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Present Progressive MC TestOral Manifestations of Viral Infections Viral infections can lead to a variety of oral manifestations, which may vary depending on the type of virus involved. Below are the key viral infections and their associated oral symptoms. --- 1. Herpes Simplex Virus (HSV) Infections Type: HSV-1 and HSV-2 Common Oral Manifestations: Primary Herpetic Gingivostomatitis: In children, presents as painful swelling and redness of the gums, with vesicular lesions on the lips, tongue, and hard palate. Recurrent Herpes Simplex: Cold sores (herpes labialis) often appear on the lips or around the mouth, and are painful and fluid-filled. Herpetic Whitlow: Infection of the fingers, often seen in healthcare workers. Clinical Features: Vesicular lesions that break to form ulcers Painful and burning sensations in affected areas Swollen lymph nodes Fever (during primary infection) Diagnosis: Direct immunofluorescence, PCR, or viral culture. --- 2. Varicella-Zoster Virus (VZV) Infections Type: Varicella (chickenpox) and Herpes Zoster (shingles) Common Oral Manifestations: Varicella: Enanthem (oral lesions) such as vesicular lesions on the hard palate, tongue, and lips, in conjunction with the characteristic skin rash. Herpes Zoster (Shingles): Unilateral painful oral lesions, often involving the hard and soft palate, and can extend to the tongue or buccal mucosa along the distribution of the trigeminal nerve. Clinical Features: Vesicular lesions that ulcerate Pain and discomfort in affected areas Fever, malaise, and headache (for chickenpox) Diagnosis: PCR, direct fluorescence antibody test, and clinical signs. --- 3. Human Papillomavirus (HPV) Infections Type: Multiple strains, including HPV types 16 and 18 Common Oral Manifestations: Oral Warts: Benign, non-painful growths typically found on the lips, palate, tongue, and floor of the mouth. Condyloma Acuminatum: Wart-like lesions in the mouth, often associated with genital HPV. Oropharyngeal Cancer: Certain high-risk HPV strains (e.g., HPV-16) are linked to cancers of the oropharynx, including tonsils and base of tongue. Clinical Features: Raised, fleshy, or cauliflower-like growths Rarely associated with pain or discomfort Diagnosis: Biopsy and PCR testing for HPV. --- 4. Coxsackievirus Infections Type: Hand, Foot, and Mouth Disease (HFMD) Common Oral Manifestations: Oral Ulcers: Painful, shallow ulcers typically seen on the soft palate, tonsils, tongue, and buccal mucosa. Vesicular Lesions: Small vesicles that ulcerate to form painful sores. Clinical Features: Red spots or vesicles that turn into ulcers Fever, sore throat, and malaise Rash and lesions on hands and feet Diagnosis: Clinical presentation and PCR. --- 5. Measles (Rubeola) Type: Paramyxovirus Common Oral Manifestations: Koplik Spots: Small, white or bluish-white spots seen on the buccal mucosa opposite the molars before the rash appears. Generalized Oral Ulceration: Following the appearance of Koplik spots, mucosal lesions may develop. Clinical Features: High fever, cough, and rash (starts on the face and spreads) Conjunctivitis Koplik spots as early indicators Diagnosis: Clinical signs and serology for measles antibodies. --- 6. HIV/AIDS Type: Human Immunodeficiency Virus Common Oral Manifestations: Oral Candidiasis: Fungal overgrowth in the mouth due to immunosuppression. Kaposi's Sarcoma: A form of cancer that appears as purple or brown lesions in the mouth, especially in the palate or gingiva. Oral Hairy Leukoplakia: White, hairy lesions on the lateral borders of the tongue, often associated with Epstein-Barr virus. Herpes Simplex and Zoster: Recurrent infections in the oral cavity. Clinical Features: Candidiasis: White plaques that can be scraped off Kaposi’s Sarcoma: Purple, macular lesions Hairy Leukoplakia: White, corrugated patches on the tongue Recurrent infections and oral ulcers Diagnosis: HIV testing, biopsy for Kaposi's sarcoma, and culture for candidiasis. --- 7. Influenza Virus Type: Influenza A and B Common Oral Manifestations: Pharyngitis: Sore throat and erythema of the oropharyngeal mucosa. Dry Mouth: Often secondary to fever and dehydration. Mucosal Erosions: Rare, but may occur in severe cases. Clinical Features: Fever, cough, sore throat, muscle aches, and headache Red or swollen tonsils and oral mucosa Diagnosis: Rapid influenza tests and PCR. --- 8. Epstein-Barr Virus (EBV) Type: Epstein-Barr virus Common Oral Manifestations: Oral Hairy Leukoplakia: White, asymptomatic, corrugated patches on the lateral borders of the tongue. Pharyngitis: Sore throat with swelling of tonsils. Oral Ulcers: Occasionally seen in association with infectious mononucleosis. Clinical Features: Fever, sore throat, and swollen lymph nodes (mononucleosis) Fatigue and malaise Diagnosis: EBV serology and PCR. --- 9. Rabies Virus Type: Rabies virus Common Oral Manifestations: Hydrophobia: Difficulty swallowing and fear of water. Increased Salivation: Resulting from dysfunction in the throat and jaw muscles. Clinical Features: Progressive neurological symptoms Paroxysms of pain or spasms in the throat and mouth Diagnosis: Clinical signs, rabies testing (saliva, CSF, or tissue biopsy). --- 10. Human Immunodeficiency Virus (HIV) Common Oral Manifestations: Oral Candidiasis: White, creamy lesions in the mouth, especially in immunocompromised individuals. Kaposi’s Sarcoma: Purple or red lesions on the palate and gingiva. Herpes Simplex: Recurrent oral lesions. Oral Hairy Leukoplakia: A condition linked with Epstein-Barr virus, presenting as white patches on the lateral borders of the tongue. --- Conclusion Oral manifestations of viral infections are varied and can provide valuable clues for diagnosing systemic viral diseases. Clinicians must consider the specific features and patterns of lesions in combination with other clinical signs for an accurate diagnosis. Some infections may also have long-term oral health implications, requiring management and prevention strategies.Chapter 22 Antihypertensive Drugs Hypertension Defined (JNC-8) Pharmacology Overview 7 main categories of drugs to treat HTN Adrenergic drugs (old friend) Angiotensin-converting enzyme (ACE) inhibitors Angiotensin II receptor blockers (ARBs) Calcium channel blockers (CCBs) Diuretics Vasodilators Direct renin inhibitors A. Adrenergic Drugs: 5 Subcategories and where they act A1. Adrenergic neuron blockers (central and peripheral)- we won’t talk about this A2. Alpha1 receptor blockers (peripheral) A3. Alpha2 receptor agonists (central) A4. Beta receptor blockers (peripheral) A5. Combined α and β receptor blockers (peripheral) A2. Peripherally Acting Adrenergic Drug Alpha1 Blockers (we’ve met these) Doxazosin, prazosin, alfuzosin Block alpha1-receptors which causes BP to decrease Reduces peripheral vascular resistance and BP by dilating both arterial and venous blood vessels Main Use: benign prostatic hyperplasia (BPH) Alpha1 Blockers REMEMBER Tamsulosin (Flomax)* is an α1 blocker BUT *Tamsulosin is not used to control BP, just for BPH. A3. Centrally Acting Adrenergic Drugs Alpha 2 agonist Clonidine and methyldopa 1- Stimulate alpha2-adrenergic receptors. in the brain Decreases sympathetic outflow from the CNS which decreases NE production 2. Stimulate alpha2-adrenergic receptors in kidneys remember alpha 2 opposes alpha 1 Dilates peripheral blood vessels → lowers peripheral resistance → Results in decreased BP So ….Clonidine (Catapres) Used primarily for its ability to decrease blood pressure in an urgent setting Also use in opioid withdrawal as previously discussed Oral (multiple times a day), and topical patch formulations Do not stop abruptly as it may lead to rebound hypertension In reality, Clonidine and methyldopa Not prescribed as first-line home antiHTN drugs High incidence of unwanted adverse effects: orthostatic hypotension, fatigue, and dizziness MIGHT be uses as adjunct drugs after other drugs have failed, in conjunction with other antiHTN such as diuretics A4. Adrenergic Drugs Selective Beta 1 Blockers Metoprolol, Atenolol Reduction of HR through β1 receptor blockade (remember adrenergic blocking of this receptor???) HR results in BP Cause reduced secretion of renin = BP A4. Adrenergic Drugs Selective Beta1 Blockers Nebivolol (Bystolic) Uses: hypertension and HF Action: blocks β1 receptors and produces vasodilatation, which results in a decrease in SVR High doses loses selectivity and blocks both β1 and β2 Less sexual dysfunction All BB- Do not stop abruptly; must be tapered over 1 to 2 weeks A4. Adrenergic Drugs NONSelective Beta Blockers Propranolol Acts equally on β1 and β2 Other uses include situational anxiety associated with public speaking, test taking As mentioned on previous slide, nebivolol at high doses becomes beta nonselective A5. Dual-Action Adrenergic Drugs α1 and β Receptor Blockers Dual antihypertensive effects of reduction in heart rate (beta1 receptor blockade) and vasodilation (alpha1 receptor blockade) Examples are carvedilol (common) and labetalol (not as common) A5. Dual-Action Adrenergic Drugs α1 and β Receptor Blockers Carvedilol (Coreg) Widely used drug that is well tolerated Uses: HTN, mild to moderate HF in conjunction with digoxin, diuretics, and ACE inhibitors Contraindications: severe bradycardia or unstable HF, bronchospastic conditions such as asthma, and various cardiac conduction problems Adrenergic Drugs Indications - HTN But also for Glaucoma (topical) BPH: doxazosin, prazosin, and terazosin (2 for 1) Management of severe HF when used with cardiac glycosides and diuretics Contraindications Acute HF- have to stabilize first MOAIs- yeah doesn’t everything interact with MAOIs? Peptic ulcers Severe liver/kidney disease Asthma (with beta blockers) Adrenergic Drugs: Adverse Effects Orthostatic hypotension 1st-dose syncope Rebound hypertension with abrupt discontinuation Most common: Dry mouth, drowsiness, constipation, sedation Interactions- always check for specific drug interactions Can cause additive CNS depression with alcohol, benzodiazepines, opioids Question #1 When administering an alpha-adrenergic drug for hypertension, it is most important for the nurse to assess the patient for the development of what response? Hypotension Hyperkalemia Oliguria Respiratory distress Answer A Hypotension This is a key point in patient education These drugs have strong vasodilating properties and may cause severe hypotension, especially at the beginning of therapy. B. Angiotensin-Converting Enzyme Inhibitors aka ACE Inhibitors or ACEi Large group of safe and effective drugs Currently are 10 ACEi Often used as first-line drugs for HF and hypertension May be combined with a thiazide diuretic, loop diuretic, or Calcium Channel Blocker (CCB) You need to understand the basics ACE Inhibitors: Review RAAS ACE converts angiotensin I, formed through the action of renin, to angiotensin II Angiotensin 2 is a potent vasoconstrictor and also induces aldosterone secretion by the adrenal glands Aldosterone stimulates sodium resorption (H20 follows Na Both act to raise BP which causes kidneys to reduce renin production ACEi= Great drug to treat HTN BUT contraindicated in pregnancy (2nd,3rd trimester due to fetal renal damage) and breastfeeding first few weeks after birth B. ACE Inhibitors - PRIL Lisinopril (Prinivil) super common, often the 1st drug Enalapril (Vasotec) also common Captopril (Capoten) great if liver disease present Benazepril (Lotensin) Fosinopril (Monopril) Perindopril (Aceon) Quinapril (Accupril) Ramipril (Altace) Trandolapril (Mavik) Primary Effects of the ACE Inhibitors Prevent Na (and H2O) resorption by inhibiting aldosterone secretion (volume reduction) (GO BACK TO RAAS DIAGRAM) blood volume decreases work of the heart preload, or the left ventricular end-diastolic volume which is important in HF ACE SUMMARY OF ACTIVITY 1) Prevent vasoconstriction caused by angiotensin 2 (2) Prevent aldosterone secretion less sodium and water resorption Cardioprotective Effects of ACEi They slow progression of left ventricular hypertrophy (ventricular remodeling) after MI so considered cardioprotective ACE inhibitors have been shown to decrease morbidity and mortality in patients with HF Renal Protective Effects of ACEi ACE inhibitors: reduce glomerular filtration pressure by volume reduction Cardiovascular drug of choice for patients with diabetes since it helps protect kidneys by reducing pressure. Sometimes used low dose for kidney protection with DM without HTN B. ACEi Enalapril (Vasotec) Only ACEi available in both oral and IV Enalapril IV does not require cardiac monitoring Oral enalapril: prodrug (metabolized in liver) Improves patient’s chances of survival after an MI Reduces the incidence of HF B. ACEi Captopril (Capoten) Uses: prevention of ventricular remodeling after MI; reduce the risk of HF after MI Shortest half-life Must be administered multiple times throughout the day so this limits its use Not a prodrug so good for patient with liver disease Question #2 A patient with diabetes has a new prescription for the ACE inhibitor lisinopril. She questions this order because her provider has never told her that she has hypertension. What is the best explanation for this order? The doctor knows best The patient is confused This medication has cardioprotective properties This medication has a protective effect on the kidneys for patients with diabetes Answer D ACE inhibitors have been shown to have a protective effect on the kidneys because they reduce glomerular filtration pressure. This property makes them the cardiovascular drug of choice for patients with diabetes. Question #3 A patient with a history of pancreatitis and cirrhosis is also being treated for hypertension. Which drug will most likely be ordered for this patient? Clonidine Prazosin Diltiazem Captopril Answer D Captopril Captopril is not a prodrug; therefore, it does not need to be metabolized by the liver to be effective. This is an advantage in patients with liver disease. ACE Inhibitors: Adverse Effects *Dry, nonproductive cough, which reverses when therapy is stopped. This is a class effect Dizziness- Note: First-dose hypotensive effect may occur Headache & Fatigue Possible hyperkalemia ** Angioedema: rare but potentially fatal Not safe in pregnancy-are contraindicated during the second and third trimesters of pregnancy because of increased risk of fetal renal damage C. Angiotensin II Receptor Blockers (ARB) Considered an alternative to ACEi Less likely to cause a dry cough and hyper K+ that is common with ACE inhibitors Angiotensin II Receptor Blockers: Mechanism of Action Go back to RAAS diagram! ARBs affect primarily 2 places 1. Vascular smooth muscle - blocks vasoconstriction 2. Adrenal gland -Selectively blocks the binding of Ang 2 to certain Ang 2 receptors inhibiting secretion of aldosterone Lowers volume retention and BP Angiotensin II Receptor Blockers -ARTAN Losartan (Cozaar)- very common Eprosartan (Teveten) Valsartan (Diovan) Irbesartan (Avapro) Candesartan (Atacand) Olmesartan (Benicar) Telmisartan (Micardis) Azilsartan (Edarbi) C. ARB Losartan (Cozaar) Beneficial in patients with HTN and HF Used with caution in patients with kidney or liver dysfunction and in patients with renal artery stenosis ***Not safe for breastfeeding women and should not be used in pregnancy (Cat C 1st trimester, Cat D 2nd-3rd trimester), potential fetal toxicity Appear to be equally effective for the treatment of hypertension and well tolerated ARBs less likely to cause cough and hyperK+ but can still happen Evidence that ARBs are associated with lower mortality after MI than ACE inhibitors Never take ACEi and ARBs at the same time* 5. Calcium Channel Blockers (CCB) Primary use: HTN, angina, some dysrhythmias Cause smooth muscle relaxation by blocking the binding of calcium to its receptors, preventing muscle contraction Results in: Relaxed blood vessels to the heart Decreased peripheral smooth muscle tone Decreased SVResistance Decreased BP E. Diuretics First-line antiHTN in JNC 8 guidelines Decreases fluid volume The results from diuresis: preload, Peripheral resistance Overall effect Decreased workload of the heart and decreased BP Thiazide diuretics are the most commonly used diuretics for HTN Ie hydrochlorothiazide (HCTZ), chlorthalidone We will discuss diuretics further in the chapter on diuretics F. Vasodilators Directly relax arterial or venous smooth muscle (or both) Results in: Decreased SVR Decreased afterload Peripheral vasodilation Indicated for treatment of HTN May be used in combination with other drugs F. Vasodilators Hydralazine (Apresoline) Orally: routine cases of essential hypertension Injectable: hypertensive emergencies BiDil: specifically indicated as an adjunct for treatment of HF in African-American patients F. Vasodilators Sodium Nitroprusside (Nitropress) *Sodium nitroprusside and IV diazoxide are reserved for the management of hypertensive emergencies. Contraindications: severe HF, known inadequate cerebral perfusion (especially during neurosurgical procedures) F. Vasodilators Adverse Effects Hydralazine: dizziness, headache, tachycardia, edema, dyspnea, N/V/D, vitamin B6 deficiency, rash Sodium nitroprusside: hypotension, bradycardia, decreased platelet aggregation, rash G. Direct Renin Inhibitors Aliskirin (Tekturna) Blocks the RAS pathway at the point of activation. Inhibiting renin production prevents the downstream production of Ang II (potent vasoconstrictor) Adverse effects: N/V, severe hypotension, hyponatremia, hyperkalemia… Contraindicated in patients with DM taking ACEi or ARB Miscellaneous Antihypertensives Eplerenone (Inspra) Newer class of drugs called selective aldosterone blockers (remember RAAS?) Reduces BP by blocking the actions of aldosterone at its corresponding receptors in the kidney, heart, blood vessels, and brain Indications: routine treatment of hypertension and for post-MI HF Contraindicated if serum potassium levels are high (above 5.6 mEq/L) A Special Form of HTN Treatment of Pulmonary Hypertension Sildenafil and Tadalafil Commonly used for erectile dysfunction Used for pulmonary hypertension but with different trade names Sildenafil: Revatio* (Viagra for ED) Tadalafil: Adcirca* (Cialis for ED) Received: 26 November 2019 Revised: 10 January 2020 Accepted: 19 January 2020 DOI: 10.1111/obr.13005 PEDIATRICS/PHYSIOLOGY Adipokines: A gear shift in puberty Desirée Nieuwenhuis | Natàlia Pujol-Gualdo Amanda J. Kiliaan Department of Anatomy, Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Preclinical Imaging Center PRIME, Nijmegen, The Netherlands Correspondence Amanda J. Kiliaan, PhD, Associate Professor, Department of Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Preclinical Imaging Center PRIME, Radboud university medical center, 6500 HB Nijmegen, Geert Grooteplein 21N 6525 EZ Nijmegen, The Netherlands. Email: amanda.kiliaan@radboudumc.nl Funding information Europees Fonds voor Regionale Ontwikkeling (EFRO), Grant/Award Number: BriteN 2016 1 | INTRODUCTION The prevalence of obesity in adolescents and children is increasing in | Ilse A.C. Arnoldussen | Summary In this review, we discuss the role of adipokines in the onset of puberty in children with obesity during adrenarche and gonadarche and provide a clear and detailed overview of the biological processes of two major players, leptin and adiponectin. Adipokines, especially leptin and adiponectin, seem to induce an early onset of puberty in girls and boys with obesity by affecting the hypothalamic-pituitary- gonadal (HPG) axis. Moreover, adipokines and their receptors are expressed in the gonads, suggesting a role in sexual maturation and reproduction. All in all, adipokines may be a clue in understanding mechanisms underlying the onset of puberty in child- hood obesity and puberty onset variability. KEYWORDS adipokines, obesity, puberty 1,2 the age of 5 years were overweight or were with obesity in 2016, and 3 Obesity is defined by an excessive accumulation of white adipose tissue (WAT), and it is often indicated by a body mass index (BMI) 4 above 30. Two main types of adipose tissue were described: WAT and brown adipose tissue (BAT), which differ in morphology and func- 5-7 Ilse A.C. Arnoldussen and Amanda J. Kiliaan contributed equally to this work. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2020 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation Obesity Reviews. 2020;21:e13005. wileyonlinelibrary.com/journal/obr 1 of 10 https://doi.org/10.1111/obr.13005 alarming rates. Specifically, worldwide, 41 million children below this number is expected to increase to 70 million in 2025. obesity is associated with various severe health complications, includ- ing increased risk of diabetes mellitus type 2, hypertension, heart dis- eases, and disturbances in sex hormone levels. 5,6 and mitochondria and plays a role in thermogenesis. Adipocytes in tion. BAT consists of adipocytes containing multiple lipid droplets WAT contain only a few mitochondria and a single lipid droplet. Adipose tissue has several functions including the storage of energy, thermogenesis, and the production and secretion of adipokines Generally, two physiological processes, adrenarche and gonadarche, 11,24 Childhood 5,7,8 a key role in puberty onset. Puberty is known as a period through which the body changes physically, being a physiological process resulting in the maturation of children, i.e. they develop sexual characteristics and obtain reproduc- 9,11 Adipokines are involved in a number of physiological processes including blood pressure, metabo- lism, glucose, and vascular homeostasis and may play amongst others 8-10 (hormones, cytokines, and peptides). tive functions. between obesity and puberty,2,12-23 the biological mechanisms under- lying obesity and puberty onset remain unclear. Hereafter, we review in detail the role of adipokines in the onset of puberty in childhood obesity. Although many studies have shown associations 2 | INITIATION OF PUBERTY PHYSIOLOGICAL PROCESSES IN THE interact to regulate the onset of puberty. During adrenarche, the adrenal cortex secretes steroid hormones (including 2 of 10 NIEUWENHUIS ET AL. androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and cortisol), insulin-like growth factor, and growth hormone, which contribute to the pubertal insights on new genetic loci (e.g. melanocortin-4 receptor, mitochon- drial carrier 2, and mitogen-activated protein kinase 13) and on sev- eral pathways that regulate the timing of puberty; however, it partly 34 9,24,25 Both adrenarche and gonadarche are involved in the development growth spurt, body odor, skin oiliness, and skeletal maturation. explains puberty timing variation. Thereby, defining the role of 25 adipokines is of importance in elucidating the variability in puberty as the expression of adipokines is sex-specific and is altered with body composition, adiposity, and during growth spurts. Moreover, adipokines and their receptors are expressed in gonads and several brain regions suggesting involvement in the onset of puberty and sex- ual maturation. Lastly, adipokines interfere in processes regulating timing and duration of puberty, for instance in the HPA and HPG axes which are both key players during adrenarche and gonadarche. Involvement of adipokines in the onset of puberty and specifically in individuals with obesity will be further reviewed in the next 2,24 3 | Puberty onset in girls is assessed using different markers, such as thelarche (breast development), menarche (the start of of pubic hair. pituitary-gonadal (HPG) axis is activated,2,26 and several hormones have been identified to participate in the activation of the HPG axis During gonadarche (Figure 1), the hypothalamic- 2,27 Kisspeptin, neurokinin B, and dynorphin are released by specialized including kisspeptin, neurokinin B, dynorphin, leptin, and ghrelin. 28 key regulator of the pulsatile secretion of gonadotropin releasing neurons, the KNDy neurons in the hypothalamus. Kisspeptin is a 29,30 B stimulates, and dynorphin inhibits the release of kisspeptin, which hormone (GnRH) from the hypothalamus. In addition, neurokinin implies that both coordinate a pulsatile release of kisspeptin. 31 Sub- sections. sequently, the activated HPG axis induces the pituitary gland to secrete luteinising hormone (LH) and follicle stimulating hormone (FSH). As a result, gametogenesis occurs, and the gonads will release sex hormones. Consequently, secondary sex characteristics develop including breast development in girls and an increased testicular vol- 2,26,32 is possibly due to differences in levels of body fat, hypothalamic-pitui- THE ONSET OF PUBERTY IN GIRLS ume in boys. The age at puberty onset varies greatly among individuals, which 19 35 menstruation), and pubic hair development. 33 genome-wide association studies have provided important new tary-adrenal (HPA) axis activity, and genetic background. Recent The average age of However, this age differs between cultures and ethnicities, and since 1980, age at menarche is girls at start of menarche is 12.4 years. 36 significantly decreasing. 36-39 F I G U R E 1 Hormonal regulation in the initiation of puberty in boys and girls. The secretion of kisspeptin, neurokinin B, and dynorphin from KNDy neurons initiate the release of gonadotropin releasing hormone (GnRH) from the hypothalamus. This activates the pituitary gland to produce and secrete luteinising hormone (LH) and follicle stimulating hormone (FSH), which in turn stimulate the gonads to produce estrogen and testosterone in girls and boys, respectively 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 3 of 10 T A B L E 1 Summary of included studies Authors Year Country Study Design Primary Outcome Sex Sample Size (n) Age (y) Data Collection Lian et al21 2019 China Cross-sectional Puberty starts earlier in Chinese Han girls with obesity compared with Chinese Han girls with normal weight. Girls 2996 9-19 2012 and 2013 Biro et al12 Lazzeri et al20 2018 USA 2018 Italy Longitudinal Cross-sectional Body mass index had a greater effect on age at menarche than did race and ethnicity. Girls 946 6-16 2004-2014 Li et al23 2018 China Longitudinal For both, boys and girls, a higher BMI (ie, overweight and obese) is associated with earlier onset of puberty Girls Girls Boys Girls 542 Deng et al22 Flom et al15 2017 China Cross-sectional Increased BMI is associated with early timing spermarche and menarche. Boys Girls Girls 1278258 9-15 2005-2012 He et al24 Holmgren et al17 2017 China 2017 Sweden Cross-sectional Longitudinal Onset of puberty is not related to obesity in boys. Boys Boys Girls Girls 782 7-17 972 929 5839 Kelly et al19 2017 UK 2016 Brazil 2016 USA Longitudinal prospective cohort Higher BMI in girls is associated with the onset of menstruation at an earlier age. 11 10-18 11-17 Barcellos Gemelli et al25 Cross-sectional Longitudinal Excess weight is associated with early age of menarche. Girls 727 2014 2003-2009 Glass et al16 Lee et al26 In girls, but not in boys, greater adiposity is associated with the earlier onset of puberty. Boys Girls 135 Cabrera et al27 Leonibus et al14 2014 USA 2013 Italy Cross-sectional Longitudinal Thelarche occurred earlier than recently reported, while age of menarche remained unchanged. Girls 610 3-17.9 2007 2005-2012 Currie et al13 2012 Europe, USA, Canada Cross-sectional Overweight/obesity during childhood predicts the early onset of puberty in girls. Girls 20410 11, 13, 15 2005-2006 2017 USA Prospective birth cohort Overweight/obese status at the age of 7 ye was associated with increased risk of early menarche 788 From birth to menarche occurred Pregnancies 1959-1966 2016 USA Cross-sectional Boys with overweight enter puberty earlier compared with boys with normal weight or obesity, while puberty starts later in boys with obesity compared with boys with normal weight and overweight. Boys 3872 6-16 2005-2010 Overweight during childhood shows a relation with the early onset of puberty in girls. 6535 4259 695 11 15 5.8-12.2 2009/2010 2013/2014 2014-2017 Higher BMI during childhood is associated with early puberty. 2008 and 2009 2000-2002 Obesity during childhood is related to the earlier onset of puberty. Boys Girls 84 123 71 (Continues) 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 4 of 10 NIEUWENHUIS ET AL. 3.1 | Fat storage For the initiation of puberty, the timing of stimulation and/or inhibi- tion of different hormones is important, and additionally, a certain amount and distribution of body fat is needed in order to start menar- che, which emphasizes the importance of body fat. From an evolution- ary point of view, body fat increases in mammalian females during puberty onset, and it highlights the need to guarantee a healthy preg- 40 women with anorexia nervosa. particularly body fat localized predominantly on the gluteofemoral fat depots, is profoundly associated with start of menarche, more than nancy, offspring, and maternal survival. fat, sex-hormones, and neuroendocrine alterations can evolve in men- strual dysfunction, for instance, in women with severe obesity or in 41-43 44-46 to gluteofemoral fat depots suggesting that leptin may convey infor- amount of total body fat. mation on body fat distribution to the hypothalamus during puberty. An improper level of body Importantly, body fat distribution, Blood leptin levels are strongly related 45 3.2 | HPG axis The HPG axis is activated by the release of kisspeptin resulting in the release of GnRH from the hypothalamus, and LH and FSH from the pituitary gland. In girls, FSH is involved in the development of the folli- cles in the ovaries, and it promotes the secretion of estrogen. LH stim- ulates the production of androgen hormones and induces ovulation 48 9,47 the release of kisspeptin and neurokinin B, and kisspeptin thereby (Figure 1). The secretion of estrogen has an inhibitory effect on inhibits the GnRH release from the hypothalamus. pattern of GnRH is important for the regulation of the menstrual cycle. This roughly 28-day-cycle comprises several phases, including the follicular phase and luteal phase. During the follicular phase, increasing levels of FSH stimulate the maturation of follicles and the production of estrogen from the ovaries. This in turn inhibits the release of FSH from the pituitary gland. A high level of estrogen will induce the production of LH by the pituitary gland, resulting in ovula- tion. The matured follicle secretes progesterone thereby inhibiting the release of GnRH. When the corpus luteum is demolished, there is less 48 3.3 | Adipokines According to results from studies reported in Table 1, girls with obe- sity enter puberty earlier compared with girls with normal higher leptin concentrations inhibit the intake of food and increases inhibition of GnRH. As a consequence, the cycle will start again. whole process, starting from the activated HPG axis, results in the development of the secondary sex characteristics in girls including 9,47 thelarche and menarche. 13,14,16-23,49-51 weight. these girls might be found in the secretion of adipokines. For instance, leptin is positively associated with the amount of body fat. Generally, energy expenditure. 9,52-54 An explanation for the early onset of puberty in The expression This TABLE 1 (Continued) Authors Year Country Study Design Primary Outcome Sample Sex Size (n) Age (y) Data Collection Herman-Giddens et al28 2012 USA Cross-sectional Observed mean ages of beginning genital and pubic hair growth and early testicular volumes were earlier than in past studies, depending on the characteristic and race/ethnicity. Boys 4131 6-16 2005-2010 Sorensen et al29 Aksglaede et al30 2010 2009 Denmark Denmark Cross-sectional/longitudinal Longitudinal Puberty onset at earlier ages was associated with an increased BMI in boys. Boys 1528 5.8-19.9 1991-1993/2006-2008 1930-1969 Juul et al31 Ribeiro et al32 2007 2006 Denmark Portugal Retrospective cohort Cross-sectional Higher BMI is associated with early voice break. 11-15 10-15 1990-1999 Kaplowitz et al18 Abbreviation: BMI, body mass USA Cross-sectional The early onset of puberty in Caucasian girls is likely related to an increased BMI. 5-12 1992-1993 2001 index. The higher BMI in boys and girls at 7 y of age, the earlier they enter puberty. Boys 21 612 Girls 135 223 Boys 463 Boys 382 Girls 437 Girls 10 750 Early sexual maturation in boys and girls is associated with overweight. 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 5 of 10 Leptin may possibly play a role in adrenarche as its plasma level increases with higher levels of body fat and as it can modulate both girls. 33 ing adrenarche. In coherence, in children with obesity, the androgen These findings suggested that lower reproductive status was associated with higher total adiponectin concentrations and that a higher reproductive status was related to higher HMW adiponectin the HPA and HPG axes. These axes are functionally integrated dur- DHEAS was positively associated with leptin levels. Nevertheless, concentrations in girls. In addition, individuals with obesity often another study showed that enhanced adrenal androgen secretion in girls with premature adrenarche was not explained by leptin or BMI 55 ated with androgen levels in girls ; however, it was not related to levels. and IL-6. TNF-α alters, and IL-6 inhibits the expression of 56 8 In addition, the adipokine adiponectin was negatively associ- 57 differences of adiponectin seem to develop during the progression of 56 adiponectin (Figure 2). Thereby, a low level of total adiponectin and/or high levels of inflammatory cytokines in individuals with obe- sity can promote the onset of puberty. Many more adipokines are secreted by WAT including omentin, 52,65-67 9,36,62,68 adrenarche in girls with Prader-Willi syndrome. Interestingly, sex puberty. adrenarche; however, both are not required factors. Thus, leptin and adiponectin might be able to influence In gonadarche, leptin can stimulate the secretion of kisspeptin, and subsequently activation of the HPG axis, which eventually increases the expression of estrogen and androstenedione in the ova- 58 2,60 65-67 The expression of these ries (Figure 2). Ob gene in WAT, resulting in the synthesis and secretion of leptin. Thus, high levels of leptin promote onset of puberty in girls via secre- tion of kisspeptin, and estrogen stimulates leptin secretion addition- ally. Moreover, adiponectin can affect the HPG axis due to the expression of adiponectin receptors in the hypothalamus, pituitary In return, estrogen stimulates the expression of the 59 gland, and gonads. onset as it inhibits the secretion of kisspeptin and GnRH in the hypo- thalamus and the release of GH and LH in the pituitary gland, and 2,60-62 52,60 63 girls with central precocious puberty (CPP). Moreover, total adiponectin had negative correlations with progression of puberty in girls (defined by Tanner stages), whereas HMW adiponectin had FIGURE 2 Adipokinesaffectingthe initiation of puberty in girls. Leptin stimulates the release of kisspeptin in KNDy neurons, which activates the hypothalamus to produce gonadotropin releasing hormone (GnRH). In response to the release of GnRH, the pituitary gland secretes follicle stimulating hormone (FSH) and luteinising hormone (LH), which stimulates the ovaries to release estrogen resulting in the formation of secondary sex characteristics in girls. Estrogen stimulates the production of leptin. Adiponectin inhibits GnRH release resulting in reduced levels of GnRH and thereby a delayed onset of puberty. TNF- α and IL-6 inhibit the production of adiponectin and therefore stimulate the onset of puberty In detail, adiponectin is a regulator of puberty thereby inhibiting the onset of puberty (Figure 2). with obesity often have low levels of adiponectin. et al. showed that total adiponectin was significantly lower, whereas high molecular weight (HMW) adiponectin was significantly higher in ment. 55 63 develop a chronic low-grade inflammatory state, which can be indi- cated by a high level of circulating inflammatory cytokines like TNF-α 64 Individuals Sitticharoon positive associations with LH levels and the progression of puberty in 63 visfatin, resistin, and chemerin. and visfatin are expressed in the ovaries. adipokines in the ovaries suggests a role within the reproductive sys- tem; however, the exact biological processes have to be examined. Thus, specifically leptin, adiponectin, and inflammatory cytokines pro- duced by WAT could be permissive key players during an early onset of puberty in girls with obesity. As an exception, HMW adiponectin seems to have a stimulatory effect on peripheral repro- ductive function as HMW is not able to cross the blood brain 63 barrier. 4 | Markers that are used to assess puberty onset in boys are THE ONSET OF PUBERTY IN BOYS spermarche, voice break, testicular volume, and pubic hair develop- 35 spermarche develop in the early stages of puberty onset, voice In women, omentin, chemerin, While pubic hair development, larger testicular volume, and 69 testicular volume increases, which occurs at an average age of break usually appears in later stages of puberty. Generally, first 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 6 of 10 NIEUWENHUIS ET AL. 11.9 years, followed by the development of pubic hair at 12.2 years of average, and lastly, boys experience spermarche around an aver- 55 related with leptin levels. Thereby, leptin plausibly has a minor impact in adrenarche in boys. Since leptin receptors are found in the hypothalamus, pituitary gland, and testes, they might be involved in the onset of puberty by affecting the HPG axis during gonadarche. Leptin stimulates the release of kisspeptin and GnRH, and as a consequence, it accelerates the onset of puberty (Table 1, Figure 3). In contrast, adiponectin inhibits the secretion of GnRH, GH, LH, and FSH therewith delaying the onset of puberty. However, adiponectin levels are generally lower in men compared with women and even lower in men with obe- age age of 13.4 years. 70 4.1 | Fat storage Many aspects of the reproductive physiology are energetically demanding,71 and therefore, an adequate energy level is necessary. In boys, a dynamic change in body composition occurs around the age of 10 to 13 years, in which they gain approximately 40% of sity. culating inflammatory cytokines. levels can stimulate the HPG axis and therewith an early onset of puberty in boys. Nevertheless, leptin can inhibit the production of tes- 72 mostly consisting of lean mass, which causes exhaustion of most of fat. Subsequently, a growth spurt follows in which they gain tissue 72 in boys, an adequate amount of body fat is important in the onset of their body fat. These alterations in amount of body fat indicate that 4.2 | Puberty in boys is initiated by the release of kisspeptin. As mentioned before, this activates the HPG axis, resulting in the release of GnRH from the hypothalamus, and consequently the release of LH and FSH 9,74 puberty. tosterone from the testes, to estrogen (Figure 3). of the development of secondary sex characteristics in boys. Additionally, leptin can affect fertility in men as it can modulate the nutritional support of spermatogenesis, and moreover, dysfunction of spermatogenesis is associated with an increased leptin level and 73 58 2,60-62 HPG axis from the pituitary gland (Figure 1). and LH stimulates the secretion of testosterone from the testes, which inhibits the release of kisspeptin from the KNDy neurons and 9,48 in men, the release of kisspeptin is more consistent, causing a con- 29,48 subsequently GnRH from the hypothalamus. receptors expressed on KNDy neurons. In humans, KNDy neurons Contrarily to women, LH-induced testosterone levels lead to the stant release of LH. development of secondary sex characteristics in boys. differences between sexes in kisspeptin release are related to a sex- specific and sex steroid-dependent kisspeptin system as estrogen and progesterone modulate kisspeptin activity through the sex-steroid 48 in the infundibular nucleus are involved in negative and positive sex- 48 tal exposure to sex steroids and result in sex-specific differences in steroid feedbacks. kisspeptin release. These sexual dimorphisms are induced by perina- 75,76 4.3 | Adipokines The association between obesity and puberty onset in boys is rather controversial compared with findings in girls. Most studies reported an early onset of puberty in boys associated with increased ate adipose tissue from actual breast tissue. stages are more difficult to assess than female stages as boys lack a more determined marker such as menarche. Thirdly, puberty onset can be indicated by the activation of the HPG axis, and the presence of these secondary sex characteristics is the result of hormonal 2 14,17,22,23,50,51,77,78 BMI, 20,49 all while others reported no associations at Current markers used 79 16,80 or a delayed onset of puberty (Table 1). The presence of excessive adipose tissue can be involved in puberty onset in boys as the secretion of adipokines can modulate both adrenarche and gonadarche. Leptin can affect adrenarche by modulating both the HPG and HPA axes,33 and moreover, androgen levels were positively 55 nal androgen secretion in boys with premature adrenarche was not associated with plasma leptin levels. Nevertheless, enhanced adre- 9 In more detail, 61,62 adiponectin, and individuals with obesity often have high levels of cir- Moreover, inflammatory cytokines, TNF-α, and IL-6, inhibit expression of the leptin receptor in the testis. FSH induces spermatogenesis, too. function and role still have to be examined. 64 High leptin and low adiponectin and fat tissue can convert testosterone Both processes might result in the delay 29,61,79 81,82 In men, other adipokines like chemerin are found in the gonads 65 Thus, particularly high leptin and low adiponectin levels stimulate the HPG axis and thereby accelerate the onset of puberty in boys. Additionally, leptin can dysregulate the development of secondary sex characteristics and spermatogenesis by affecting testosterone levels and nutritional sup- port of spermatogenesis. 5 | LIMITATIONS AND FUTURE RESEARCH DIRECTIONS Even though multiple epidemiological studies have shown the link between puberty onset and obesity, there are some important limita- tions. Firstly, determining both the onset and stage of puberty is rather difficult. For instance, assessing the stage of breast develop- ment in girls with obesity is complicated as clinicians should differenti- 2 changes in response to the activated HPG axis. to determine the onset of puberty refer to secondary sex characteris- tics, such as testicular volume in boys and breast development in girls. A more accurate measurement of puberty onset would be to combine secondary sex characteristics with plasma or serum hormone level measurements such as LH, FSH, adipokines, e.g. leptin. Thereby, differences in puberty measurements could explain variations in the age of puberty onset between boys and girls within different Thereby, resistin is expressed in the testes of rats, but its exact 83 Secondly, male pubertal 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 7 of 10 FIGURE 3 Adipokines affecting the initiation of puberty in boys. Leptin activates kisspeptin secretion in KNDy neurons, this activates the production of gonadotropin releasing hormone (GnRH) from the hypothalamus. GnRH stimulates the pituitary gland to secrete follicle stimulating hormone (FSH) and luteinising hormone (LH), activating the production of testosterone from the testes allowing the development of secondary sex characteristics. Leptin also inhibits the production of testosterone, which may cause a delayed onset of puberty. Adiponectin inhibits GnRH release. Low levels of adiponectin, as a result of TNF-α and IL-6 expression, lead to a reduced inhibition of GnRH. In response to GnRH release, the pituitary gland will secrete FSH and LH, and the testes will produce testosterone resulting in the development of secondary sex characteristics in boys countries, and In addition, the inclusion of a of puberty. ferent time points is complicated, as subjects examined several decades ago presented pronounced differences concerning lifestyle patterns such as nutrition and exercise habits. Lastly, obesity or over- weight is often determined by BMI, a classification based on weight and height measurements. Additionally, it is important that all studies studies or across continents, ethnicities proper age range (8-16 years) is important when assessing the onset (Figure 4). 12-15,17,20-23,49,77-79,84,85 30,47 Furthermore, comparison between studies from dif- 86 Specifically in children, BMI is often dependent on age and growth use the same anthropometric standards and sex-specific cut-offs. 13,14,16-23,49-51,77-80 fat and would represent a more accurate measurement in its regard. Based on this review, several suggestions can be made for further research. Firstly, the roles of adipokines like resistin, chemerin, visfatin, and omentin in puberty onset, fertility, and sexual maturation should be examined in detail. Secondly, future research examining the onset of puberty should combine indicators of puberty onset (e.g. breast development or testicular volume) with plasma or serum hor- mone measurements such as LH, FSH, sex-steroids, adipokines (e.g. spurts. ment in case of growth spurts. distribution of body fat should be taken into account in determining puberty and obesity in children. For instance, the body adiposity index (BAI), which was introduced in 2011 by Bergman et al.,87 uses hip cir- cumference and height in order to estimate the percentage of body 87 Thereby, BMI is a less accurate measure- F I G U R E 4 87,88 Therefore, both percentage and Average age of puberty onset in Europe, China, and the United States according to several studies from Table 1. Age of puberty onset ranges from 8.47 to 13.33 years in girls and from 8.63 leptin), and body fat distribution (e.g. BAI,87 waist-hip ratio's and/or dual-energy X-ray absorptiometry (DXA)2). Additionally, defining con- sistent and general measurements of puberty in both boys and girls, combined with a proper age range (8-16 years), would facilitate the comparisons between different studies and their results. 12-15, 17, 20-23, 25-29, 31 to 13.7 years in boys. included if average age of markers used to assess puberty was not reported. Pink: girls. Blue: boys Studies (Table 1) were not 39, 56 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 8 of 10 NIEUWENHUIS ET AL. 6 | CONCLUSION In conclusion, epidemiological data regarding obesity and puberty onset in girls show similar outcomes as adiposity results in the early onset of puberty in girls. The majority of the studies examining boys with obesity indicate an early onset of puberty, while not all reported an earlier onset of puberty. In detail, high leptin, TNF-α, and IL-6 levels combined with low adiponectin levels stimulate the activation of the HPG axis in girls and boys with obesity, and 5, 45, 50, 51 REFERENCES 1. Kumar S, Kelly AS. Review of childhood obesity: from epidemiology, etiology, and comorbidities to clinical assessment and treatment. May- o Clin Proc. 2017;92(2):251-265. 2. Reinehr T, Roth CL. Is there a causal relationship between obesity and puberty? The Lancet Child & adolescent health. 2019;3(1):44-54. 3. WorldHealthOrganization. Facts and figures on childhood obesity. 2017. 4. Guglielmi V, Sbraccia P. Obesity phenotypes: depot-differences in adipose tissue and their clinical implications. Eat Weight Disord. 2018; 23(1):3-14. 5. Gomez-Hernandez A, Beneit N, Diaz-Castroverde S. Escribano O. 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FUNDING INFORMATION This research was funded by Europees Fonds voor Regionale Ontwikkeling (EFRO), project BriteN 2016. ORCID Ilse A.C. Arnoldussen Amanda J. Kiliaan https://orcid.org/0000-0002-7395-5284 https://orcid.org/0000-0002-2158-6210 13, 14, 16-26, 29-32 Furthermore, several receptors Nevertheless, We conclude Search strategy We searched PubMed for articles published before Novem- ber 15th, 2019 using relevant keywords, including ‘onset of puberty and adiposity/obesity’, ‘onset of puberty’, ‘children with obesity’, ‘adipose tissue’, ‘childhood obesity’, ‘adiposity’, ‘obesity’, ‘adipokine(s)’, ‘HPG axis’, ‘adipokines ovary/ova- ries’, or ‘adipokines testes’, either alone or in combination. 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Obesity Reviews. 2020;21:e13005. https://doi.org/ 10.1111/obr.13005 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are goverL'attentato alle Torri Gemelle dell'11 settembre 2001 è stato orchestrato dall'organizzazione terroristica al-Qaida, guidata da Osama bin Laden. Al-Qaida, un gruppo estremista islamico, aveva l'obiettivo di colpire gli Stati Uniti per una serie di motivi, tra cui la loro presenza militare in Medio Oriente, il sostegno a Israele e le politiche economiche e geopolitiche percepite come oppressive nei confronti dei Paesi musulmani. L'attacco ha coinvolto 19 terroristi, che hanno dirottato quattro aerei commerciali: due hanno colpito le Torri Gemelle a New York, un altro il Pentagono vicino a Washington, D.C., mentre il quarto, United Airlines Flight 93, è precipitato in un campo in Pennsylvania dopo che i passeggeri hanno tentato di riprendere il controllo dell'aereo. Osama bin Laden ha rivendicato la responsabilità dell'attentato, che ha provocato circa 3.000 morti e ha avuto un impatto duraturo sulla politica internazionale, portando alle guerre in Afghanistan e Iraq e a significativi cambiamenti nella sicurezza globale Il fatto che quattro aerei dirottati siano riusciti a deviare dalla loro rotta senza un immediato intervento da parte delle autorità aeree è legato a una serie di fattori: 1. **Dirottamenti inattesi**: Prima dell'11 settembre 2001, il protocollo per gestire i dirottamenti aerei era molto diverso. I dirottamenti aerei, quando accadevano, di solito erano gestiti attraverso negoziazioni e si presumeva che i dirottatori cercassero principalmente attenzione o denaro, non attacchi suicidi. Non c'era una preparazione specifica per l'eventualità che gli aerei venissero usati come armi. 2. **Interruzione delle comunicazioni**: I dirottatori hanno spento i transponder sugli aerei (dispositivi che inviano segnali radar con informazioni su altitudine e posizione), rendendo difficile per i controllori del traffico aereo tracciare con precisione gli aerei. Gli aerei risultavano ancora visibili sui radar primari, ma senza i dati specifici del transponder era difficile capire immediatamente che c'era una deviazione fuori rotta. 3. **Tempo di reazione**: Gli eventi si sono svolti in un breve arco di tempo. I primi segni di problemi sui voli sono emersi intorno alle 8:14 (con l'American Airlines Flight 11), e il primo schianto contro la Torre Nord è avvenuto alle 8:46. Tra l'inizio dei dirottamenti e gli impatti, il tempo per reagire è stato limitato. La portata dell'attacco era senza precedenti, e nessuno si aspettava che i dirottatori avrebbero usato gli aerei come armi contro obiettivi civili. 4. **Coordination failures**: Anche se ci sono stati segnali di problemi, la comunicazione tra le varie agenzie coinvolte (Federal Aviation Administration, NORAD, ecc.) non era ottimale. La procedura per attivare la difesa aerea in caso di dirottamento era complessa, e la possibilità che aerei civili venissero utilizzati come armi suicide non era contemplata nei protocolli. 5. **NORAD e tempi di risposta**: Il NORAD (North American Aerospace Defense Command), incaricato della difesa aerea, aveva una capacità limitata di intercettare rapidamente aerei dirottati nello spazio aereo interno. Prima dell'11 settembre, le operazioni di difesa erano concentrate su possibili minacce esterne, e non su attacchi interni. Anche quando i caccia furono inviati, era troppo tardi per impedire gli impatti. Questi fattori, combinati con l'incredulità che un tale attacco potesse realmente accadere, hanno reso possibile che quattro aerei fossero dirottati e usati come armi senza un intervento preventivo efficace. Dopo l'11 settembre, furono apportati significativi cambiamenti ai protocolli di sicurezza aerea per prevenire simili attacchi in futuro. L'idea che l'11 settembre abbia fornito un "pretesto" per attaccare l'Afghanistan è stata ipotizzata da diverse teorie del complotto e punti di vista critici sulla politica estera degli Stati Uniti. Tuttavia, è importante distinguere tra i fatti documentati e le ipotesi non verificate. ### Fatti documentati: 1. **Al-Qaida e Osama bin Laden**: Gli attacchi dell'11 settembre sono stati rivendicati da al-Qaida, che aveva il suo quartier generale in Afghanistan sotto la protezione del regime talebano. Gli Stati Uniti hanno chiesto ai talebani di consegnare Osama bin Laden, ma il governo talebano ha rifiutato. Questo ha portato all'intervento militare in Afghanistan con l'obiettivo dichiarato di smantellare al-Qaida e rimuovere i talebani dal potere. 2. **Legittimazione internazionale**: L'invasione dell'Afghanistan è stata ampiamente appoggiata a livello internazionale, con il sostegno delle Nazioni Unite e della NATO. Il Consiglio di Sicurezza delle Nazioni Unite ha approvato risoluzioni che condannavano gli attacchi e riconoscevano il diritto di difesa degli Stati Uniti. ### Teorie del complotto: Alcuni teorici sostengono che l'11 settembre potrebbe essere stato usato come pretesto per giustificare una guerra che rientrava in più ampi interessi geopolitici. Secondo questa visione, l'invasione dell'Afghanistan non riguardava solo la lotta contro il terrorismo, ma anche: - **Influenza geopolitica**: Gli Stati Uniti avrebbero cercato di stabilire una maggiore presenza militare e influenza in una regione strategica, vicina a Paesi come l'Iran, la Cina e la Russia. - **Risorse naturali**: L'Afghanistan ha un'importanza geopolitica anche per i suoi potenziali corridoi energetici e per le sue risorse minerarie, anche se non ha ricchezze petrolifere significative come altri Paesi del Medio Oriente. ### Critiche legittime: Al di là delle teorie del complotto, ci sono critiche legittime alla risposta degli Stati Uniti e all'espansione della guerra al terrorismo. Ad esempio: - **La guerra in Iraq**: Mentre l'invasione dell'Afghanistan fu largamente supportata, l'invasione dell'Iraq nel 2003 fu molto più controversa. Molti analisti ritengono che l'amministrazione Bush abbia sfruttato la paura generata dall'11 settembre per giustificare un attacco all'Iraq, anche se non c'erano prove concrete di un collegamento tra il regime di Saddam Hussein e al-Qaida. - **Durata della guerra**: La guerra in Afghanistan si è trasformata in un conflitto di lunga durata, che molti vedono come fallimentare, con risultati incerti nonostante il grande impegno militare ed economico. ### Conclusione: Sebbene sia possibile che alcune figure politiche o militari abbiano sfruttato l'attacco dell'11 settembre per portare avanti agende geopolitiche preesistenti, i fatti storici mostrano che l'invasione dell'Afghanistan fu una reazione diretta agli attacchi e alla minaccia di al-Qaida. Le decisioni successive, in particolare l'espansione della "guerra al terrorismo", sono state oggetto di forti critiche e controversie, ma non ci sono prove concrete che l'11 settembre sia stato pianificato o lasciato accadere per giustificare un'invasione. La **caduta delle Torri Gemelle** l'11 settembre 2001 è stata causata principalmente dai **danni strutturali provocati dall'impatto degli aerei e dal conseguente incendio**, secondo le indagini ufficiali. Le teorie che ipotizzano l'uso di esplosivi sono state ampiamente investigate ma smentite dalle analisi tecniche e dalle prove disponibili. ### Versione ufficiale: 1. **Impatto degli aerei**: Gli aerei di linea colpirono le Torri Gemelle a una velocità molto elevata, causando danni immediati e significativi alle colonne portanti esterne e interne degli edifici. Questi danni strutturali compromettevano già parte della stabilità delle torri. 2. **Incendi**: L'impatto degli aerei ha causato l'esplosione del carburante contenuto nei serbatoi, innescando vasti incendi. Il calore generato dagli incendi all'interno degli edifici raggiunse temperature estremamente elevate (fino a 1000°C o più), che indebolirono ulteriormente l'acciaio delle strutture portanti. 3. **Cedimento strutturale**: L'acciaio non deve necessariamente fondere per perdere la sua capacità portante; a temperature elevate, l'acciaio diventa più malleabile e perde resistenza. Questo, unito al danno meccanico già causato dall'impatto degli aerei, ha portato al cedimento progressivo delle strutture superiori, che sono collassate sui piani inferiori in una sorta di effetto domino. Questo spiega il "crollo verticale" delle torri. ### Investigazioni tecniche: 1. **Rapporto del NIST**: Il **National Institute of Standards and Technology (NIST)** ha condotto un'indagine approfondita sulla caduta delle torri. Secondo il rapporto del NIST, **non ci sono prove** che suggeriscano l'uso di esplosivi o ordigni nei crolli delle torri. I crolli sono stati attribuiti esclusivamente ai danni strutturali causati dagli impatti e agli incendi successivi. 2. **Simulazioni e analisi**: Gli ingegneri hanno simulato il comportamento degli edifici durante l'attacco e hanno concluso che l'indebolimento delle strutture portanti a causa del calore è stato sufficiente a spiegare il collasso. Il crollo avvenne in maniera progressiva e non con le caratteristiche di una demolizione controllata, come l'uso di esplosivi. ### Teorie del complotto: Nonostante le spiegazioni tecniche ufficiali, alcune persone sostengono che il crollo sia stato causato da esplosivi piazzati all'interno delle torri. Queste teorie si basano su: - **Testimonianze di esplosioni**: Alcune persone hanno riportato di aver sentito rumori di esplosioni prima o durante i crolli. Tuttavia, gli esperti hanno spiegato che questi rumori possono essere attribuiti a numerosi fattori, come i cedimenti strutturali e le esplosioni secondarie dovute al cedimento di infrastrutture interne (ad esempio, serbatoi di gas o trasformatori elettrici). - **Crollo simmetrico**: Alcuni teorici sostengono che il crollo delle torri sia stato troppo "ordinato" per essere casuale. Tuttavia, il collasso verticale è stato spiegato come il risultato del cedimento simultaneo di più colonne portanti indebolite dal calore. - **Teoria del crollo controllato**: Alcuni sostengono che le torri siano cadute con la rapidità e la precisione di una demolizione controllata. Tuttavia, studi dettagliati del NIST e altre organizzazioni non hanno trovato alcuna prova di esplosivi o segni di una demolizione pianificata. ### Conclusione: Le indagini ufficiali e i rapporti tecnici indicano chiaramente che il crollo delle Torri Gemelle è stato causato dagli impatti degli aerei e dai successivi incendi che hanno indebolito la struttura, portando al collasso progressivo. Le teorie che ipotizzano l'uso di esplosivi sono state esaminate ma non supportate da prove concrete. L'11 settembre 2001 ha avuto un impatto profondo anche sulla musica, influenzando artisti di diversi generi e portandoli a esprimere il dolore, la rabbia, la riflessione e la speranza che l'evento ha generato. La musica ha raccontato l'episodio da diverse prospettive, esplorando sia il trauma individuale che quello collettivo, e offrendo una forma di guarigione o commemorazione per chi l'ha vissuto. ### Canzoni che hanno affrontato l'11 settembre: 1. **Bruce Springsteen – "The Rising" (2002)** Questo album è uno dei più emblematici legati all'11 settembre. La title track, "The Rising", racconta la storia di un pompiere che sale verso le Torri Gemelle e riflette sul sacrificio e la speranza. L'intero album esplora i temi della perdita e della resilienza attraverso il prisma dell'America post-11 settembre, e rappresenta una sorta di catarsi per molte persone che hanno cercato conforto nella musica. 2. **Paul McCartney – "Freedom" (2001)** Paul McCartney era a New York il giorno degli attacchi e ha scritto questa canzone in risposta, cercando di trasmettere un messaggio di forza e resistenza. "Freedom" è stata eseguita al concerto benefico **"The Concert for New York City"**, un evento organizzato per raccogliere fondi per le vittime dell'attacco e celebrare il coraggio dei soccorritori. 3. **Toby Keith – "Courtesy of the Red, White and Blue (The Angry American)" (2002)** Questa canzone country ha rappresentato il lato più patriottico e arrabbiato della reazione americana agli attentati. Toby Keith esprime il desiderio di giustizia (o vendetta), e la canzone è diventata molto popolare tra coloro che volevano una risposta forte agli attacchi. Sebbene controversa per i suoi toni duri, ha rappresentato una parte significativa del sentimento nazionale. 4. **Alan Jackson – "Where Were You (When the World Stopped Turning)" (2001)** Questa ballata country ha cercato di catturare lo shock, la confusione e il dolore collettivo che l'11 settembre ha causato. La canzone pone domande che molti si sono fatti: "Dov'eri quando il mondo si è fermato?" Il tono è riflessivo e malinconico, ed è diventata una delle canzoni più ricordate che trattano direttamente dell'evento. 5. **U2 – "Walk On" (2001)** Sebbene scritta prima dell'11 settembre, "Walk On" è diventata una sorta di inno di resilienza dopo l'attacco. U2 ha dedicato diverse performance della canzone alle vittime dell'11 settembre, e il testo, che parla di andare avanti di fronte alle avversità, è stato interpretato come un messaggio di forza per chi cercava di ricostruire la propria vita. 6. **Neil Young – "Let’s Roll" (2001)** Questa canzone è stata ispirata dagli atti eroici dei passeggeri del volo United 93, che si sono ribellati contro i dirottatori, impedendo che l'aereo colpisse un obiettivo a terra. La frase "Let's roll" era ciò che uno dei passeggeri, Todd Beamer, ha detto mentre guidava la ribellione. Neil Young ha scritto questo brano per onorare quei passeggeri coraggiosi. ### Concerti e eventi musicali commemorativi: - **The Concert for New York City (2001)** Subito dopo gli attacchi, questo grande concerto benefico si è tenuto al Madison Square Garden per raccogliere fondi a favore delle vittime e per rendere omaggio ai soccorritori. Vi hanno partecipato artisti come Paul McCartney, The Who, Mick Jagger, David Bowie e molti altri. L'evento è stato una celebrazione dell'unità e della solidarietà di fronte alla tragedia. - **America: A Tribute to Heroes (2001)** Questo telethon, trasmesso a livello nazionale, ha visto la partecipazione di artisti come Bruce Springsteen, U2, Celine Dion e molti altri. Lo scopo era quello di raccogliere fondi per le vittime e i loro familiari, e molte delle performance erano riflessive e piene di emozione, offrendo un momento di unità e commiserazione collettiva. ### Effetti sull’industria musicale: L'11 settembre ha avuto anche un impatto diretto sull'industria musicale: - **Censura e sensibilità**: Molte canzoni che potevano essere considerate inappropriate o troppo aggressive dopo l'11 settembre furono temporaneamente rimosse dalle playlist radiofoniche, come "Imagine" di John Lennon (per il suo messaggio pacifista) o "New York, New York" di Frank Sinatra, per il legame con la città colpita. - **Modifiche ai testi e alle copertine**: Alcuni artisti modificarono testi o copertine di album che potevano sembrare insensibili o inappropriate nel clima post-11 settembre. Ad esempio, i Dream Theater cambiarono la copertina del loro album "Live Scenes from New York" perché raffigurava il World Trade Center in fiamme, una coincidenza che uscì pochi giorni prima degli attacchi. ### Conclusione: La musica ha offerto un modo per elaborare il trauma dell'11 settembre, sia attraverso canzoni che commemorano i caduti, sia con inni che hanno ispirato resistenza e speranza. Artisti di ogni genere hanno interpretato l'evento in modi diversi, riflettendo la complessità delle emozioni che ha suscitato, dall'angoscia e la perdita alla forza e la solidarietà. Sì, le **Dixie Chicks** (oggi conosciute come **The Chicks**) hanno avuto notevoli problemi, ma non per aver trattato direttamente il tema dell'11 settembre. I problemi che hanno affrontato sono legati alle loro critiche alla guerra in Iraq e alla presidenza di **George W. Bush**, che erano strettamente connesse al clima politico post-11 settembre. ### Contesto: Nel marzo 2003, durante un concerto a Londra, la cantante **Natalie Maines**, frontwoman delle Dixie Chicks, fece una dichiarazione che scatenò una controversia a livello nazionale negli Stati Uniti. Mentre l'invasione dell'Iraq era imminente, Maines disse al pubblico: > **"Just so you know, we’re ashamed that the President of the United States is from Texas."** Questa dichiarazione era una critica diretta al presidente **George W. Bush**, nato in Texas come Maines e il resto della band. La critica arrivava in un momento in cui il patriottismo e il sostegno alla guerra erano fortemente presenti negli Stati Uniti, specialmente nel Sud, dove le Dixie Chicks avevano una vasta base di fan nella comunità country. ### Conseguenze: 1. **Boicottaggi e censure**: Dopo il commento di Maines, molte stazioni radio, soprattutto quelle country, **boicottarono le Dixie Chicks**, rimuovendo le loro canzoni dalle playlist. In alcune parti degli Stati Uniti, i fan organizzarono pubblici **roghi dei loro album**. 2. **Perdita di supporto nel mondo country**: La comunità della musica country, che spesso riflette valori patriottici e conservatori, si rivolse contro di loro. Molti artisti e fan country criticarono duramente le Dixie Chicks per aver espresso opinioni contro la guerra e contro il presidente in un momento in cui il sostegno alla leadership nazionale era considerato importante. 3. **Minacce e ostilità**: Le Dixie Chicks ricevettero **minacce di morte** e furono soggette a intense campagne di odio. Questo dimostrò quanto fossero polarizzate le opinioni politiche negli Stati Uniti all'epoca, specialmente nell'industria della musica country. 4. **Carriera messa in pausa**: Dopo la controversia, la loro carriera negli Stati Uniti subì un grave colpo. Le vendite dei loro album calarono, e per diversi anni furono considerate una "band alienata" dall'industria country. Tuttavia, il gruppo trovò maggiore supporto nel pubblico internazionale e in generi musicali non tradizionalmente legati al country. ### La risposta delle Dixie Chicks: Le Dixie Chicks risposero alla controversia con coraggio e determinazione. Nel 2006, pubblicarono l'album **"Taking the Long Way"**, che includeva la famosa canzone **"Not Ready to Make Nice"**. Questo brano affrontava direttamente le critiche ricevute e il loro rifiuto di scusarsi per aver espresso le proprie opinioni. > **"Not Ready to Make Nice"** fu un grande successo e vinse diversi Grammy Awards, incluso quello per il **Miglior Album dell'Anno** e la **Canzone dell'Anno**. L'album rappresentava un chiaro messaggio: non erano pronte a cedere alla pressione e non si scusavano per aver esercitato la loro libertà di espressione. ### Riflessione sulla controversia: La controversia rifletteva una tensione più ampia nella società americana post-11 settembre, dove il patriottismo era visto da molti come un valore sacro e la critica alle politiche governative, specialmente riguardo alla guerra, poteva essere percepita come un tradimento. Le Dixie Chicks divennero un simbolo di questa polarizzazione e del conflitto tra libertà di espressione e patriottismo. ### Conclusione: Sebbene le Dixie Chicks non abbiano trattato direttamente l'11 settembre, la loro critica alla guerra in Iraq e a George W. Bush, strettamente connessa agli eventi post-11 settembre, portò a una delle più grandi controversie nella storia della musica country. Tuttavia, con il tempo, il gruppo è riuscito a superare le difficoltà e ha ottenuto una sorta di redenzione artistica e pubblica, guadagnando il rispetto di molti per la loro integrità e il loro coraggio nel difendere le proprie opinioni. Sì, i **Green Day** hanno trattato indirettamente i temi legati all'11 settembre e le sue conseguenze, soprattutto attraverso il loro album più famoso, **"American Idiot"** (2004). L'album non affronta direttamente gli attacchi dell'11 settembre, ma esplora il clima politico e sociale che si è sviluppato negli Stati Uniti dopo gli attentati, in particolare la guerra in Iraq, il patriottismo estremo e la manipolazione dei media. ### Contesto di "American Idiot": "American Idiot" è un concept album che segue un personaggio chiamato **Jesus of Suburbia**, che rappresenta la frustrazione e l'alienazione della generazione cresciuta nell'America post-11 settembre. L'album racconta una storia di rabbia, disillusione e ribellione contro il governo, i media e la società americana dell'epoca. ### Temi principali legati all'11 settembre e alle sue conseguenze: 1. **Critica ai media e alla manipolazione dell'informazione**: - La title track, **"American Idiot"**, critica aspramente la manipolazione dei media e il modo in cui la società americana è stata spinta verso un patriottismo cieco e un clima di paura. La canzone si scaglia contro l'idea che gli americani vengano indotti a seguire passivamente le direttive dei media e del governo, un tema strettamente legato alla narrazione post-11 settembre e alla propaganda che ha accompagnato la guerra in Iraq. > "Don't wanna be an American idiot, Don't want a nation under the new media." Qui, la band esprime il loro disgusto per l'influenza della propaganda mediatica e la crescente polarizzazione politica. 2. **Disillusione verso il governo e la guerra**: - Il brano **"Holiday"** è una feroce critica alla guerra in Iraq e alla politica estera dell'amministrazione Bush, spesso vista come una conseguenza diretta degli attacchi dell'11 settembre. La canzone denuncia l'ipocrisia e l'avidità che, secondo i Green Day, hanno guidato la decisione di invadere l'Iraq. > "This is the dawning of the rest of our lives, On holiday." Il termine "holiday" viene usato sarcasticamente per indicare una pausa dalla realtà, mentre la guerra viene condotta senza una giustificazione morale valida. 3. **Riflessioni sulla paura e l'ansia della generazione post-11 settembre**: - **"Boulevard of Broken Dreams"** esplora temi più personali di alienazione e solitudine, ma riflette anche l'ansia e la disillusione che molti americani, specialmente giovani, hanno provato nell'era post-11 settembre. Il senso di isolamento e la perdita di speranza di Jesus of Suburbia rappresentano simbolicamente il malessere di una generazione confusa e incerta sul futuro. > "I walk a lonely road, The only one that I have ever known." 4. **Rabbia verso l'apatia sociale**: - In **"Wake Me Up When September Ends"**, molti hanno visto una connessione simbolica con gli attacchi dell'11 settembre. Sebbene la canzone sia stata scritta dal frontman **Billie Joe Armstrong** come una riflessione personale sulla morte di suo padre, è diventata una sorta di inno per chiunque cercasse di elaborare il dolore e il trauma degli eventi del 2001. L'uso di "September" nel titolo ha portato molti a collegare il brano agli eventi dell'11 settembre e al desiderio di superare quel periodo buio. > "Here comes the rain again, Falling from the stars, Drenched in my pain again, Becoming who we are." La canzone evoca sentimenti di perdita e desiderio di guarigione, temi che risuonano con l'atmosfera post-attentati. ### Impatto di "American Idiot": "American Idiot" è stato un successo enorme e ha avuto un impatto culturale significativo. L'album ha dato voce a una generazione di giovani disillusi dalla politica americana e dalla guerra, riflettendo il malcontento diffuso verso l'amministrazione Bush e il modo in cui il paese aveva reagito agli eventi dell'11 settembre. Il successo dell'album ha portato anche alla produzione di un musical omonimo, che ha continuato a esplorare questi temi. ### Conclusione: I Green Day non hanno trattato direttamente gli attacchi dell'11 settembre, ma il loro album "American Idiot" è una risposta critica alle conseguenze politiche e sociali di quell'evento, in particolare la guerra in Iraq, la manipolazione dei media e la disillusione dei giovani. L'album è stato un potente veicolo di protesta contro il clima politico dell'epoca e ha dato voce alla frustrazione di molti americani.Present Progressive110.31.b.17.C Topic: Reading/Vocabulary Development