrome-c-oxidase, and acid phosphatase; the activities of glycogen synthase and glycogen phosphorylase were strongly decreased. The hepatocytic alterations downstream of the transplanted follicles could be explained by effects of T3. On the other hand, they resembled alterations characteristic of amphophilic preneoplastic liver foci observed in different models of hepatocarcinogenesis.

Animals↗
PubMed2000

Basal inhibin B and the testosterone response to human chorionic gonadotropin correlate in prepubertal boys.

During childhood, the quiescent phase of testicular activity, the hCG stimulation test is widely used to evaluate testicular function. Inhibin B, a gonadal peptide regulating FSH secretion, is an established marker of Sertoli cell function and spermatogenesis in adults. In contrast to the other hormones of the hypothalamo-pituitary-gonadal axis, inhibin B is also secreted in detectable amounts during childhood. The aim of this study was to determine whether basal inhibin B levels are able to predict prepubertal testicular function, so as to avoid a stimulation test. Inhibin B and testosterone before and after hCG stimulation were measured in 54 male children with various testicular disorders by an immunoassay specific for inhibin B. Basal inhibin B was compared to the testosterone increase after hCG. Inhibin B and the hCG-induced testosterone increment correlated strongly (r = 0.84; P<0.0001). Patients with anorchia were clearly distinguishable from those with abdominal testes, having undetectable (inhibin B, <15 pg/mL) respective normal inhibin B levels for age. Inhibin B and the testosterone response to hCG were low in boys with testicular damage (delayed diagnosis of cryptorchidism; after testicular torsion) and in patients with gonadal dysgenesis, but were normal or increased in children with androgen insensitivity syndrome. We conclude that basal inhibin B predicts the testosterone response to hCG in boys and therefore gives reliable information about both the presence and function of the testes. The diagnostic procedure in cryptorchidism may be reduced to a single inhibin B measurement. Furthermore, inhibin B levels show specific alterations in patients with sexual ambiguity, adding a valuable diagnostic tool to the complex differential diagnosis of male pseudohermaphroditism.

Adolescent↗
PubMed1999

Does octreotide treatment improve the surgical results of macro-adenomas in acromegaly? A randomized study.

It is not clear whether the pre-operative treatment of GH-secreting pituitary adenomas with Octreotide improves the surgical remission rates of acromegaly. In a prospective controlled study the results of transsphenoidal surgery in newly diagnosed GH-secreting macro-adenomas were compared in patients with (n = 11, group A) and without (n = 13, group B) preoperative Octreotide treatment. During the treatment with a daily dosage of 470 +/- 160 micrograms Octreotide for 16.5 +/- 10 weeks, the GH- and IGF-1-values of group A dropped significantly from 38.9 +/- 34.1 to 6.8 +/- 4.9 micrograms/l and from 2.7 +/- 1 to 1.7 +/- 0.7 arbitrary units respectively. The adenoma-shrinkage from 5.9 +/- 5.8 to 4.7 +/- 4.9 cm3 missed statistical significance by little. There was no statistically significant difference between the postoperative acromegaly remission rates of 55% in group A and 69% in group B. Of the adenomas that postoperatively were not in remission, 80% in group A and 75% in group B disclosed an infiltrative growth pattern not influenced by the Octreotide pretreatment. All other patients not cured presented with initial GH-values of > 50 micrograms/l. There was no statistically significant difference between the postoperative anterior pituitary function in the two patient groups. In this study Octreotide was not beneficial in improving the results of GH-secreting pituitary macro-adenoma surgery. However, larger prospective controlled studies are needed to address this issue.

Acromegaly↗
PubMed1999

The influence of hydrocortisone substitution on the quality of life and parameters of bone metabolism in patients with secondary hypocortisolism.

OBJECTIVE: Hydrocortisone replacement regimes remain rather empirical and produce serum cortisol profiles very different from normal physiology. We have analysed the effects of different dosages of hydrocortisone (HC) replacement therapy on the health perception and general well-being of patients with secondary hypocortisolism. We also evaluated the effects of these regimens on bone metabolism. DESIGN: In a prospective randomized double-blind study, 3 groups of 3 patients were treated with 3 different dosages of HC (15, 20 and 30 mg/day), in different sequences, each sequence for two weeks. PATIENTS: Nine adult patients with complete secondary hypocortisolism. MEASUREMENTS: Serum cortisol, ACTH, aldosterone, renin, alkaline phosphatase, bone specific alkaline phosphatase, osteocalcin, PTH, C-telopeptides of type-I collagen, sodium, potassium, phosphate; urinary free cortisol, pyridinium cross-links, urine sodium, potassium and phosphate were measured at the beginning and after each week of the study. For quality of life assessment the patients completed three different questionnaires, the Basler Befindlichkeits-Skala (BBS), the Befindlichkeits-Skala (Bf-S), the Beschwerde-Liste (BL) each week. RESULTS: With increasing doses of 15, 20 and 30 mg hydrocortisone a significant increase of free urinary cortisol was achieved (298 +/- 26 nmol/day, 454 +/- 43, 819 +/- 59, respectively; P < 0.01). The mean scores of the psychological questionnaires did not change significantly during the whole study (BBS 81.8 +/- 3.9; 82.8 +/- 3.9, 83.6 +/- 3.9; Bf-S 15.9 +/- 3.4, 11.3 +/- 2.6, 12.5 +/- 2.8; BL 15.7 +/- 2.3, 14.4 +/- 2.5, 14.8 +/- 2.6, respectively). Osteocalcin decreased significantly (2. 3 +/- 0.49, 2.1 +/- 0.42, 1.8 +/- 0.38, P < 0.01) with increasing HC doses but remained within the normal range. The other investigated parameters were within or nearly within the normal range in all patients at the beginning and did not change during the study. CONCLUSION: Dosages of 15, 20 or 30 mg hydrocortisone/day have equivalent effects on quality of life in patients with secondary hypocortisolism. With 15 or 20 mg hydrocortisone/day the patients feel nearly as well and content as normal healthy individuals. Since long-term treatment with a high replacement dose of glucocorticoids (hydrocortisone 30 mg/day) induces bone loss, this risk can be avoided with a substitution dosage of 20 mg or even 15 mg hydrocortisone/day, without influencing the well-being of the patient.

Adult↗
PubMed1999

Characterization of 17beta-hydroxysteroid dehydrogenase activity in brain tissue: testosterone formation in the human temporal lobe.

Sex steroids exert important effects on the central nervous system (CNS). Although the formation of 17beta-hydroxysteroid dehydrogenase (17beta-HSD) metabolites in the CNS was discovered almost 30 years ago, conclusive studies concerning 17beta-HSD activity in the human brain are still lacking. Therefore, we investigated 17beta-HSD in vitro activity in human temporal lobe biopsies of 13 women and 13 men using radioactively labelled androstenedione, testosterone, oestrone and 17beta-oestradiol and compared it to that in human placenta, liver, testis and prostate. We could demonstrate androgenic and oestrogenic 17beta-HSD activities in all tissues under investigation. The reduction of androstenedione and oestrone in brain was NADPH dependent with a broad pH optimum between 6.5 and 9.0, whereas the oxidation of testosterone and 17beta-oestradiol was NAD dependent with a pH optimum of >/=9.0. Using optimum cofactors sex differences of brain 17beta-HSD activities were not observed. Conversion of androstenedione, testosterone, oestrone and 17beta-oestradiol was significantly higher in the subcortical white matter than in the cerebral cortex. We could demonstrate a significant formation of testosterone in the brain tissue of all patients under investigation. Substrate specificity and cofactor requirement patterns as well as pH optima and kinetic properties suggest the occurrence of 17beta-HSD type 3 and type 4 in the human temporal lobe.

17-Hydroxysteroid Dehydrogenases↗
PubMed1999

Sex- and age-specific differences in human brain CYP11A1 mRNA expression.

While the presence of CYP11A1 (P450SCC, cholesterol side-chain cleavage enzyme) has been well established in the brain of rodents, limited information is available on CYP11A1 expression in human brain. In both species, little is known regarding postnatal changes or sex specific differences in cerebral CYP11A1 expression. In the present study, we used a sensitive competitive reverse transcriptase polymerase chain reaction (RT-PCR) assay to quantify the amount of CYP11A1 mRNA in a large number of human brain tissue specimens obtained at neurosurgery. CYP11A1 mRNA is expressed approximately 200 times lower in the temporal lobe, frontal lobe and hippocampus than in adrenal tissue, known for high CYP11A1 mRNA expression. During childhood CYP11A1 mRNA concentrations in the temporal lobe increase markedly and reach adult levels at puberty. CYP11A1 mRNA is significantly higher in the temporal and frontal lobe cortex of women than in that of men. Our data demonstrate for the first time an age and sex dependent expression of CYP11A1 mRNA in the human brain.

Adrenal Glands↗
PubMed1999

Lymphocytic hypophysitis: non-invasive diagnosis and treatment by high dose methylprednisolone pulse therapy?

Criteria for the non-invasive diagnosis of lymphocytic hypophysitis (LyHy) and the results of the first prospective trial of high dose methylprednisolone pulse therapy (HDMPT) in nine patients are presented. In three patients, the diagnosis was established histologically, and in the others by clinical and endocrinological assessment, MRI, CSF examination, and measurement of thyroglobulin autoantibody concentration. After HDMPT, adenopituitary function improved in four of the nine patients and diabetes insipidus ceased or improved in all four concerned patients. The MRI findings improved in seven patients. LyHy has to be considered in the differential diagnosis of sellar lesions. The presumptive non-invasive diagnosis of LyHy seems possible in a high proportion of patients. HDMPT may result in the improvement of clinical, endocrinological, and MRI findings.

Adult↗
PubMed1999

Characterization of aromatase cytochrome P450 activity in the human temporal lobe.

Local aromatase-mediated conversion of androgens plays an important role in androgen action on the brain. To characterize estrogen formation in the human brain, we measured the microsomal aromatase activity of temporal lobe biopsies and compared it to that of human placenta using a highly sensitive 3H2O assay with [1beta-3H]androstenedione as substrate. Brain tissue was removed neurosurgically from 23 patients with epilepsy. Data of kinetic studies were analyzed with a computer-assisted, nonlinear, curve-fitting method using the Michaelis-Menten plus a nonspecific metabolism model. In contrast to data for placental aromatase activity, that for brain always had to be corrected for nonspecific tritium release. The mean K, values were 22.2 nmol/L in brain and 49.6 nmol/L in placenta. Inhibition experiments with atamestane, an inhibitor of aromatase cytochrome P450, revealed specific, dose-responsive, and competitive inhibition of both brain and placental aromatase activities. Placental aromatase activity was completely suppressible by atamestane, whereas in brain tissue there remained a residue of nonspecific tritium release. Subsequent experiments with cerebral cortex and subcortical white matter specimens of children and adults revealed a significantly higher aromatase activity in cerebral cortex than in subcortical white matter, but no sex or age differences were found.

Adolescent↗
PubMed1999

Expression of 17beta-hydroxysteroid dehydrogenase types 1, 2, 3 and 4 in the human temporal lobe.

Sex steroid hormones exert important biological effects on the brain. Moreover, an extensive sex steroid metabolism occurs in the brain. In sex steroid metabolism 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) play essential roles in catalyzing the final steps in androgen and estrogen biosynthesis. Recently four types of human 17beta-HSDs and a pseudogene of the type 1 isoform were identified. To date, 17beta-HSD has not been extensively studied in the human brain. Therefore, we investigated the mRNA expression of the four isozymes of 17beta-HSD as well as the pseudogene of the type 1 isoform in the human temporal lobe to determine the predominant isoforms and, moreover, to elucidate the existence of possible sex and age differences. We studied biopsy materials from the temporal lobe of 34 women, 32 men and 10 children. Quantification of different mRNAs was achieved by competitive reverse transcription-PCR. 17beta-HSD 1, 17beta-HSD 3 and 17beta-HSD 4 were expressed in the human temporal lobe of children and adults, whereas 17beta-HSD 2 and the pseudogene of 17beta-HSD 1 were not expressed. In adults, 17beta-HSD 3 and 17beta-HSD 4 mRNA concentrations were significantly higher in the subcortical white matter (17beta-HSD 3: 14 591+/-3457 arbitrary units (aU), mean+/-s.e.m.; 17beta-HSD 4: 1201+/-212 aU) than in the cortex (17beta-HSD 3: 5428+/-1057 aU, P<0. 0002; 17beta-HSD 4: 675+/-74 aU, P<0.004). 17beta-HSD 1 concentrations did not differ significantly between the white matter (3860+/-1628 aU) and the cortex (2525+/-398 aU) of adults. In conclusion, the present study demonstrates the expression of 17beta-HSD 1, 3 and 4 mRNAs in the human temporal lobe. Together with CYP19AROM and 5alpha-reductase, known to be expressed in the human brain, the expression of 17beta-HSD 1, 3 and 4 mRNAs indicates the major importance of local steroid biosynthesis in the brain.

17-Hydroxysteroid Dehydrogenases↗
PubMed1998

Expression of CYP19 (aromatase) mRNA in the human temporal lobe.

The conversion of androgens to estrogens by CYP19 (cytochrome P450AROM, aromatase) is an important step in the mechanism of androgen action in the brain. CYP19 expression has been demonstrated in various animal species, but studies in human postnatal brain tissue are lacking. Therefore, we investigated CYP19 mRNA expression in human temporal lobe tissues. We studied biopsy materials removed at neurosurgery from 34 women, 32 men and 10 children with temporal lobe epilepsy. Quantification of CYP19 mRNA was achieved by nested competitive reverse transcription-PCR. CYP19 mRNA concentrations did not differ significantly between women (2.6 +/- 0.6 arbitrary units, aU; mean +/- SEM) and men (1.6 +/- 0.3 aU) nor between cerebral cortex tissue (2.0 +/- 0.4 aU) and subcortical white matter tissue of adults (2.4 +/- 0.7 aU), but they were significantly lower in cerebral cortex specimens of children (0.9 +/- 0.6 aU) than in those of adults (p < 0.02). In conclusion, CYP19 mRNA is expressed in the temporal lobe of children and adults. CYP19 mRNA concentrations are significantly lower in specimens of children than in those of adults.

Adult↗
PubMed1998

Pretreatment follicle-stimulating hormone: a prognostic serum marker of spermatogenesis status in patients treated for germ cell cancer.

PURPOSE: We evaluate the use of pretreatment follicle-stimulating hormone (FSH) in patients with germ cell tumors as a prognostic serum marker of spermatogenesis after standard treatment. Additionally, Leydig cell function was investigated by estimation of luteinizing hormone (LH) and testosterone (T), and calculation of the T/LH ratio. MATERIALS AND METHODS: Serum FSH, LH and T were determined radioimmunologically associated with semen analyses in 20 patients with seminoma (pathological stages IA to IIB) after unilateral orchiectomy before and up to 24 months after infradiaphragmatic radiotherapy. Additionally, hormone analyses were performed in 18 patients with nonseminomatous germ cell tumor (pathological stages IIA to C) before and up to 36 months after standard cisplatin based chemotherapy. RESULTS: Seminoma patients undergoing radiotherapy were divided into 2 groups consisting of 12 patients with normal pretreatment serum FSH and 8 with elevated FSH reflecting spermatogenesis deficits even before treatment. Six months after irradiation a significant increase in FSH (p <0.01) associated with a decrease in sperm density was observed in both groups and 24 months after radiotherapy patients with initially normal FSH had significantly lower serum FSH (p <0.01) associated with higher sperm density than those with initially elevated FSH (p <0.01), indicating less impairment of Sertoli cell function. Comparable results were observed in chemotherapy treated germ cell tumor patients with initially normal (11) and elevated serum FSH (7), respectively, and 36 months after chemotherapy patients with initially normal FSH had significantly lower FSH concentrations than those with initially elevated FSH (p <0.01). Compensated impairment of Leydig cell function reflected by a subnormal T/LH ratio was evident before chemotherapy in 16.7% of patients increasing up to 41.2% 36 months after therapy. In contrast, 24 months after radiotherapy only 25% of seminoma patients showed a subnormal ratio reflecting less damage to the Leydig cells caused by irradiation. CONCLUSIONS: Pretreatment FSH is a prognostic serum marker of spermatogenesis status of germ cell tumor patients receiving standard radiotherapy or chemotherapy. In contrast to seminoma patients after radiotherapy, impairment of Leydig cell function was evident in germ cell tumor patients after cisplatin based chemotherapy.

Adult↗
PubMed1998

Serum sex hormones are altered in patients with chronic temporal lobe epilepsy receiving anticonvulsant medication.

PURPOSE: To evaluate the changes in serum sex hormones of gonadal or adrenal origin, the gonadotropic hormones, and sex hormone-binding globulin (SHBG) in men and women with chronic temporal lobe epilepsy (TLE), who are undergoing monotherapy with carbamazepine or receiving carbamazepine in combination with other anticonvulsant drugs. METHODS: Gonadal hormones (estradiol, testosterone, free testosterone, and inhibin B), adrenal hormones [cortisol, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and 17alpha-hydroxyprogesterone], and gonadotropic hormones (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) were measured in 22 women and 26 men with TLE. The study also measured prolactin; human growth hormone and its major mediator, insulin-like growth factor-I; thyroid hormones (free thyroxine and free triiodothyronine); thyroid-stimulating hormone (TSH); and SHBG. The results were compared with those obtained from 60 healthy women and 106 healthy men. RESULTS: In the female patients, TSH, DHEAS, follicular-phase LH, and luteal-phase estradiol were significantly lower than in the control groups, with prolactin and SHBG significantly higher. In the male patients, DHEAS, 17alpha-hydroxyprogesterone, free testosterone, inhibin B, and the testosterone/LH ratio were significantly lower than in the control group, with LH, FSH, and SHBG significantly higher. Increased FSH in 31% of the men indicates an impairment of spermatogenesis; lowered inhibin B in 12% indicates an impaired Sertoli's cell function; and the decreased testosterone/LH ratio in 50% indicates an impaired Leydig's cell function. CONCLUSIONS: The case patients had endocrine disorders, mainly concerning the gonadotropic and gonadal functions in both sexes; the adrenal function, with lowered DHEAS levels in both sexes; and lowered 17alpha-hydroxyprogesterone levels in the men. SHBG levels were increased in patients taking anticonvulsant medications.

Adult↗
PubMed1998

Expression of 5alpha-reductase in the human temporal lobe of children and adults.

Androgens exert important biological effects on the brain, and 5alpha-reductase plays a crucial role in androgen metabolism. Therefore, we investigated the expression of the two isozymes of 5alpha-reductase in the human temporal lobe to determine the predominant isoform and to elucidate the existence of possible sex differences and differences between children and adults. We studied biopsy materials from the temporal lobe of 34 women, 32 men, and 12 children. Quantification of 5alpha-reductase 1 and 2 messenger ribonucleic acid (mRNA) was achieved by competitive RT-PCR. 5Alpha-reductase activity was determined in tissue homogenates using [1,2-3H]androstenedione as the substrate. Only 5alpha-reductase 1 mRNA was expressed in human temporal lobe tissue; 5alpha-reductase 2 mRNA was not expressed. 5Alpha-reductase 1 mRNA concentrations did not differ significantly in the cerebral cortex of women [25.9+/-7.9 arbitrary units (aU); mean +/-SEM] and men (20.4+/-2.8 aU) or in the cerebral cortex (23.3+/-4.4 aU) and the subcortical white matter of adults (32.6+/-5.6 aU), but they were significantly higher in the cerebral cortex of adults than in that of children (6.4+/-2.3 aU; P < 0.005). The apparent Km of 5alpha-reduction did not show significant differences between the two sexes. In conclusion, 5alpha-reductase 1 mRNA is expressed in the temporal lobe of children and adults, but 5alpha-reductase 2 mRNA is not. 5Alpha-reductase 1 mRNA concentrations did not differ significantly in the sexes, but they were significantly higher in specimens of adults than in those of children.

Adult↗
PubMed1998

Insulinomas derived from hyperplastic intra-hepatic islet transplants.

Insulinomas were induced in a new animal model by transplanting a low number of isologous pancreatic islets via the portal vein into the livers of 66 streptozotocin-induced diabetic rats. In contrast to high-number islet transplantation, which restored normoglycemia in 25 control animals, the low-number islet transplantation was followed by persisting hyperglycemia for at least 13 months. Hyperplasia of islet cells developed in the transplanted islets as a consequence of hyperglycemia, which for the beta cells is not only a secretory but also a proliferative stimulus. Six of thirty-three animals between the 18th and the 24th month after islet transplantation changed from hyperglycemia to severe hypoglycemia, due to insulinomas that had developed in the liver from the transplanted islets. In contrast to other animal models, insulinoma development in this new model does not result from DNA damage by chemicals or radiation or from the expression of transgenes, but starts from apparently normal islets prepared from untreated isologous donors, which are exposed to an imbalance in glucose metabolism. The persistent proliferative stimulus and the metabolic alterations caused by the longstanding hyperglycemia seem to be the most relevant oncogenic factors in this model.

Animals↗
PubMed1997

An optimized protocol for mRNA quantification using nested competitive RT-PCR.

Nested competitive reverse transcription polymerase chain reaction is an effective tool for the quantification of low level expressed mRNAs. Competitive RNA standards with small deletions allow the use cRT-PCR. The sensitivity is further increased by the utilization of nested PCR protocols. To optimize quantification of low abundance mRNAs we modified established protocols for use of automated labstations and semiautomated sequencers. In placental tissue, known for a very high CYP19 (P450AROM, aromatase) expression, cRT-PCR and nested cRT-PCR yielded virtually identical results which could be confirmed by Northern blotting. CYP19 mRNA in breast tumour tissue ranged below detection levels for Northern blotting; however, using our modified assay CYP19 showed 1.5 to 15 fold higher expression levels than in normal glandular breast tissue. Our approach proved to be useful for the quantification of a gene with low level expression. The employment of labstations and semiautomated sequencers allows rapid analysis of large sample numbers.

Aromatase↗
PubMed1997

[Initial symptoms and anamnestic time in 517 patients with pituitary adenoma].

OBJECTIVE: To find out whether recent techniques of investigating hypophyseal adenoma (computed tomography, magnetic resonance imaging and hormonal measurements) have brought about earlier diagnosis. PATIENTS AND METHODS: The time of onset of first symptoms and the duration from first symptoms to diagnosis (anamnestic time) were determined retrospectively from clinical, endocrinological, ophthalmological and localizing data on 517 patients (311 women, 206 men) with hypophyseal adenoma. RESULTS: The most common initial symptom was oligo- or amenorrhoea, in 57.9% of women, and disturbed libido or potency in 38.5% of men. Next most common were visual field deficits (women: 11.6%, men: 26.7%), signs of acromegaly (women: 11.3%, men 18.2%) and headaches (women: 11.3%, men 15.5%). The median anamnestic time in women, 3.0 years, was significantly longer than the 2.3 years in men (P < 0.001). In hormonally inactive adenoma the corresponding times were 2.0 years in women and 1.0 year in men; in prolactinoma 4.2 years and 2.0 years; in growth-hormone secreting adenoma 5.0 years and 5.5; and in ACTH-secreting adenoma 5.0 years and 1.0 year. CONCLUSIONS: Although diagnostic techniques have greatly improved, the anamnestic time for hypophyseal adenoma is not shorter than in earlier studies. This findings underlines the need for clearly directed history-taking and for good training in endocrinology.

Acromegaly↗