The 11th edition of Harrison's Principles of Internal Medicine welcomes Anthony Fauci to its editorial staff, in addition to more than 85 new contributors. While the organization of the book is similar to previous editions, major emphasis has been placed on disorders that affect multiple organ systems. Important advances in genetics, immunology, and oncology are emphasized. Many chapters of the book have been rewritten and describe major advances in internal medicine. Subjects that received only a paragraph or two of attention in previous editions are now covered in entire chapters. Among the chapters that have been extensively revised are the chapters on infections in the compromised host, on skin rashes in infections, on many of the viral infections, including cytomegalovirus and Epstein-Barr virus, on sexually transmitted diseases, on diabetes mellitus, on disorders of bone and mineral metabolism, and on lymphadenopathy and splenomegaly. The major revisions in these chapters and many

Harrison's Principles of Internal Medicine

There is still an unresolved paradox with respect to the immunomodulating role of estrogens. On one side, we recognize inhibition of bone resorption and suppression of inflammation in several animal models of chronic inflammatory diseases. On the other hand, we realize the immunosupportive role of estrogens in trauma/sepsis and the proinflammatory effects in some chronic autoimmune diseases in humans. This review examines possible causes for this paradox. This review delineates how the effects of estrogens are dependent on criteria such as: 1) the immune stimulus (foreign antigens or autoantigens) and subsequent antigen-specific immune responses (e.g., T cell inhibited by estrogens vs. activation of B cell); 2) the cell types involved during different phases of the disease; 3) the target organ with its specific microenvironment; 4) timing of 17beta-estradiol administration in relation to the disease course (and the reproductive status of a woman); 5) the concentration of estrogens; 6) the variability in expression of estrogen receptor alpha and beta depending on the microenvironment and the cell type; and 7) intracellular metabolism of estrogens leading to important biologically active metabolites with quite different anti- and proinflammatory function. Also mentioned are systemic supersystems such as the hypothalamic-pituitary-adrenal axis, the sensory nervous system, and the sympathetic nervous system and how they are influenced by estrogens. This review reinforces the concept that estrogens have antiinflammatory but also proinflammatory roles depending on above-mentioned criteria. It also explains that a uniform concept as to the action of estrogens cannot be found for all inflammatory diseases due to the enormous variable responses of immune and repair systems.

/pdf/the-complex-role-of-estrogens-in-inflammation-29aw75ptuv.pdf

The complex role of estrogens in inflammation

Sedentary behaviour is associated with deleterious health outcomes, which differ from those that can be attrib- uted to a lack of moderate to vigorous physical activity. This has led to the field of ''sedentary physiology'', which may be considered as separate and distinct from exercise physiology. This paper gives an overview of this emerging area of re- search and highlights the ways that it differs from traditional exercise physiology. Definitions of key terms associated with the field of sedentary physiology and a review of the self-report and objective methods for assessing sedentary behaviour are provided. Proposed mechanisms of sedentary physiology are examined, and how they differ from those linking physi- cal activity and health are highlighted. Evidence relating to associations of sedentary behaviours with major health out- comes and the population prevalence and correlates of sedentary behaviours are reviewed. Recommendations for future research are proposed.

/pdf/physiological-and-health-implications-of-a-sedentary-55lyzvdbza.pdf

Physiological and health implications of a sedentary lifestyle

Muscarinic receptors--characterization, coupling and function.

It has been more than three decades since the first monoclonal antibody was approved by the United States Food and Drug Administration (US FDA) in 1986, and during this time, antibody engineering has dramatically evolved. Current antibody drugs have increasingly fewer adverse effects due to their high specificity. As a result, therapeutic antibodies have become the predominant class of new drugs developed in recent years. Over the past five years, antibodies have become the best-selling drugs in the pharmaceutical market, and in 2018, eight of the top ten bestselling drugs worldwide were biologics. The global therapeutic monoclonal antibody market was valued at approximately US$115.2 billion in 2018 and is expected to generate revenue of $150 billion by the end of 2019 and $300 billion by 2025. Thus, the market for therapeutic antibody drugs has experienced explosive growth as new drugs have been approved for treating various human diseases, including many cancers, autoimmune, metabolic and infectious diseases. As of December 2019, 79 therapeutic mAbs have been approved by the US FDA, but there is still significant growth potential. This review summarizes the latest market trends and outlines the preeminent antibody engineering technologies used in the development of therapeutic antibody drugs, such as humanization of monoclonal antibodies, phage display, the human antibody mouse, single B cell antibody technology, and affinity maturation. Finally, future applications and perspectives are also discussed.

/pdf/development-of-therapeutic-antibodies-for-the-treatment-of-4g7fs3ndpf.pdf

Development of therapeutic antibodies for the treatment of diseases

Treatment of migraine is on the cusp of a new era with the development of drugs that target the trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) or its receptor. Several of these drugs are expected to receive approval for use in migraine headache in 2018 and 2019. CGRP-related therapies offer considerable improvements over existing drugs as they are the first to be designed specifically to act on the trigeminal pain system, they are more specific and they seem to have few or no adverse effects. CGRP receptor antagonists such as ubrogepant are effective for acute relief of migraine headache, whereas monoclonal antibodies against CGRP (eptinezumab, fremanezumab and galcanezumab) or the CGRP receptor (erenumab) effectively prevent migraine attacks. As these drugs come into clinical use, we provide an overview of knowledge that has led to successful development of these drugs. We describe the biology of CGRP signalling, summarize key clinical evidence for the role of CGRP in migraine headache, including the efficacy of CGRP-targeted treatment, and synthesize what is known about the role of CGRP in the trigeminovascular system. Finally, we consider how the latest findings provide new insight into the central role of the trigeminal ganglion in the pathophysiology of migraine.

CGRP as the target of new migraine therapies — successful translation from bench to clinic

The hormone melatonin (5-methoxy- N -acetyltryptamine) is synthesized primarily in the pineal gland and retina, and in several peripheral tissues and organs. In the circulation, the concentration of melatonin follows a circadian rhythm, with high levels at night providing timing cues to target tissues endowed with melatonin receptors. Melatonin receptors receive and translate melatonin's message to influence daily and seasonal rhythms of physiology and behavior. The melatonin message is translated through activation of two G protein-coupled receptors, MT1 and MT2, that are potential therapeutic targets in disorders ranging from insomnia and circadian sleep disorders to depression, cardiovascular diseases, and cancer. This review summarizes the steps taken since melatonin's discovery by Aaron Lerner in 1958 to functionally characterize, clone, and localize receptors in mammalian tissues. The pharmacological and molecular properties of the receptors are described as well as current efforts to discover and develop ligands for treatment of a number of illnesses, including sleep disorders, depression, and cancer.

https://pharmrev.aspetjournals.org/content/pharmrev/62/3/343.full.pdf

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

The cerebral vasculature is a target tissue for sex steroid hormones. Estrogens, androgens, and progestins all influence the function and pathophysiology of the cerebral circulation. Estrogen decreases cerebral vascular tone and increases cerebral blood flow by enhancing endothelial-derived nitric oxide and prostacyclin pathways. Testosterone has opposite effects, increasing cerebral artery tone. Cerebrovascular inflammation is suppressed by estrogen but increased by testosterone and progesterone. Evidence suggests that sex steroids also modulate blood-brain barrier permeability. Estrogen has important protective effects on cerebral endothelial cells by increasing mitochondrial efficiency, decreasing free radical production, promoting cell survival, and stimulating angiogenesis. Although much has been learned regarding hormonal effects on brain blood vessels, most studies involve young, healthy animals. It is becoming apparent that hormonal effects may be modified by aging or disease states such as diabetes. Furthermore, effects of testosterone are complicated because this steroid is also converted to estrogen, systemically and possibly within the vessels themselves. Elucidating the impact of sex steroids on the cerebral vasculature is important for understanding male-female differences in stroke and conditions such as menstrual migraine and preeclampsia-related cerebral edema in pregnancy. Cerebrovascular effects of sex steroids also need to be considered in untangling current controversies regarding consequences of hormone replacement therapies and steroid abuse.

https://www.physiology.org/doi/pdf/10.1152/japplphysiol.01095.2005

Influence of sex steroid hormones on cerebrovascular function.

We report here that estrogen (E2) modulates mitochondrial function in the vasculature. Mitochondrial dysfunction is implicated in the etiology of vascular disease; thus, vasoprotection by estrogen may involve hormonal effects on the mitochondria. To test this hypothesis, mitochondria were isolated from cerebral blood vessels obtained from ovariectomized female rats, with or without E2 replacement. Estrogen receptor-α (ER-α) was detected in mitochondria by immunoblot and confocal imaging of intact vessels. E2 treatment in vivo increased the levels of specific proteins in cerebrovascular mitochondria, such as ER-α, cytochrome c, subunit IV of complex IV, and manganese superoxide dismutase, all encoded in the nuclear genome, and subunit I of complex IV, encoded in the mitochondrial genome. Levels of glutathione peroxidase-1 and catalase, however, were not affected. Functional assays of mitochondrial citrate synthase and complex IV, key rate-limiting steps in energy production, showed that E2 treatment increased enzyme activity. In contrast, mitochondrial production of hydrogen peroxide was decreased in vessels from E2-treated animals. In vitro incubation of cerebral vessels with 10 nM 17β-estradiol for 18 h also elevated levels of mitochondrial cytochrome c. This effect was blocked by the estrogen receptor antagonist fulvestrant (ICI-182,780, Faslodex) but was unaffected by inhibitors of nitric-oxide synthase or phosphoinositide-3-kinase. Nuclear respiratory factor-1 protein, a primary regulator of nuclear gene-encoded mitochondrial genes, was significantly increased by long-term estrogen treatment in vivo. In summary, these novel findings suggest that vascular protection by E2 is mediated, in part, by modulation of mitochondrial function, resulting in greater energy-producing capacity and decreased reactive oxygen species production.

https://molpharm.aspetjournals.org/content/molpharm/early/2005/06/30/mol.105.014662.full.pdf

Diana N. Krause

Papers

CGRP as the target of new migraine therapies — successful translation from bench to clinic

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

Influence of sex steroid hormones on cerebrovascular function.

Estrogen Increases Mitochondrial Efficiency and Reduces Oxidative Stress in Cerebral Blood Vessels

Melatonin mediates two distinct responses in vascular smooth muscle