Identification of Novel, Selective Ataxia-Telangiectasia Mutated Kinase Inhibitors with the Ability to Penetrate the Blood-Brain Barrier: The Discovery of AZD1390.

The inhibition of ataxia-telangiectasia mutated (ATM) has been shown to chemo- and radio-sensitize human glioma cells in vitro and therefore might provide an exciting new paradigm in the treatment of glioblastoma multiforme (GBM). The effective treatment of GBM will likely require a compound with the potential to efficiently cross the blood-brain barrier (BBB). Starting from clinical candidate AZD0156, 4, we investigated the imidazoquinolin-2-one scaffold with the goal of improving likely CNS exposure in humans. Strategies aimed at reducing hydrogen bonding, basicity, and flexibility of the molecule were explored alongside modulating lipophilicity. These studies identified compound 24 (AZD1390) as an exceptionally potent and selective inhibitor of ATM with a good preclinical pharmacokinetic profile. 24 showed an absence of human transporter efflux in MDCKII-MDR1-BCRP studies (efflux ratio <2), significant BBB penetrance in nonhuman primate PET studies (Kp,uu 0.33) and was deemed suitable for development as a clinical candidate to explore the radiosensitizing effects of ATM in intracranial malignancies.

Use of Behavior Change Techniques and Quality of Commercially Available Inflammatory Bowel Disease Apps.

BACKGROUND: Inclusion of evidence-based behavior change techniques (e.g., self-monitoring) in mobile health apps has the potential to promote adherence to inflammatory bowel disease treatment. While inflammatory bowel disease management apps exist, the extent to which they incorporate behavior change techniques remains unknown. AIMS: The present study systematically evaluated the content and quality of free, commercially available inflammatory bowel disease management apps. METHODS: Apps were identified using a systematic search of the Apple App and Google Play stores. Apps were evaluated using Abraham and Michie's taxonomy of 26 behavior change techniques. A literature search was conducted to identify behavior change techniques specific and relevant for people with inflammatory bowel disease. App quality was assessed using the Mobile App Rating Scale with scores ranging from 1 (Inadequate) to 5 (Excellent). RESULTS: A total of 51 inflammatory bowel disease management apps were evaluated. Apps included 0-16 behavior change techniques (Mean = 4.55) and 0-10 inflammatory bowel disease management behavior change techniques (Mean = 3.43). App quality ranged from 2.03 to 4.62 (Mean = 3.39) out of 5.00. Two apps, My IBD Care: Crohn's & Colitis and MyGiHealth GI Symptom Tracker, included the highest number of overall and inflammatory bowel disease management behavior change techniques along with high-quality scores. Bezzy IBD was the only app with a high number of overall and inflammatory bowel disease management behavior change techniques with a primary focus on social support/change. CONCLUSION: Most inflammatory bowel disease management apps reviewed included evidence-based inflammatory bowel disease management behavior change techniques.

Hereditary Hemochromatosis: Rapid Evidence Review.

Hereditary hemochromatosis is an autosomal recessive disorder that disrupts iron homeostasis, resulting in systemic iron overload. It is the most common inherited disorder among people of northern European ancestry. Despite the high prevalence of the gene mutation, there is a low and variable clinical penetrance. The deposition of excess iron into parenchymal cells leads to cellular dysfunction and the clinical manifestations of the disease. The liver, pancreas, joints, heart, skin, and pituitary gland are the most commonly involved organs. Hereditary hemochromatosis is usually diagnosed in the 40s or 50s. Women are often diagnosed later than men, likely because of menstrual blood loss. There is no typical presentation or pathognomonic signs and symptoms of hereditary hemochromatosis. Because of increased awareness and earlier diagnosis, the end-organ damage secondary to iron overload is not often seen in clinical practice. A common initial presentation is an asymptomatic patient with mildly elevated liver enzymes who is subsequently found to have elevated serum ferritin and transferrin saturation. Ferritin levels greater than 300 ng per mL for men and 200 ng per mL for women and transferrin saturations greater than 45% are highly suggestive of hereditary hemochromatosis. Phlebotomy is the mainstay of treatment and can help improve heart function, reduce abnormal skin pigmentation, and lessen the risk of liver complications. Liver transplantation may be considered in select patients. Individuals with hereditary hemochromatosis have an increased risk of hepatocellular carcinoma and colorectal and breast cancers. Genetic testing for the hereditary hemochromatosis genes should be offered after 18 years of age to first-degree relatives of patients with the condition.

Parental Pain Catastrophizing, Communication Ability, and Post-surgical Pain Outcomes Following Intrathecal Baclofen Implant Surgery for Patients With Cerebral Palsy.

There is strong evidence that psychosocial variables, including pain catastrophizing, influence parental and child ratings of pain, pain expression, and long-term outcomes among children with chronic pain. The role of these factors among children who have communication deficits due to cerebral palsy (CP) and other intellectual and developmental disabilities is currently unclear. In this study, parental pain catastrophizing was assessed before intrathecal baclofen (ITB) pump implantation for spasticity management in 40 children and adolescents with CP, aged 4 to 24 years. Pain was assessed before and after surgery with two methods: a parent-reported pain interference scale, and behavioral pain signs during a standardized range of motion exam. Linear mixed models with clinical/demographic factors and scores from the Pain Catastrophizing Scale for Parents (PCS-P), and child spoken language ability as predictors and the pain variables as the outcomes were implemented. On average, both pain outcomes improved after surgery. Only child spoken language ability predicted change in behavioral reactivity scores, with children with phrase speech showing an increase in reactivity at follow-up compared to pre-surgery levels, on average. A significant interaction between PCS-P scores and spoken language ability on change in pain interference scores over time showed that dyads with children with phrase speech whose parents reported high PCS-P scores reported the least improvement in pain interference at follow-up. Due to the preliminary nature of the study, future work is needed to investigate the parental behaviors that mediate the relationships between parental catastrophizing and pain outcomes in this population.

Illness Uncertainty Longitudinally Predicts Distress Among Caregivers of Children Born With DSD.

OBJECTIVE: A subset of parents of children with disorders/differences of sex development (DSD) including ambiguous genitalia experience clinically elevated levels of anxious and depressive symptoms. Research indicates that uncertainty about their child's DSD is associated with parent psychosocial distress; however, previous studies have been cross-sectional or correlational in nature. The current study is the first to examine the longitudinal trajectory of the relationship between caregiver-perceived uncertainty about their child's DSD and caregiver anxious and depressive symptoms across the first 12 months following genital surgery in young children, or if surgery was not performed, the first 12 months following study entry. METHODS: One hundred and thirteen caregivers (Mage = 32.12; 57.5% mothers; 72.6% Caucasian) of children (N = 70; Mage = 9.81 months; 65.7% female) with DSD were recruited from 12 DSD specialty clinics in the United States. Caregivers completed psychosocial measures at baseline, 6 and 12 months following genitoplasty, or study entry if parents elected not to have surgery for their child. RESULTS: Caregiver illness uncertainty and both anxious and depressive symptoms were highest at baseline and decreased over time (ps < .05). Caregiver illness uncertainty predicted symptoms of anxious and depressive symptoms across all time points (ps < .05). CONCLUSIONS: Caregivers' perceptions of uncertainty about their child's DSD are highest soon after diagnosis, and uncertainty continues to predict both anxious and depressive symptoms across time. Thus, the initial diagnostic period is a critical time for psychological assessment and intervention, with parent illness uncertainty being an important clinical target.

Psychological adjustment outcomes among pediatric brain tumor survivors: A meta-analysis.

BACKGROUND: Pediatric brain tumor survivors (PBTS) are at significant risk for psychological adjustment difficulties, including greater depressive and anxious symptomology. Systematic reviews have identified this heightened risk among youth with medical conditions, but these reviews have not been specific to PBTS. Therefore, the current study aimed to directly examine the psychological adjustment of PBTS as compared to healthy peers. PROCEDURE: A systematic review and meta-analysis was conducted using PubMed, PsychInfo, and Academic Search Premier databases. The search yielded 2833 articles, with 22 articles meeting inclusion criteria. RESULTS: A statistically significant overall medium effect size (Hedge's g = 0.32) indicated that PBTS exhibited poorer overall psychological adjustment relative to healthy comparison groups. Studies that included younger children were associated with larger between-group differences. When evaluating specific outcomes, PBTS had relatively higher levels of depressive symptoms (Hedge's g = 0.36), anxious symptoms (Hedge's g = 0.11), and general distress (Hedge's g = 0.22), but not more externalizing problems. CONCLUSIONS: The present study confirmed that PBTS are indeed at greater risk for psychological adjustment difficulties relative to healthy comparison groups. These findings highlight the importance of psychosocial screening among this population. Given that depressive symptoms were the most elevated relative to healthy peers, investigation of such symptomatology among PBTS is particularly important.

CSF studies which ultimately led to the possible diagnosis of anti-NMDAR encephalitis.

A 17-year-old man with no significant medical history presented with new-onset seizure activity and altered mental status manifesting as bizarre behaviour, which included rapid pressured and tangential speech, psychomotor agitation, insomnia and delusions. He also had autonomic dysregulation, manifested in labile blood pressures. He had been recently discharged from his first psychiatric hospitalisation. Many studies were performed, including electroencephalogram (EEG), head CT, laboratory work, urine drug screen and lumbar puncture with cerebral spinal fluid studies, which ultimately led to the diagnosis of anti-N-methyl-D-aspartate receptor (NMDAR) autoimmune encephalitis. He was treated with five rounds of plasmapheresis with complete resolution of his altered mental status. This case highlights the importance of being familiar with the presentation of anti-NMDAR autoimmune encephalitis, especially in cases of new-onset mental status changes with psychotic like symptoms, seizure-like activity and autonomic dysregulation as early detection and treatment improves chances of good prognosis with return to baseline cognitive function.

Principal component analysis of adipocytokines and insulin associate with risk factors of cardiovascular diseases.

OBJECTIVES: Obesity plays an important role in the development of chronic diseases like cardiovascular diseases and diabetes. The possible underlying mechanism for this connection is that adipose tissue secretes an array of chemical messenger adipokines proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-6, and interleukin-1-beta). This study aimed to investigate the linkage between adipocytokines and insulin with the cardiovascular disease risk, with particular reference to the adipokines galectin-3, plasminogen activator inhibitor-1, and interleukin-1-beta, C-reactive protein, and monocyte chemoattractant protein. RESULT: Two patterns were identified. The first pattern was galectin-3, plasminogen activator inhibitor-1 and interleukin-1-beta and the second one was C-reactive protein, insulin and monocyte chemoattractant protein-1. The second pattern was strongly associated with the higher scores for resting metabolic rate, diastolic blood pressure, homeostasis model insulin resistance index, lipid profile (except low density lipoprotein, total cholesterol), and body composition parameters (except fat free mass index and waist hip ratio), while negatively associated with age and high density lipoprotein level (all p < 0.05). The first pattern was, however, significantly associated with body fat mass, obesity degree percentage, waist circumference, fat mass index, and waist hip ratio (p < 0.05 for all). This is a retrospective study. Ethics approval (IR.TUMS.VCR.REC.1395.1597).

The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models.

Poor survival rates of patients with tumors arising from or disseminating into the brain are attributed to an inability to excise all tumor tissue (if operable), a lack of blood-brain barrier (BBB) penetration of chemotherapies/targeted agents, and an intrinsic tumor radio-/chemo-resistance. Ataxia-telangiectasia mutated (ATM) protein orchestrates the cellular DNA damage response (DDR) to cytotoxic DNA double-strand breaks induced by ionizing radiation (IR). ATM genetic ablation or pharmacological inhibition results in tumor cell hypersensitivity to IR. We report the primary pharmacology of the clinical-grade, exquisitely potent (cell IC50, 0.78 nM), highly selective [>10,000-fold over kinases within the same phosphatidylinositol 3-kinase-related kinase (PIKK) family], orally bioavailable ATM inhibitor AZD1390 specifically optimized for BBB penetration confirmed in cynomolgus monkey brain positron emission tomography (PET) imaging of microdosed 11C-labeled AZD1390 (Kp,uu, 0.33). AZD1390 blocks ATM-dependent DDR pathway activity and combines with radiation to induce G2 cell cycle phase accumulation, micronuclei, and apoptosis. AZD1390 radiosensitizes glioma and lung cancer cell lines, with p53 mutant glioma cells generally being more radiosensitized than wild type. In in vivo syngeneic and patient-derived glioma as well as orthotopic lung-brain metastatic models, AZD1390 dosed in combination with daily fractions of IR (whole-brain or stereotactic radiotherapy) significantly induced tumor regressions and increased animal survival compared to IR treatment alone. We established a pharmacokinetic-pharmacodynamic-efficacy relationship by correlating free brain concentrations, tumor phospho-ATM/phospho-Rad50 inhibition, apoptotic biomarker (cleaved caspase-3) induction, tumor regression, and survival. On the basis of the data presented here, AZD1390 is now in early clinical development for use as a radiosensitizer in central nervous system malignancies.

Examining pregnant smokers' attitudes toward cessation aids and electronic nicotine delivery systems.

INTRODUCTION: Tobacco remains one of the most commonly used substances during pregnancy. Despite the many health risks, pregnant women report low nicotine replacement therapy (NRT) adherence and associated quit rates due partially to perceptions of increased harm related to NRT use. The health risks coupled with the continuation of tobacco use reinforce the need for a greater understanding of these behaviors and attitudes towards NRT and electronic nicotine delivery systems (ENDS) in pregnant women. Therefore, the current study aims to understand pregnant smokers' attitudes towards cessation aids and various tobacco products. METHODS: Pregnant women who reported current cigarette smoking (N = 85) were recruited from a Perinatal Center. Participants completed a 19-item self-administered survey relating to tobacco use and NRT interest. RESULTS: Overall, participants reported smoking fewer cigarettes per day since becoming pregnant. Those who had used NRT and/or ENDS prior were willing to use them during their current or future pregnancies. Overall, interest in ENDS use was high (50.6% during pregnancy, 53.5% after pregnancy), despite only 5.9% of participants currently reporting use. DISCUSSION: This study is the first to find that pregnant smokers may be hesitant to use NRT and ENDS instead of combustible tobacco during pregnancy, potentially due to the perceived harmfulness of these products, but feel more willing to use products that they have used previously. Therefore, education and counseling by medical providers regarding varying levels of harm related to use of NRT and nicotine/tobacco products should be included in the routine healthcare of pregnant smokers.

High Performance Liquid Chromatography Separation of Epigenetic Cytosine Variants.

Epigenetic modifications enable cells to genetically respond to chemical inputs from environmental sources. These marks play a pivotal role in normal biological processes (e.g., differentiation, host defense and metabolic programs) but also contribute to the development of a wide variety of pathological conditions (e.g., cancer and Alzheimer's disease). In particular, DNA methylation represents very stable epigenetic modification of cytosine bases that is strongly associated with a reduction in gene activity. Although High Performance Liquid Chromatography (HPLC) methodologies have been used to resolve methylated cytosine from unmodified cytosine bases, these represent only two of the five major cytosine analogs in the cell. Moreover, failure to resolve these other cytosine analogs might affect an accurate description of the cytosine methylation status in cells. In this present study, we determined the HPLC conditions required to separate the five cytosine analogs of the methylation/demethylation pathway. This methodology not only provides a means to analyze cytosine methylation as a whole, but it could also be used to more accurately calculate the methylation ratio from biological samples.

Molar pregnancy after tubal ligation in a patient with neuroendocrine tumour: when a rare condition coincides with an unexpected diagnosis.

A 40-year-old woman with a history of bilateral tubal ligation and a recent diagnosis of metastatic neuroendocrine tumour in the liver presented with severe nausea, vomiting, diarrhoea and dehydration. She had an inconclusive urine pregnancy test in the emergency department that was followed by an extremely high serum ß-human chorionic gonadotropin. Transvaginal ultrasound, MRI and subsequent pathology from a dilation and curettage (D&C) revealed that the patient had a complete molar pregnancy. This is a case of an unusual patient who reminds us that one person can have a rare diagnosis and an unexpected obstetrical outcome. We could find no evidence in the medical literature of a causal link between these two diagnoses but present this case report of a reproductive age woman with neuroendocrine tumour and complete molar pregnancy. This case also serves as an example of the phenomenon of the 'hook effect.'

Global characterization of signalling networks associated with tamoxifen resistance in breast cancer.

Acquired resistance to the anti-estrogen tamoxifen remains a significant challenge in breast cancer management. In this study, we used an integrative approach to characterize global protein expression and tyrosine phosphorylation events in tamoxifen-resistant MCF7 breast cancer cells (TamR) compared with parental controls. Quantitative mass spectrometry and computational approaches were combined to identify perturbed signalling networks, and candidate regulatory proteins were functionally interrogated by siRNA-mediated knockdown. Network analysis revealed that cellular metabolism was perturbed in TamR cells, together with pathways enriched for proteins associated with growth factor, cell-cell and cell matrix-initiated signalling. Consistent with known roles for Ras/MAPK and PI3-kinase signalling in tamoxifen resistance, tyrosine-phosphorylated MAPK1, SHC1 and PIK3R2 were elevated in TamR cells. Phosphorylation of the tyrosine kinase Yes and expression of the actin-binding protein myristoylated alanine-rich C-kinase substrate (MARCKS) were increased two- and eightfold in TamR cells respectively, and these proteins were selected for further analysis. Knockdown of either protein in TamR cells had no effect on anti-estrogen sensitivity, but significantly decreased cell motility. MARCKS expression was significantly higher in breast cancer cell lines than normal mammary epithelial cells and in ER-negative versus ER-positive breast cancer cell lines. In primary breast cancers, cytoplasmic MARCKS staining was significantly higher in basal-like and HER2 cancers than in luminal cancers, and was independently predictive of poor survival in multivariate analyses of the whole cohort (P < 0.0001) and in ER-positive patients (P = 0.0005). These findings provide network-level insights into the molecular alterations associated with the tamoxifen-resistant phenotype, and identify MARCKS as a potential biomarker of therapeutic responsiveness that may assist in stratification of patients for optimal therapy.

Synthesis and in vitro evaluation of analogues of avocado-produced toxin (+)-(R)-persin in human breast cancer cells.

A structure-activity study of several new synthetic analogues of the avocado-produced toxin persin has been conducted, with compounds being evaluated for their cytostatic and pro-apoptotic effects in human breast cancer cells. A 4-pyridinyl derivative demonstrated activity comparable to that of the natural product, suggesting future directions for exploration of structure-activity relationships.

Synergistic cytotoxicity between tamoxifen and the plant toxin persin in human breast cancer cells is dependent on Bim expression and mediated by modulation of ceramide metabolism.

Phytochemicals have provided an abundant source of novel therapeutics for the treatment of human cancers. We have previously described a novel plant toxin, persin, derived from avocado leaves, which has unique in vivo actions in the mammary epithelium and Bim-dependent, cytotoxic effects in human breast cancer cells in vitro. Compounds structurally similar to persin, such as the polyunsaturated fatty acid, conjugated linoleic acid, can attenuate steroid hormone receptor signaling and modulate the response of breast cancer cells to antiestrogens. Here, we provide evidence that persin may have similar effects by showing its potent proapoptotic synergy with the antiestrogen 4-hydroxytamoxifen. However, although persin transcriptionally down-regulates estrogen receptor (ER) expression, unlike conjugated linoleic acid, it also shows efficacy in ER-negative breast cancer cells, both alone and in combination with 4-hydroxytamoxifen, whereas normal breast epithelial cells are unaffected, suggesting it may act via a distinct, ER-independent mechanism. These proapoptotic synergistic interactions are associated with increased de novo ceramide synthesis and are dependent on expression of the proapoptotic protein Bim. These data show that persin should be further investigated as a potential novel cancer therapeutic agent because it significantly enhances the sensitivity of breast cancer cells to the cytotoxic effects of tamoxifen, regardless of their ER status, while displaying apparent specificity for the malignant phenotype.

Efficacy and safety of statin monotherapy in older adults: a meta-analysis.

BACKGROUND: Statin therapy significantly reduces cardiovascular events. Older patients, however, are less likely to be prescribed statins than younger patients due to concern over lack of indication, lower predictive value of cholesterol levels, and increased risk of adverse events. To determine the effect of statins on all-cause mortality and on major cardiovascular events, including stroke, we performed a meta-analysis of statin trials that included older adult participants. METHODS: Mortality, cardiovascular events, and adverse event outcomes were extracted from published randomized, placebo-controlled clinical trials of persons aged 60 years and older. RESULTS: Data on 51,351 patients were evaluated. Statins reduced all-cause mortality by 15% (95% confidence interval, 7%-22%), coronary heart disease (CHD) death by 23% (15%-29%), fatal or nonfatal myocardial infarction (MI) by 26% (22%-30%), and fatal or nonfatal stroke by 24% (10%-35%). The relative risk of cancer comparing statins to placebo was 1.06 (0.95-1.18). Adverse event data were not consistently reported. CONCLUSIONS: Statin therapy significantly reduced all-cause and CHD mortality, as well as risk of stroke and MI. Statin therapy should be offered to older patients at high risk of atherosclerotic disease events.

Variants in scavenger receptor class B type I gene are associated with HDL cholesterol levels in younger women.

OBJECTIVE: Variants within the scavenger receptor class B type I (SCARB1) receptor gene have been previously associated with lipid levels, especially in women, with some studies reporting the association to be stronger in the presence of diabetes or post-menopausal estrogen use. Based on the reported gender-specific association and modification effect of estrogen on lipid levels according to SCARB1 variants, we explored the relationship between SCARBI single nucleotide polymorphisms (SNPs) and lipid levels in an Amish population to assess sex and age differences. METHODS: Eight SCARB1 SNPs, identified from public databases, were genotyped in 919 subjects. RESULTS: Rs5888 and rs3782287 were in high linkage disequilibrium (LD), with r(2) > 0.8. None of the SNPs were significantly associated with lipid levels in men; however in women, rs5888 (p = 0.04) and rs5891 (p < 0.001) were significantly associated with higher HDL-C levels. Rs5891 had an allele frequency of 3% and predicts a missense mutation (Ile135Val), which may be functional. Moreover, rs3782287 (p = 0.023) and rs5888 (p = 0.003) were significantly associated with higher HDL-C levels in women younger than 50 years but not in women aged 50 years or older (p for interaction between age and rs5888 = 0.045). None of the SNP effects on HDL-C were modified in the presence of diabetes, in either men or women. CONCLUSIONS: SCARB1 SNPs influence HDL-C levels in women, particularly in those less than 50 years old. CONDENSED ABSTRACT: We assessed associations between SCARB1 SNPs and lipid traits in 919 Amish men and women. Two SNPs, rs3782287 and rs5888, were significantly associated with higher HDL-C levels in women younger than 50 years but not in women aged 50 years or older, supporting an interaction between common sequence variants in SCARB1 and estrogen on HDL-C.

A novel plant toxin, persin, with in vivo activity in the mammary gland, induces Bim-dependent apoptosis in human breast cancer cells.

Phytochemicals have provided an abundant and effective source of therapeutics for the treatment of cancer. Here we describe the characterization of a novel plant toxin, persin, with in vivo activity in the mammary gland and a p53-, estrogen receptor-, and Bcl-2-independent mode of action. Persin was previously identified from avocado leaves as the toxic principle responsible for mammary gland-specific necrosis and apoptosis in lactating livestock. Here we used a lactating mouse model to confirm that persin has a similar cytotoxicity for the lactating mammary epithelium. Further in vitro studies in a panel of human breast cancer cell lines show that persin selectively induces a G2-M cell cycle arrest and caspase-dependent apoptosis in sensitive cells. The latter is dependent on expression of the BH3-only protein Bim. Bim is a sensor of cytoskeletal integrity, and there is evidence that persin acts as a microtubule-stabilizing agent. Due to the unique structure of the compound, persin could represent a novel class of microtubule-targeting agent with potential specificity for breast cancers.

Hypothyroidism.

Hypothyroidism is common, potentially serious, often clinically overlooked, readily diagnosed by laboratory testing, and eminently treatable. The condition is particularly prevalent in older women, in whom autoimmune thyroiditis is common. Other important causes include congenital thyroid disorders, previous thyroid surgery and irradiation, drugs such as lithium carbonate and amiodarone, and pituitary and hypothalamic disorders. Worldwide, dietary iodine deficiency remains an important cause. Hypothyroidism can present with nonspecific constitutional and neuropsychiatric complaints, or with hypercholesterolaemia, hyponatraemia, hyperprolactinaemia, or hyperhomocysteinaemia. Severe untreated hypothyroidism can lead to heart failure, psychosis, and coma. Although these manifestations are neither specific nor sensitive, the diagnosis is confirmed or excluded by measurements of serum thyrotropin and free thyroxine. Thyroxine replacement therapy is highly effective and safe, but suboptimal dosing is common in clinical practice. Patient noncompliance, drug interactions, and pregnancy can lead to inadequate treatment. Iatrogenic thyrotoxicosis can cause symptoms, and, even when mild, provoke atrial fibrillation and osteoporosis. We summarise present understanding of the history, epidemiology, pathophysiology, and clinical diagnosis and management of hypothyroidism.