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Biomedical subjects

D Ziegler

Publications and source records attributed to D Ziegler.

At least 55 records · Page 3Linked to original sources

[13C]octanoic acid breath test for non-invasive assessment of gastric emptying in diabetic patients: validation and relationship to gastric symptoms and cardiovascular autonomic function.

Since there is a need for a widely applicable non-invasive test to assess gastric emptying in diabetic patients, we evaluated the sensitivity, specificity, and reproducibility of the [13C]octanoic acid breath test as compared with scintigraphy. Moreover, we examined the relationship between the breath test indices and gastric symptoms, cardiovascular autonomic function, and metabolic parameters. Forty healthy control subjects and 34 diabetic patients were studied. Three indices of gastric emptying, assessed by the breath test, were computed: half-emptying time (t1/2breath), gastric emptying coefficient (GEC), and lag phase. Furthermore, the half-emptying time, measured by scintigraphy (t1/2scint), was calculated and gastric symptoms and cardiovascular autonomic neuropathy (CAN) were scored. The coefficients of variation of day-to-day reproducibility in 10 healthy subjects were 29.6% for t1/2breath, 7.4% for GEC, and 46.5% for lag phase. An abnormal delay for t1/2scint (> 100 min) or t1/2breath (> 200 min) was noted in 12 patients. Based on the results for t1/2scint, the sensitivity of t1/2breath and GEC was 75% and the specificity was 86%. Both t1/2breath (rs = 0.523; p < 0.05) and GEC (r2 = -0.594; p < 0.05) were significantly associated with the gastric symptom score. A significant relationship to the CAN score was demonstrated for t1/2breath (rs = 0.448; p < 0.05), GEC (rs = -0.467; p < 0.05), and t1/2scint (rs = 0.602; p < 0.05). There were no significant associations of the breath test indices with the blood glucose levels during the test, HbA1c, age, and duration of diabetes. In patients with abnormal t1/2scint (n = 12) not only was t1/2breath significantly prolonged and GEC reduced, but also the scores of CAN and gastric symptoms were significantly increased as compared with those who had a normal t1/2scint (n = 22). We conclude that the [13C]octanoic acid breath test represents a suitable measure of delayed gastric emptying in diabetic patients which is associated with the severity of gastric symptoms and CAN but not affected by the blood glucose level.

Adult↗

Differential activation of T cells by antibody-modulated processing of the flanking sequences of class II-restricted peptides.

Despite poor presentation of measles virus (MV) nucleoprotein (NP) by MHC class II of infected cells, NP-specific antibodies are one of the hallmarks of the early immune response against this virus. To study the influence of antibodies on processing and presentation of NP to three different T cell hybridomas, mAb recognizing distinctive llnear NP epitopes were developed. Two T cell hybridomas TNP408B and TNP408 reacted with the same core epitope of NP (amino acids 383-391), but differed in their sensitivity to the flanking sequences of peptides containing this epitope. TNP408B reacted with minimal concentrations of NP when this was complexed with mAb BNP146. NP alone or saturating concentrations of other mAb did not activate this T cell. Both T cells, TNP408 and TNP408B, were similar in their sensitivity to NP in the presence of saturating concentrations of BNP146 or of appropriate peptide (NP379). TNP408 did not differ from another T cell hybridoma (TNP79) in its sensitivity to different mAb, suggesting a specificity-dependent and a specificity-independent effect of mAb. Antibody-mediated activation was attributed to FcR-mediated uptake independent of the fine specificity of the mAb. In the case of TNP408B, this effect was further enhanced by a specific effect of BNP146. While all NP-specific mAb were sufficient to enhance presentation to TNP408 and TNP79 of their respective peptides derived from processed NP, BNP146 was necessary to generate the peptides with the proper flanking sequences required by TNP408B. Since the binding site of BNP146 coincides with the T cell epitope of TNP408B (and TNP408) it is suggested that binding of this mAb modulates processing of the flanking sequences of the peptides corresponding to this epitope. This study shows that antibodies can influence the T cell response to an antigenic protein quantitatively and qualitatively by taking advantage of the sensitivity of T cells to flanking sequences of class II-restricted peptides.

Amino Acid Sequence↗

Pharmacology of moxonidine, an I1-imidazoline receptor agonist.

Moxonidine is a second-generation, centrally acting antihypertensive drug with a distinctive mode of action. Moxonidine activates I1-imidazoline receptors (I1-receptors) in the rostroventrolateral medulla (RVLM), thereby reducing the activity of the sympathetic nervous system. Moxonidine leads to a pronounced and long-lasting blood pressure reduction in different animal models of hypertension, e.g., spontaneously hypertensive rats, renal hypertensive rats, and renal hypertensive dogs. Blood pressure reduction with moxonidine is usually accompanied by a reduction in heart rate which, however, in most studies is of shorter duration and lesser magnitude than the fall in blood pressure. Chronic administration of moxonidine to SHRs with established hypertension causes normalization of myocardial fibrosis, capillarization, and regressive changes in myocytes, in parallel with the reduction of blood pressure. Left ventricular hypertrophy and renal glomerulosclerosis are also significantly reduced. After withdrawal of chronic moxonidine treatment, blood pressure gradually rises to pretreatment values. Direct injection of moxonidine into the vertebral artery of cats elicits a more pronounced fall in blood pressure compared with i.v. injection of an equivalent dose. This observation and others clearly indicate that moxonidine's antihypertensive activity is centrally mediated. The RVLM is the site of action within the CNS that mediates pronounced blood pressure reduction after direct administration of moxonidine into the RVLM of anesthetized SHRs. Selective I1-receptor antagonists introduced into this area abolish the action of systemic moxonidine. Receptor binding studies have shown high and selective affinity of moxonidine for I1-receptors vs. alpha(2)-adrenergic receptors. In vivo studies using a variety of selective I1 or alpha(2)-adrenergic agonists and antagonists have confirmed the primary role of I1-receptors in blood pressure regulation by moxonidine. In addition to lowering blood pressure, moxonidine possesses further properties that appear likely to be relevant in its therapeutic application in the hypertensive syndrome. Moxonidine increases urine flow rate and sodium excretion after central and direct intrarenal administration. It is active against ventricular arrhythmias in a variety of experimental settings. It lacks the respiratory depressant effect attributed to central alpha 2 activation. It exerts beneficial effects on glucose metabolism and blood lipids in genetically hypertensive obese rats. It exhibits anti-ulcer activity. And, finally, moxonidine lowers intraocular pressure, suggesting a possible benefit in glaucoma. Therefore, moxonidine, by its novel mode of action, represents a new therapeutic principle in the treatment of hypertension. Because of its unique profile, moxonidine may prove to be effective in slowing progression of the disease by providing protective effects beyond merely blood pressure reduction. Further studies are needed to verify this potential.

Animals↗

Protection against measles virus encephalitis by monoclonal antibodies binding to a cystine loop domain of the H protein mimicked by peptides which are not recognized by maternal antibodies.

After immunization with measles virus (MV) several monoclonal antibodies (MAbs) were obtained, which reacted with peptides corresponding to the amino acids 361-410 of the haemagglutinin protein (MV-H). Three of these MAbs (BH6, BH21 and BH216) inhibited haemagglutination, neutralized MV in vitro and protected animals from a lethal challenge of rodent-adapted neurotropic MV. These MAbs reacted with the 15-mer peptides H381 and H386 defining their overlapping region 386-395 as a sequential neutralizing and protective epitope, which can be imitated by a short peptide. H381 and H386 share two Cys residues (C(386)KGKIQALC(394)ENPEWA) and for optimal MAb binding of peptide (or MV) disulphide bonds were required in addition to a linear C-terminal extension. Other MAbs bound to peptides C- (BH147, BH195) and N-terminally (BH 168, BH 171) adjacent to the loop but did not neutralize or protect. When sera from measles patients or from women of child-bearing age were tested with the peptides corresponding to this haemagglutinating and neutralizing epitope (HNE), none of the sera recognized the 15-mer peptides of this region, while some reactivity was found to 30-mers homologous to different wild-type mutants. Its lack of recognition by maternal antibodies and its high degree of conservation would make the HNE loop an attractive candidate to include into a subunit vaccine, which could be administered during early childhood, independent of immune status.

Amino Acid Sequence↗

[Clinical aspects, diagnosis and therapy of diabetic neuropathy].

Diabetic neuropathy is regarded as the most common form of neuropathy in the Western industrial countries. At least one third of the diabetic patients is affected by a clinically manifest peripheral neuropathy, which can be diagnosed by the clinical neurological examination without a great deal of effort. The involvement of the autonomic nervous system may be associated with an increased mortality. It may result in erectile impotence as well as severe physical disability from orthostatic hypotension, fecal incontinence or bladder dysfunction and life-threatening complications such as silent myocardial infarction or sudden death. Diabetic cardiovascular autonomic neuropathy is detected in more than 20% of the patients. The best possible glycaemic control including patient education is regarded as the most important therapeutic measure. However, additional drug treatment is frequently needed to maintain the patient's quality of life. It is usually effective in reducing symptoms of diabetic peripheral neuropathy. The therapeutic prospects depend not only on the treatment approach but also on the stage of the neuropathic process. Favourable effects can be expected particularly in terms of prevention and in the early stages of the disease. Treatment options based on the current pathogenetic concepts are restricted to clinical trials, except for the antioxidant mode of action. The efficacy of symptomatic treatment is limited for some drugs, and significant adverse reactions are common. Therefore, before any symptomatic drug treatment is initiated, its potential risk should be thoroughly weighed against its possible benefit.

Autonomic Nervous System Diseases↗

[Arachnoid cyst as the differential diagnosis of ischemic optic neuropathy in type-II diabetes].

HISTORY AND CLINICAL FINDINGS: A 71-year-old woman, a diabetic (type IIb) for 27 years, developed bilateral hemianopsia over a period of about 2 years. A few weeks before hospital admission the defect in her visual fields increased more rapidly and double vision occurred intermittently. The hemianopsia was demonstrated by finger perimetry. There was no evidence of heart failure or peripheral vascular disease. Muscle reflexes were normal, but there was a decrease in vibratory sensation in both feet. The cause of the visual disturbance was at first thought to be an ischaemic optic neuropathy. INVESTIGATIONS: Biochemical tests showed an HbA1 of 12.8%, blood sugar levels were between 230 and 359 mg/dl, and there was increased intravascular platelet activation. Ophthalmological examination confirmed bitemporal hemianopsia and early retinopathy. Magnetic resonance imaging of the skull revealed an intra- and suprasellar cystic space-occupying lesion extending to the right optic chiasma. These findings, taken together, indicated an arachnoidal cyst. TREATMENT AND COURSE: After the diabetic metabolic state had been normalized with insulin treatment (average of 30 IU of an intermediary insulin) and dietary measures, the cyst was evacuated stereotactically. The hemianopsia quickly improved markedly and the patient was discharged 4 days after the operation with her vision nearly fully restored.

Aged↗

Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study).

Anti-oxidant treatment has been shown to prevent nerve dysfunction in experimental diabetes mellitus, thus providing a rationale of potential therapeutic value for diabetic patients. The effects of the anti-oxidant alpha-lipoic acid (thioctic acid) were studied in a 3-week multicentre, randomized, double-blind placebo-controlled trial (Alpha-Lipoic Acid in Diabetic Neuropathy; ALADIN) in 328 non-insulin-dependent diabetic patients with symptomatic peripheral neuropathy who were randomly assigned to treatment with intravenous infusion of alpha-lipoic acid using three doses (1200, 600, or 100 mg ALA) or placebo (PLAC). Neuropathic symptoms (pain, burning, paraesthesiae, and numbness) were scored at baseline and at each visit (days 2-5, 8-12, and 15-19) prior to infusion. In addition, the Hamburg Pain Adjective List, a multidimensional specific pain questionnaire, and the Neuropathy Symptom and Disability Scores were assessed at baseline and day 19. According to the protocol 260 (65/63/66/66) patients completed the study. The total symptom score in the feet decreased from baseline to day 19 by -4.5 +/- 3.7 (-58.6%) points (mean +/- SD) in ALA 1200, -5.0 +/- 4.1 (-63.5%) points in ALA 600, -3.3 +/- 2.8 (-43.2%) points in ALA 100, and -2.6 +/- 3.2 (-38.4%) points in PLAC (ALA 1200 vs PLAC: p = 0.003; ALA 600 vs PLAC: p < 0.001). The response rates after 19 days, defined as an improvement in the total symptom score of at least 30%, were 70.8% in ALA 1200, 82.5% in ALA 600, 65.2% in ALA 100, and 57.6% in PLAC (ALA 600 vs PLAC; p = 0.002). The total scale of the Pain Adjective List was significantly reduced in ALA 1200 and ALA 600 as compared with PLAC after 19 days (both p < 0.01). The rates of adverse events were 32.6% in ALA 1200, 18.2% in ALA 600, 13.6% in ALA 100, and 20.7% in PLAC. These findings substantiate that intravenous treatment with alpha-lipoic acid using a dose of 600 mg/day over 3 weeks is superior to placebo in reducing symptoms of diabetic peripheral neuropathy, without causing significant adverse reactions.

Adolescent↗

[Incompatibility of tuberculosis therapy in a patient with AIDS].

A man with advanced HIV infection (CD4 lymphocytes 90/microliter, CD4/CD8 ratio 0.2) was admitted to hospital with fever, cough and weight loss. The radiological and bronchoscopic findings, together with the presence of acid-fast bacilli in the sputum, pointed to open pulmonary tuberculosis caused by Mycobacterium tuberculosis, a diagnosis confirmed by histological examination and culture. Quadruple antibiotic therapy with isoniazid (INH), rifampicin (RMP), ethambutol (EMB) and amikacin was immediately begun and was at first clinically successful. Ten days later, however, a rash appeared; it was ascribed to RMP (anaphylactoid reaction after re-exposure). All the other first-line drugs tried during the ensuing eight months evoked severe adverse reactions (INH: rash and itching; amikacin: hearing impairment and tinnitus; EMB, pyrazinamide, prothionamide, p-aminosalicylic acid: rash and itching). Treatment was nevertheless clinically and microbiologically successful, and the patient insisted upon a 2 1/2 months' rest without therapy. This period was followed by extrapulmonary spread (severe arthritis of the elbow) and recurrence of pulmonary tuberculosis. The tubercle bacilli were sensitive to all the drugs so far employed. Renewed and lasting control of the infection was achieved only by continuous administration of steroids (prednisolone 10 mg twice daily) in conjunction with an unconventional antibiotic regimen consisting of amikacin, protionamide, terizidone, clarithromycin and sparfloxacin for some five months. Because of an episode of cerebral convulsions during treatment of cytomegalovirus retinitis with ganciclovir, the terizidone was discontinued (it was suspected of interacting with ganciclovir). The patient has had no more fits and sputum culture has remained negative for six months.

AIDS-Related Opportunistic Infections↗

Cerebral glucose metabolism in type 1 diabetic patients.

To evaluate whether cerebral glucose metabolism is impaired in diabetes the [18F]-2-deoxy-2-fluoro-D-glucose method and positron emission tomography were used to determine the regional cerebral metabolic rate of glucose in 12 healthy subjects, 8 newly diagnosed Type 1 diabetic patients 6 Type 1 diabetic subjects without peripheral neuropathy, and 7 Type 1 diabetic patients with symptomatic peripheral neuropathy, all of whom were men. In addition, multimodal evoked potentials were assessed. Cerebral glucose consumption was significantly reduced in the group with neuropathy as compared with the newly diagnosed diabetic patients and the healthy subjects (26.9 +/- 1.0 vs 33.9 +/- 1.9 and 32.5 +/- 1.1 mumol 100 g-1 min-1; p < 0.05), while in the patients without neuropathy it was 30.2 +/- 2.5 mumol 100 g-1 min-1 (NS vs the remaining groups). There were no significant differences between the groups regarding brainstem auditory and visual evoked potentials. No relationship was noted between cerebral glucose metabolism and P300 latency of event-related potentials as an index of cognitive function, but there was an inverse correlation with age (r = -0.42; p < 0.05) and duration of diabetes (r = -0.67; p < 0.05). These results suggest that cerebral glucose metabolism is normal at the time of diagnosis of Type 1 diabetes, but may become altered with both increasing duration of diabetes and age in the absence of central conduction deficits or cognitive dysfunction. Diabetic neuropathy may constitute a possible additional correlate of reduced cerebral glucose consumption.

Adult↗

Dihydroergotamine nasal spray for the acute treatment of migraine.

We conducted a multicenter, double-blind, parallel-group study to compare the efficacy and safety of dihydroergotamine (DHE) nasal spray and placebo over 4 hours in the treatment of migraine. Of the 112 patients enrolled, 100 were included in the "intent-to-treat" efficacy analysis. The patients self-administered either 2.0 mg DHE (0.5 mg per nostril, repeated after 15 minutes) or placebo at the onset of two separate headaches and rated hourly the drugs' effects on pain severity, pain relief, nausea, and vomiting. The physicians assessed the overall effectiveness of the drugs in relieving headache pain, nausea, and vomiting. Both the patients' and physicians' ratings indicated that DHE was significantly superior to placebo in improving headache and nausea; according to the patients' ratings, these between-group differences were already significant at the first (hour 1) evaluation. There were no significant differential treatment effects with respect to relief of vomiting. Most adverse events were mild or moderate, confined to the nasopharyngeal area, and probably related to the route of administration. We conclude that DHE nasal spray is a safe and effective treatment for the pain and nausea of migraine attacks.

Administration, Intranasal↗

Prevalence of gastrointestinal symptoms in diabetic patients and non-diabetic subjects.

To determine the frequency of gastrointestinal symptoms in diabetic patients, 190 patients, consecutively referred to the Diabetes Research Institute, reported their gastrointestinal symptoms on a standardized symptom list. One hundred and eighty non-diabetic healthy subjects served as (matched) controls. Finally, 75 patients with Type 1 (insulin-dependent) diabetes mellitus (33 male, 43 female; age 34,1 (18-60) yrs, diabetes duration: 11,1 (0,3-41) yrs) and 68 patients with Type 2 (non-insulin-dependent) diabetes mellitus (31 male, 37 female, age: 61,4 (37-88) yrs, diabetes duration: 10,7 (0,3-40) yrs) were studied and compared with two cohorts of controls of the same size. There were no differences in prevalence of symptoms referrable to the upper and lower GI-tract in type 1 diabetic patients as compared with controls. Among patients with type 2 diabetes the main gastrointestinal complaint was constipation (22,1% vs 10,3%; p < 0.05). Upper gastrointestinal symptoms were also more frequent among Type 2 diabetic subjects (nausea 11,8% vs 2,9%, p < 0.05). There was a tendency for an increased symptom prevalence with higher age in both type 1 and type 2 diabetes. Presence of peripheral neuropathy was associated with a higher symptom prevalence in type 1 diabetes. After stratification, diabetes duration and glycaemic control (HbA1c) did not influence the frequency of symptoms. Thus, gastrointestinal symptoms occur frequently among both diabetic patients and non-diabetic subjects. However, significant differences were found only in type 2 (non-insulin-dependent) diabetes, the commonest symptom being constipation. These findings support the need of a nondiabetic control group in epidemiological studies evaluating symptom prevalence in diabetes mellitus.

Adolescent↗

Mortality in diabetic patients with cardiovascular autonomic neuropathy.

Cardiovascular autonomic diabetic neuropathy (CADN) may carry an increased risk of mortality. However, in previous studies the prognosis of patients with CADN seemed to be influenced by life-threatening macro- and microvascular complications which had already been present at the start of the study period. Between 1981 and 1983, 1015 diabetic patients have been examined for CADN (abnormal heart rate variation at rest and during deep respiration) at the Diabetes Research Institute, Düsseldorf. Thirty-five patients (28 with Type 1 diabetes, 7 with Type 2 diabetes) with CADN have been retrospectively recruited and reviewed 8 years later and compared with 35 patients without CADN who were matched for sex, age, and duration of diabetes. Exclusion criteria for entry into the study included severe micro- or macrovascular complications, such as proliferative retinopathy, proteinuria or symptomatic coronary artery disease. During the 8-year observation period, 8 patients with CADN and 1 patient without CADN died. The survival rate estimates steadily declined in patients with CADN over the whole period studied. The 8-year survival rate estimate in patients with CADN was 77% compared with 97% in those with normal autonomic function (p < 0.05). Deaths were mainly due to macrovascular diseases (n = 3) and sudden unexpected deaths (n = 3). One patient with CADN died after an episode of severe hypoglycaemia. Among the decreased patients, coefficient of variation of R-R intervals during deep breathing was significantly reduced when compared with those who survived (1.04 +/- 0.5% vs 1.87 +/- 1.0%; p < 0.05), and symptoms of autonomic neuropathy (orthostatic hypotension, gastroparesis, gustatory sweating) were more frequent (7/8 vs 10/27 patients).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Tibial nerve somatosensory evoked potentials at various stages of peripheral neuropathy in insulin dependent diabetic patients.

To determine whether central nervous conduction deficits are related to the degree of peripheral neuropathy somatosensory evoked potentials (SEP) were measured after tibial nerve stimulation in 51 healthy subjects aged 39.3 (SE 2.0, (range 21-71) years and 100 insulin dependent diabetic patients aged 37.3 (1.5, 18-73) years. Five criteria were used for staging of peripheral neuropathy: nerve conduction; thermal discrimination threshold; vibration perception threshold; tendon reflexes; and neuropathic symptoms. Thirty seven patients had fewer than two abnormalities among the first four criteria and no symptoms (stage 0 = no neuropathy), 37 had 2 or more abnormalities but no symptoms (stage 1 = subclinical neuropathy); 26 had 2 or more abnormalities in conjunction with symptoms (stage 2 = symptomatic neuropathy). Multiple regression analysis was used to define the age and height dependent limits of normal of SEP at the 97.5th and 2.5th centiles. In five patients with stage 1, seven patients with stage 2, but no patient with stage 0 the individual SEP components were unrecordable. The relative frequencies of abnormally prolonged or non-evokable popliteal N8 latency as well as cortical N33 latency and N33/P40 amplitude increased significantly from stage 0 (3-30%) to stage 1 (22-62%) and stage 2 (46-84%) (p < 0.05 for each component and stage). The numbers and percentages of abnormal recordable spinal N22-30 and supraspinal N30-33 interpeak latencies were two (6.3%) and four (11.8%) in patients with stage 0, but these rates did not increase in subjects with stage 1 or 2. The components of SEP were significantly associated with the indices of peripheral and autonomic function tests. There were no major relations between the latencies of SEP and duration of diabetes or prevailing glycaemic control. These findings suggest that the degree of dysfunction along the somatosensory afferent pathways in insulin dependent diabetic patients depends on the stage of peripheral neuropathy; is not related to the degree of glycaemic control or duration of diabetes; and can be characterized mainly by an alteration of the cortical sensory complex and peripheral transmission delay, while spinal and supraspinal conduction deficits are detected infrequently.

Adult↗

Prevalence and clinical correlates of cardiovascular autonomic and peripheral diabetic neuropathy in patients attending diabetes centers. The Diacan Multicenter Study Group.

The objective of the study was to evaluate the prevalence of and the factors associated with cardiovascular autonomic diabetic neuropathy (CADN) and peripheral neuropathy in patients attending clinical and outpatient diabetes centers. The design was a multicenter cross section study with random selection of patients with Type 1 or Type 2 diabetes from seventeen German, three Swiss, and two Austrian inpatient and outpatient diabetes centers. A total of 1,642 patients were recruited, 1,171 of whom (Type 1: n = 647, age: 11-69 years; Type 2: n = 524, age: 16-72 years) were studied. Measurements and results. The following six autonomic function tests based on heart rate variation were used for the diagnosis of CADN: coefficient of variation and power spectrum in the low- and mid-frequency bands at rest, mean circular resultant during deep breathing, Valsalva ratio, and max/min 30:15 ratio to standing. The age-dependent lower limit of the normal range in these tests had previously been defined at the 2.3 centile in 120 healthy subjects. Definite CADN defined by the strict criterion of abnormal results in > or = 3 of these 6 tests was detected in 16.8% of the Type 1 and 22.1% of the Type 2 diabetic patients (p < 0.05). The corresponding rates of borderline CADN defined as the presence of 2 abnormalities were 8.5% and 12.2%, respectively (p < 0.05). Peripheral neuropathy defined as the presence of > or = 2 abnormalities among 3 criteria (neuropathic symptoms, absent tendon reflexes, and abnormal malleolar vibration perception threshold) was observed in 17.1% of Type 1 and 34.8% of Type 2 diabetic patients (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗