bluuebunny/crossref_metadata_2025 huggingface dataset:
Monkeys with World-Spanning Voices
Authors: Bentley Peter J.
Published: November 2020

The howler monkey is one of the loudest animals in the world. Its haunting calls can be heard several miles away in dense forest. Today, with the help of the computer, even the quietest human voice can be heard anywhere on the planet. Computers are social machines. They constantly talk to each other in a network that crosses oceans, mountains, and continents. They speak a common universal language, independent of country. Their pulsing, error-correcting messages comprise the industry, knowledge, culture, thoughts, and dreams of the human species. The virtual Web of knowledge now connects humans together in ways never before possible. But with this freedom comes problems. Should we trust everyone who communicates with us? Do we need new ways to protect our privacy? . . . Claude Shannon took his hand from the chess piece and looked up. His sharp eyes fixed on his young opponent. ‘Check!’ Shannon was visiting from Bell Labs in 1955. It was only natural that he should spend an occasional evening at the Palo Alto Chess Club, for he had a keen interest in chess. Five or six years previously he had published several papers about how computers could be programmed to play chess and he was increasingly becoming interested in how machines could be made to perform intelligent tasks. His opponent, Peter Kirstein, a twenty-two-year-old PhD student of Stanford University, was enjoying the game. He had been playing chess since school and was no pushover. Kirstein didn’t really know Shannon, but found the thirty-nine-year-old scientist to be an impressive person, very thin, with piercing eyes. Although the two players didn’t realize it, this was a chance meeting of an established pioneer and a future pioneer who would build on Shannon’s work in ways neither could have dreamed. In 1955, the work that would become so important to Kirstein in the future was already in Shannon’s past. It had originated because of crackling telephone lines. The research and development group in Bell Labs had been struggling with the issue of long-distance communications. At the time, telephone communication was analogue.
A Computer Changed My Life
Authors: Bentley Peter J.
Published: November 2020

Our world is digitized. Thanks to pioneers such as Turing, Shannon, and von Neumann, we have the amazing technologies of today. We have strong mathematical foundations for remarkable silicon machines that run amazing software. We have connections to everyone in the world through easy-to- use interfaces. We even have intelligent machines that help us in ways we could never have dreamed. The journey has only just begun. Every year new pioneers exploit the technologies of computer science for startling and imaginative applications. Artists and musicians use computers to entertain us, biologists use computers to understand us, doctors use computers to heal us. We even use computers to protect ourselves from crime. It’s an exciting time. . . . The young artist enters the large room, rolls of drawings under his arm. There are twelve large cube-shaped computer monitors on desks surrounding him, apparently connected to mainframe computers on the floor below. Blinds cover all the windows, darkening the room, and allowing strange graphics on the screens to shine brightly. The artist nervously unrolls his drawings on the floor of the computer lab, filling the space with his carefully drawn renderings. One large sheet looks like a strange abstract swirling piece of Hindu art with snakes or tentacles fl owing outwards from the centre. Another looks like a weird bug-collector’s display with a myriad differently shaped bugs placed randomly—except that similar bugs are always next to each other. Another looks like an evolutionary tree of abstract shapes, from Viking helmets to beehives, each morphing into another. The watching group of scientists and computer programmers have never seen anything quite like this. The artist had struggled to gain acceptance for his ideas from his own community. The art world was not ready for his use of computers to help generate his art. Would this audience be any different? William Latham looks up at his audience of scientists, and begins to explain his work. Latham was no ordinary artist. Born in 1961, he grew up in Blewbury, England. It was a rural setting, but because of the nearby Harwell Atomic Energy Research Establishment, he came into contact with scientists throughout his childhood.
Gastroenterology
Authors: Emmett Stevan R. , Hill Nicola , Dajas-Bailador Federico
Published: November 2020

Nausea and vomiting can be defined, respectively, as the urge to or the actual act of expelling undigested food from the stomach. It is thought to be an evolutionary defence mechanism to protect against toxic insult (drugs or mi­crobes) and over- eating, while it can also be triggered during pregnancy, or by unpleasant sights or smells. In some instances, it may be the symptom of a more severe underlying pathology. Severity of nausea and vomiting varies considerably between individuals exposed to the same stimulus and symptoms can be highly detrimental to patient quality of life affecting not only their nutritional intake, but also mood and well- being. Although nausea itself is a subjective term, vomiting is a pathophysiological reflex triggered by the vomiting centre located in the medulla. The vomiting centre re­ceives signals from a number of afferent inputs, i.e. the chemoreceptor trigger zone (CTZ), vestibular nucleus, ab­dominal and cardiac vagal afferents, and cerebral cortex (Table 6.1). It may also be activated by hormonal triggers, which accounts for hyperemesis in pregnancy, and the increased incidence of nausea and vomiting associated with the female gender. As the vomiting centre is located close to centres responsible for salivation and breathing, vomiting is often associated with hypersalivation and hyperventilation. The CTZ is highly vascularized and lo­cated at the floor of the fourth ventricle, just outside the blood– brain barrier and, therefore, is itself directly sensi­tive to chemical stimuli. Afferent inputs activate the vomiting centre through several known neurotransmitter pathways; dopamine (D2), serotonin (5- HT3, 5- HT4), acetylcholine (ACh), and substance P (neurokinin 1; NK1). Each of which provides a potential pharmacological target in the management of nausea and vomiting, once the cause has been established. Efferent pathways from the vomiting centre induce autonomic changes, including vasoconstriction, pallor, tachycardia, salivation, sweating, and relaxation of the lower oesophagus and fundus of the stomach. In vomiting, oesophageal relaxation leads to contraction of the pyloric sphincter, thereby emptying the contents of the jejunum, duodenum, and pyloric stomach into the relaxed fundus. Coordination of muscle contraction occurs within the dia­phragm and abdomen, and retrograde contractions from the intestine then expel the contents of the fundus.
Civil Partnerships: Lewis Acid–Base Reactions
Authors: Atkins Peter
Published: November 2020

One of the most remarkable chemists of the twentieth century, Gilbert Lewis (1875–1946), who died in a rather peculiar event involving cyanide (which will figure further in this account) took the story of acids and bases that I described in Reaction 2, extended its reach, and thereby captured a further huge swathe of chemical countryside. As I remarked in that section, chemists seek patterns of behaviour, partly because it systematizes their subject but also because it gives insight into the molecular events accompanying a reaction. Lewis contributed greatly to this enlargement of chemistry’s vision, as I shall unfold in this section. I explained in Reaction 2 how Lowry and Brønsted had extended Arrhenius’s vision of acids and bases by proposing that all reactions between acids and bases involve the transfer of a proton (a hydrogen ion, H+) from the acid, the proton donor, to the base, the proton acceptor. For instance, hydrochloric acid, HCl, can provide a proton that sticks to an ammonia molecule, NH3, 1, converting it into NH4+, 2. The Lowry–Brønsted account of an acid–base reaction involves a proton as an essential part of the definition: if protons aren’t around, then Lowry and Brønsted are silent on whether a substance is an acid or a base. There are, however, many reactions that resemble acid–base reactions but in which no protons are transferred. I will give what might seem to be a rather esoteric example, but it makes the point in a simple and direct way, so please bear with me; you will soon see the relevance of this presentation to everyday life. The esoteric example I have in mind is a reaction in which a boron trifluoride molecule, BF3, 3, sticks to an ammonia molecule to form NH3BF3, 4. This reaction clearly resembles the proton transfer reaction in which H+ attaches to NH3 to form NH4+, but with BF3 playing the role of H+. Lewis brought these aspects together in a very simple idea in 1923, at about the same time as Lowry and Brønsted made their proposals. A base, he proposed, is any species that can use two of its electrons to attach to an incoming species.
Breast and endocrine surgery
Authors: Al-Alaak Asmaa
Published: November 2020

One of the main ‘complaints’ about breast disease is that ‘it is all so similar’ and that there are lots of treatment options which can seem confusing at first. The key to understanding breast disease and preparing for questions about it is to keep the basic facts about breast anatomy and pathology to the forefront, learn to recognize key patterns of clinical signs and symptoms, and then match them to the clinical scenario. The EMQs are particularly useful at practising fitting questions into clinical patterns and rehearsing the patterns. Endocrine disease poses its own challenges. Even for a surgeon it is important to understand and recognize the underlying biochemistry and how this affects the clinical presentations. Endocrine surgical disease is much less about anatomy or surgical procedures themselves as it is about understanding how treatment is matched to the pathophysiology of the conditions.
Beginning of an Era: The First Blockbuster Drug, Tagamet
Authors: Li Jie Jack
Published: November 2020

Tagamet emerged as the first blockbuster drug when its sales exceeded $1 billion in 1986, three years after its introduction to the market. An anti–peptic ulcer drug, Tagamet was discovered by James W. Black and his colleagues at Smith Kline & French’s (SK&F) British subsidiary in Welwyn Garden City. Before Tagamet, SK&F was a little-known U.S. drug firm in Philadelphia. After Tagamet, SK&F became one of the largest pharmaceutical companies in the world. The history of Tagamet is one of the most extraordinary in the annals of medicine. It is a saga of a drug that almost escaped detection because the research efforts that began in 1964 did not seem to produce results within the first 11 years! Smith Kline started as a humble drug store in Philadelphia in 1830. During the American Civil War, Smith Kline was founded as a small apothecary by two physicians, John K. Smith and John Gilbert on North Second Street. Not only was Philadelphia the birthplace of the United States of America, it was also the cradle of American pharmacy. Wyeth, McNeil, Rorer, and Warner-Lambert all trace their origins to small drug stores established there during the Civil War. In the 1880s, Mahlon N. Kline led the company into research and manufacturing of its own products. In 1891, it absorbed French, Richards & Co. founded by Harry B. French, creating Smith Kline & French. After its establishment, the company slowly expanded its inventory. By the 1920s, it had some 15,000 products ranging from aspirin to liniment. Their Eskay’s Albumenized Food was highly popular as a digestible food for infants and the disabled. Later, the company did very well with Eskay’s Tablets for Seasickness. Its specialty, Eskay’s Neurophosphates, a nerve tonic, soothed millions of people at home and abroad. In 1929, Smith Kline & French Laboratories was created to devote itself solely to research and development (R&D). During the Great Depression year of 1936, the company stepped up its efforts in R&D (in a recent contrast, many pharmaceutical companies stepped down their R&D investments during the last recession of 2008).
Industry and Government Labs
Authors: Brown Jeannette
Published: November 2020

Dr. Hopkins is one of the few American women to have held a doctorate in science and a license to practice before the U.S. Patent and Trademark Office. Her career included academia, industry, and government. Esther was born Esther Arvilla Harrison on September 16, 1926, in Stamford, Connecticut. She was the second of three children born to George Burgess Harrison and Esther Small Harrison. Her father was a chauffeur and sexton at a church, and her mother worked in domestic service. Neither of her parents had an advanced education. Her father had some high school education; her mother attended only primary school. However, both of her parents wanted to make sure their children had a good education. When Esther was three and a half years old, her mother took her along to register her older brother for school. Because Esther was taller than her brother, the teacher suggested that she take the test to start school. She passed the test and was able to start kindergarten at the age of three and a half! She and her brother went to school together all through elementary school. Boys and girls were separated in junior high school; in high school they remained separate but attended the same school. She decided in junior high school that she wanted to be a brain surgeon. This was because she met a woman doctor in Stamford who had an office in one of the buildings that her father cleaned. The woman was a physician and graduate of Boston University Medical School. Esther decided that she wanted to be just like her. Therefore, when Esther entered high school, she chose the college preparatory math and science track. She took as many science courses as possible in order to get into Boston University. She spent a lot of time at the local YWCA, becoming a volunteer youth leader. One speaker at a YWCA luncheon discouraged her from entering science and suggested that she become a hairdresser. Esther was hurt but not discouraged by this. She graduated from Stamford High School in 1943.
Orbital Bones
Authors: Jordan David , Mawn Louise , Anderson Richard L.
Published: November 2020

The paired orbital cavities are formed by the facial bones and serve as sockets for the eyes. The orbital bones and the structures contained within the orbit (connective tissue, fat, nerves, vessels) act to support, protect, and maximize the function of the eye. In form, the orbit is roughly a quadrilateral pyramid with rounded angles and resembles a pear. Its volume in the average individual is 30 cc, of which the eyeball contributes about 7.5 cc (range: 6.9–9.0 cc). There are four surfaces: the roof, floor, lateral wall, and medial wall. The base of the pyramid is the opening onto the face (orbital entrance) and is circumscribed by the orbital margin (or orbital rim). The orbit narrows inward to its termination, the apex. The widest portion of the orbital cavity lies 5 to 10 mm behind the orbital rim. The orbit is made up of seven bones: frontal, sphenoid, zygomatic, malar, palatine, lacrimal, and ethmoid. Superiorly, the orbit is bordered by the anterior cranial fossa and the frontal sinus. Nasally, the ethmoid sinus is separated from the medial orbital wall by the thin lamina papyracea of the ethmoid bone. Inferiorly, the maxillary sinus lies beneath the orbital floor. The lateral orbit is bordered anteriorly by the temporalis fossa, and posteriorly it borders the middle cranial fossa. The lateral and medial walls of each orbit form an angle of approximately 45 ° with each other. The two medial walls diverge somewhat posteriorly but are almost parallel to each other (being about 3 mm farther apart posteriorly than at the orbital margin). The lateral orbital walls of the two orbits form a 90 ° angle with each other. The four walls of each orbit converge posteriorly toward the apex, where the optic canal and superior orbital fissure pass into the middle cranial fossa. The overall dimensions of the orbit, especially its depth, are quite variable. An orbital surgeon cannot rely on precise measurements as a guide to the exact location of the optic canal or superior orbital fissure.
Orbital Vascular And Lymphatic Systems
Authors: Jordan David , Mawn Louise , Anderson Richard L.
Published: November 2020

The anatomy of the orbital vascular bed is complex, with tremendous individual variation. The main arterial supply to the orbit is from the ophthalmic artery, a branch of the internal carotid artery. The external carotid artery normally contributes only to a small extent. However, there are a number of orbital branches of the ophthalmic artery that anastomose with adjacent branches from the external carotid artery, creating important anastomotic communications between the internal and external carotid arterial systems. The venous drainage of the orbit occurs mainly via two ophthalmic veins (superior and inferior) that extend to the cavernous sinus, but there are also connections with the pterygoid plexus of veins, as well as some more anteriorly through the angular vein and the infraorbital vein to the facial vein. A working knowledge of the orbital vasculature and lymphatic systems is important during orbital, extraocular, or ocular surgery. Knowing the anatomy of the blood supply helps one avoid injury to the arteries and veins during operative procedures within the orbit or the eyelid. Inadvertent injury to the vasculature not only distorts the anatomy and disrupts a landmark but also prolongs the surgery and might compromise blood flow to an important orbital or ocular structure. Upon entering the cranium, the internal carotid artery passes through the petrous portion of the temporal bone in the carotid canal and enters the cavernous sinus and middle cranial fossa through the superior part of the forame lacerum . It proceeds forward in the cavernous sinus with the abducens nerve along its side. There it is surrounded by sympathetic nerve fibers (the carotid plexus ) derived from the superior cervical ganglion. It then makes an upward S-shaped turn to form the carotid siphon , passing just medial to the oculomotor, trochlear, and ophthalmic nerves (V1). After turning superiorly in the anterior cavernous sinus, the carotid artery perforates the dura at the medial aspect of the anterior clinoid process and turns posteriorly, inferior to the optic nerve.
What Would Have Been Is Not What Would Be: Counterfactuals of the Past and Potential Outcomes of the Future
Authors: Schwartz Sharon , Gatto Nicolle M.
Published: November 2020

Epidemiology is often described as the basic science of public health. A mainstay of epidemiologic research is to uncover the causes of disease that can serve as the basis for successful public-health interventions (e.g., Institute of Medicine, 1988; Milbank Memorial Fund Commission, 1976). A major obstacle to attaining this goal is that causes can never be seen but only inferred. For this reason, the inferences drawn from our studies must always be interpreted with caution. Considerable progress has been made in the methods required for sound causal inference. Much of this progress is rooted in a full and rich articulation of the logic behind randomized controlled trials (Holland, 1986). From this work, epidemiologists have a much better understanding of barriers to causal inference in observational studies, such as confounding and selection bias, and their tools and concepts are much more refined. The models behind this progress are often referred to as ‘‘counterfactual’’ models. Although researchers may be unfamiliar with them, they are widely (although not universally) accepted in the field. Counterfactual models underlie the methodologies that we all use. Within epidemiology, when people talk about a counterfactual model, they usually mean a potential outcomes model—also known as ‘‘Rubin’s causal model.’’ As laid out by epidemiologists, the potential outcomes model is rooted in the experimental ideas of Cox and Fisher, for which Neyman provided the first mathematical expression. It was popularized by Rubin, who extended it to observational studies, and expanded by Robins to exposures that vary over time (Maldonado & Greenland, 2002; Hernan, 2004; VanderWeele & Hernan, 2006). This rich tradition is responsible for much of the progress we have just noted. Despite this progress in methods of causal inference, a common charge in the epidemiologic literature is that public-health interventions based on the causes we identify in our studies often fail.
Rare Variant Approaches to Understanding the Causes of Complex Neuropsychiatric Disorders
Authors: State Matthew W.
Published: November 2020

The distinction between genetic variation that is present in more than 5% of the population (defined as common) and genetic variation that does not meet this threshold (defined as rare) is often lost in the discussion of psychiatric genetics. As a general proposition, the field has come to equate the hunt for common variants (or alleles) with the search for genes causing or contributing to psychiatric illness. Indeed, the majority of studies on mood disorders, autism, schizophrenia, obsessive–compulsive disorder, attention-deficit/hyperactivity disorder, and Tourette syndrome have restricted their analyses to the potential contribution of common alleles. Studies focusing on rare genetic mutations have, until quite recently, been viewed as outside the mainstream of efforts aimed at elucidating the biological substrates of serious psychopathology. Both the implicit assumption that common alleles underlie the lion’s share of risk for most common neuropsychiatric conditions and the notion that the most expeditious way to elucidate their biological bases will be to concentrate efforts on common alleles deserve careful scrutiny. Indeed, key findings across all of human genetics, including those within psychiatry, support the following alternative conclusions: (1) for disorders such as autism and schizophrenia, the study of rare variants already holds the most immediate promise for defining the molecular and cellular mechanisms of disease (McClellan, Susser, & King, 2007; O’Roak & State, 2008); (2) common variation will be found to carry much more modest risks than previously anticipated (Altshuler & Daly, 2007; Saxena et al., 2007); and (3) rare variation will account for substantial risk for common complex disorders, particularly for neuropsychiatric conditions with relatively early onset and chronic course. This chapter addresses the rare variant genetic approach specifically with respect to mental illness. It first introduces the distinction between the key characteristics of common and rare genetic variation. It then briefly addresses the methodologies employed to demonstrate a causal or contributory role for genes in complex disease, focusing on how these approaches differ in terms of the ability to detect and confirm the role of rare variation.
Ockham’s Razor and Chemistry
Authors: Minkin Vladimir I . , Carpenter Barry K .
Published: November 2020

Scientists think they are born with logic; God forbid they should study this discipline with a history of more than two and a half millenia. Isn’t it curious that some of our competitors and critics, pretty good scientists (except when they review our papers), seem to be strangely deficient in logic! While scientists think they can do without philosophy, occasionally principles of logic or philosophy do enter scientific discourse explicitly. One of these philosophic notions is Ockham’s Razor, generally taken to mean that one should not complicate explanations when simple ones will suffice. The context in which Ockham’s Razor is used in science is either that of argumentation (trying to distinguish between the quality of hypotheses) or of rhetoric (deprecating the argument of someone else). Either way, we think that today appeal to the venerable Razor has a bit of a feeling of showing off , of erudition adduced for the rhetorical purposes. This attitude reveals a double ambiguity. The first is toward learning—today’s science, no longer elitist, does not depend on men steeped in classical learning. And appeal to Ockham’s Razor also points to a certain ambiguity in the relationship of science to philosophy. Let’s learn something of the man whose name the principle bears, and its various meanings. Then we give a personal account of the use of Ockham’s Razor in chemistry, with specific reference to the analysis of reaction mechanisms. And we enter a dialogue on the validity and limitations of this device. Neither today’s scientists nor medieval theologians and philosophers, one of whom was William of Ockham (or Occam), can avoid the politics of their times. We know precious little of William of Ockham’s early life. He was born in the village of Ockham in Surrey near London, probably within five years of 1285. The first certain date we have in his life is February 26, 1306 when he was ordained subdeacon of Southwork.
Mind the Shade
Authors: Hoffmann Roald
Published: November 2020

Sentenced to create—be it molecules, or laws, or paintings you may love or hate—we give in, with feeling, make new substances, transform old ones. Still others in the economic chain sell them; I teach about them. Each of us has a role in the use of chemicals. That use does immense good. And just sometimes does harm to people or property. Even though molecules are molecules, not in and of themselves good or evil. What is an individual chemist’s ethical responsibility when this occurs? Well, each of us confronts ethical questions in the light of his or her traditions. Nothing is simple when goods collide. I don’t want to preach; the only advice I would presume to give is: “Mind the shade.” Let me explain. Political campaign ads to the contrary, very little in this world is pure good or pure evil. Yet evil gets done. No, it is not the work of Satan; it is the work of pretty normal men and women, who are likely to be kind to their children and goldfish. And those who mean ill intuitively know that responsibility for exploitation or hurt had best be diffused, so that an individual in a necessarily long chain be little tempted to see the ethical consequences of the whole. Also people intent on no good construct, subconsciously, for themselves (and their collaborators) a mind-set that transforms the act psychically, taking it outside some personal ethic. In the analysis of evildoing by real people, not comic-book characters, one finds incredible compartmentalization, and the fanning of dehumanizing prejudices. Why? To self-justify actions that—in another part of life, dealing with others—would clearly be counter to the ethics that everyone, even evildoers, carries around. Given this tendency of evil to diffuse and transform itself, it is precisely those actions that are ethically gray or shaded, neither clearly good nor bad, which should be thought through in greatest depth. If there be a data point that indicates disagreement with a theory, or hints at side effects of a drug, shall I discard it before I tell my supervisor? To do so seems easy, so harmless, especially when little is certain.
Visual Field Testing
Authors: Close Troy
Published: November 2020

• Glaucoma results in progressive visual field deterioration, and detecting changes or recording stability in the visual field is important in the management of glaucoma. • Visual field testing is a highly subjective and operator-dependent test. • In patients with glaucoma, the visual field is tested in monocular fashion. •The boundaries of the visual field (in a well-lit environment with an easily visible target) are grossly 60 degrees superiorly, 75 degrees inferiorly, 100 degrees temporally, and 60 degrees nasally. • Basic concept in determination of visual field is “threshold” •Definition of “threshold”: weakest test stimulus that is just visible in a particular location (stimulus intensity at which the patient responds 50% of the time) •Types of visual field testing strategies •Confrontation •Spot testing •Kinetic spot testing •Static spot testing •An initial screening tool to look for large and dense visual field defects that may be present in very advanced glaucoma •Both hands should be used in the testing processed. The patient should occlude the untested eye with the palm of the hand. •If the visual acuity will allow the finger counting technique, all four quadrants may be tested at 3 to 4 feet from the patient at an approximate 45-degree angle holding up either one or two fingers, or a whole hand. • If the visual acuity is HM or LP, then test for light perception in the respective 4 quadrants. • It is important that the patient be able to tell you where the light is located in the field of vision, not simply the presence of light. • Factors that affect the visibility of the spot • Size Intensity • Background illumination Others: color, movement, duration of presentation, attentiveness of the patient, and refractive state of the eye • Kinetic • Usually Goldmann perimetry (though some of the automated machines such as the Octopus will perform kinetic perimetry) • The perimetrist may adjust the location, size, and intensity of the stimulus throughout the test. •Useful in the following cases: Those who need coaching and an altered pace of testing (e.g., elderly, wheelchair-bound, or limited concentration)
Medical Management for Glaucoma
Authors: Sood-Mendiratta Shalini
Published: November 2020

When evaluating patients for glaucoma or ocular hypertension, the question remains whether or not the patient should be treated, and when treatment should be initiated. Treatment decisions are usually guided by risk factor assessment, and these include race, age, family history, medical history, IOP, central corneal thickness, and clinical examination, including optic nerve appearance and ancillary diagnostic testing. The information is compiled in each individual to determine the risk of significant visual loss in the patient’s lifetime. Numerous studies have demonstrated that lowering IOP slows progression of this disease. Most common current medical therapies are therefore ocular hypotensive medications. The armamentarium of medications has expanded over the past two decades in terms of number and classes. Future potential therapies may include those that provide neuroprotection, but the main focus of this chapter will be on medications most frequently used to treat glaucoma. The goal of therapy is to slow progression of disease with the fewest side effects and medications and the lowest doses and cost of therapy. Consideration of these issues maximizes compliance and effectiveness of therapy in long-term disease control. An effective medication lowers the IOP 20% to 30% from baseline. Figure 10.1 lists the most common classes of medications with mechanism of action and common side effects; sample bottles of medications are also shown. We will discuss each class of medications and offer clinical pearls. • Direct-acting: pilocarpine HCl, pilocarpine gel •Indirect-acting: echothiophate iodide, eserine sulfate ointment, demecarium bromide, isofluorophate •Affect the parasympathetic or cholinergic system through direct- or indirect-acting Agents •In addition to effects on ciliary muscle, parasympathomimetics stimulate muscarinic receptors of the iris sphincter to cause miosis. This may improve outflow facility in eyes with angle-closure glaucomas by relieving pupillary block or by changing the anatomy of the peripheral iris in the angle. •Miosis may cause dimness of vision, contraction of visual fields, and pinhole effect. •Patients may develop brow ache due to ciliary muscle spasm.
Functional Group Protection
Authors: Taber Douglass
Published: November 2020

Alcohols are usually protected as alkyl or silyl ethers. Michael P. Jennings of the University of Alabama found (Tetrahedron Lett. 2008, 49, 5175) that pyridinium tribromide can selectively remove the TBS (or TES) protection from the primary alcohol of a protected primary-secondary alcohol such as 1. Propargyl ethers are useful because they are stable, but can be selectively removed in the presence of other protecting groups. Shino Manabe and Yukishige Ito at RIKEN showed (Tetrahedron Lett. 2008, 49, 5159) that SmI2 could reductively remove a propargyl group in the presence of acetonides (illustrated, 3), MOM, benzyl and TBS ethers. Hisanaka Ito of the Tokyo University of Pharmacy and Life Sciences took advantage (Organic Lett. 2008, 10, 3873) of the reducing power of Cp2Zr to selectively remove the allyl ethers from 5, to give 6. These conditions might also remove propargyl ethers. Esters can also be useful protecting groups. Naoki Asao of Tohoku University developed (Tetrahedron Lett . 2008, 49, 7046) the o-alkynyl ester 7. Au catalyst in EtOH removed the ester, leaving benzoates, acetates, OTBS and OTHP intact. Alternatively, an o-iodobenzoate can be removed by Sonogashira coupling followed by the Au hydrolysis. N-Formylation is usually accomplished using mixed anhydrides. Weige Zhang and Maosheng Chang of Shenyang Pharmaceutical University put forward ( Chem. Commun. 2008 , 5429) an intriguing alternative, heating a secondary amine 9 with KCN in the presence of dimethyl malonate to give 10. Many of the current methods for amination that have been developed deliver the aryl amine. John F. Hartwig of the University of Illinois established (J. Am. Chem. Soc. 2008, 130, 12220) that exposure of the amine 11 to Boc2O followed by CAN led to the protected, dearylated amine 12. Adam McCluskey of The University of Newcastle observed (Tetrahedron Lett. 2008, 49, 6962) that microwave heating removed Boc protecting groups when there was a free carboxylic acid elsewhere in the molecule. Michael Lefenfeld of SiGNa Chemistry and James E. Jackson of Michigan State University used (Organic Lett. 2008, 10, 5441) easilyhandled Na/silica gel to remove primary and secondary sulfonamides (e.g. 15 → 16). Methanesulfonamides were also removed under these conditions.
Reactions of Alkenes
Authors: Taber Douglass
Published: November 2020

One of the most powerful of alkene transformations is enantioselective epoxidation. Tsutomu Katsuki of Kyushu University has developed (Angew. Chem. Int. Ed. 2007, 46, 4559) a Ti catalyst that with H2O2, selectively epoxidized terminal alkenes with high ee. The same catalyst converted a Z 2-alkene such as 3 into the epoxide. This is signiﬁcant, because such epoxides are opened with nucleophiles selectively at the less congested center. Novel procedures for alkene functionalization have been put forward. Philippe Renaud of the University of Berne has developed (Adv. Synth. Cat. 2008, 350, 1163) a simple protocol for terminal halogenation, based on catalyzed addition of catecholborane, followed by free radical substitution. Sulfides and selenides were also prepared. H. Zoghlami of the Faculty of Sciences of Tunis has devised (Tetrahedron Lett. 2007, 48, 5645) an oxidative sulfinylation, converting a terminal alkene 7 to the sulfide 8. M. Christina White of the University of Illinois (J. Am. Chem. Soc. 2008, 130, 3316) and Guosheng Liu of the Shanghai Institute of Organic Chemistry (Angew. Chem. Int. Ed. 2008, 47, 4733) independently developed Pd catalysts for the oxidation of a terminal alkene 9 to the terminal allylic amine 10. Shannon S. Stahl of the University of Wisconsin-Madison has established (Organic Lett. 2007, 9, 4331) conditions for the complementary transformation of a terminal alkene 11 to the enamide 12. Douglas B. Grotjahn of San Diego State University has optimized (J. Am. Chem. Soc. 2007, 129, 9592) Ru-catalyzed alkene (“zipper”) migration, effecting the conversion of 13 to 14 and of 15 to 16 . There have been several new observations on alkene cleavage. Marcus A. Tius of the University of Hawaii and Bakthan Singaram of the University of California, Santa Cruz have found (Tetrahedron Lett. 2008, 49, 2764) that epoxides such as 17 are cleaved directly by NaIO4, providing a simple alternative to ozonolysis. Rolando A. Spanevello of the Universidad Nacional de Rosario has extended (Tetrahedron 2007, 63, 11410) unsymmetrical ozonolysis to highly substituted norbornene derivatives such as 19, observing 20 as the only product. Patrick H. Dussault of the University of Nebraska–Lincoln has established (J. Org. Chem. 2008, 73, 4688) that alkene ozonolysis in wet acetone delivered the ketone or aldehyde directly, without reductive workup.
Enantioselective Assembly of Aminated Stereogenic Centers
Authors: Taber Douglass
Published: November 2020

Although natural amino acids are readily available, there is a continuing need for unnatural amino acids. Jon C. Antilla of the University of South Florida has described (J. Am. Chem. Soc. 2007, 129, 5830) a promising approach, based on the enantioselective organocatalytic reduction of imines such as 1 derived from α-keto esters. The aryl group is easily removed to give the primary amine. Mukund P. Sibi of North Dakota State University has developed (J. Am. Chem. Soc. 2007, 129, 4522) an enantioselective Mg catalyst that mediated the addition of benzyl hydrazine 6 to imides such as 5. The initial adduct cyclized to the pyrazolidinone 7. Karl Anker Jørgensen of Aarhus University has reported (Angew. Chem. Int. Ed. 2007, 46, 1983) a complementary protocol for the enantioselective conjugate addition of a nitrogen nucleophile. Enantioselective homologation can also be a powerful approach. Benjamin List of the Max-Planck-Institute, Mülheim has found (Angew. Chem. Int. Ed. 2007, 46, 612; Organic Lett. 2007, 9, 1149) that three-component coupling of acetyl cyanide, an aldehyde and benzylamine under the influence of the Jacobsen thiourea catalyst 10 delivered the onecarbon homologated nitrile 12 in high ee. Other homologation methods are also effective. Li Deng of Brandeis University has shown (Organic Lett. 2007, 9, 603) that under the influence of cinchona-derived quaternary salts, malonates will add to racemic amido sulfones such as 13 to give the β-amino malonate 14 in high ee. Fujie Tanaka and Carlos F. Barbas III of Scripps/La Jolla have found (Angew. Chem. Int. Ed. 2007, 46, 1878) that the simple organocatalyst proline will mediate the aza-Baylis Hillman addition of an unsaturated aldehyde such as 15 to 16 in high ee. The alkene 17 is the kinetic product. On prolonged exposure to the reaction conditions, 17 was equilibrated to the more stable 18 . Ming-Hua Xu and Guo-Qiang Lin of the Shanghai Institute of Organic Chemistry have established (J. Am. Chem. Soc. 2007, 129, 5336) a robust protocol for the enantioselective assembly of -arylated benzylamines such as 21.
Stereocontrolled C-O Ring Construction: The Morimoto Synthesis of ( + )-Omaezakianol
Authors: Taber Douglass
Published: November 2020

Tobin J. Marks of Northwestern University observed (J. Am. Chem. Soc. 2009, 131, 263) high geometric control in the cyclization of 1 to 2 . Tristan H. Lambert of Columbia University found (Organic Lett. 2009, 11, 1381) that Bi could catalyze both the addition of the ketene silyl acetal 4 to 3, and the subsequent cyclization of the secondary alcohol so formed, to give the product ether 5 with high diastereocontrol. Glenn M. Sammis of the University of British Columbia devised (Organic Lett. 2009, 11, 2019) a radical relay cyclization of 6 to 7, again with high diastereocontrol. Eric Fillion of the University of Waterloo established (Organic Lett. 2009, 11, 1919) that conjugate addition to the Meldrum’s acid derivative 8 proceeded with high stereoselectivity, delivering the useful chiron 10. Gregory C. Fu of MIT found (Angew. Chem. Int. Ed. 2009, 48, 2225) that both five- and six-membered ring ethers could be formed with high enantiocontrol from alkyne alcohols such as 11. The catalyst was a chiral phosphine. Christian M. Rojas of Barnard College established (Organic Lett. 2009, 11, 1527) a route to 2-amino sugars such as 15, by Rh-mediated intramolecular nitrene addition in the presence of the trapping agent 14. J. S. Yadav of the Indian Institute of Chemical Technology, Hyderabad devised (Tetrahedron Lett. 2009, 50, 81) a route to C-glycosides such as 18, by condensation of a glycal 16 with an isonitrile 17. Michel R. Gagné of the University of North Carolina developed (Organic Lett. 2009, 11, 879) a complementary route to C-glycosides such as 21, with control of side chain relative configuration. Note that the addition to the methacrylate 20 is likely proceeding by initial one-electron reduction, since reductive β-elimination is not observed. It is also possible to construct larger rings. Frank E. McDonald of Emory University devised a flexible route to protected tetraols such as 22, and showed (Organic Lett. 2009 , 11, 851) that it could be cyclized selectively to the septanoside 23. Kenshu Fujiwara of Hokkaido University found (Tetrahedron Lett. 2009, 50, 1236) that ring-closing metathesis of 24 delivered the eight-membered ring product 25 in near quantitative yield.
Synthesis of Substituted Benzenes: The Carter Synthesis of Siamenol
Authors: Taber Douglass
Published: November 2020

Tosylates are among the least expensive, but also among the least reactive toward Pd(0) oxidative addition, of aryl sulfonates. Jie Wu of Fudan University has now devised conditions (J. Org. Chem. 2007, 72, 9346) for the Pd-catalyzed coupling of aryl tosylates such as 1 with arene trifluoroborates. Kei Manabe of RIKEN has found (Organic Lett. 2007, 9, 5593) that an ortho OH activates an adjacent Cl for Pd-mediated coupling, allowing the conversion of 4 to 6 . Philippe Uriac and Pierre van de Weghe of the Université de Rennes I have developed (Organic Lett. 2007, 9, 3623) conditions for the catalytic acylation of aryl halides with alkenyl acetates such as 8. Multi-component coupling lends itself well to diversity-oriented synthesis. As illustrated by the combination of 10 with 11 and 12 to give 13 reported (Organic Lett. 2007, 9, 5589) by Michael F. Greaney of the University of Edinburgh, benzynes can do double addition with high regiocontrol. For other recent references to unsymmetrical double additions to arynes, see Angew.Chem. Int. Ed. 2007, 46, 5921; Chem. Commun. 2007, 2405; and J. Am. Chem. Soc. 2006, 128, 14042. C-H functionalization of arenes is of increasing importance. John F. Hartwig of the University of Illinois has described (Organic Lett. 2007, 9, 757; 761) improved conditions for Ir-catalyzed meta borylation, and conditions for further coupling of the initial borate 16 to give amines such as 17. Lei Liu and Qing-Xiang Guo of the University of Science and Technology, Hefei have found (Tetrahedron Lett. 2007, 48, 5449) that oxygen can be used as the stoichiometric oxidant in the Pd-catalyzed functionalization of H’s ortho to anilides. Two other research groups (J. Am. Chem. Soc. 2007, 129, 6066; Angew. Chem. Int. Ed. 2007, 46, 5554; J. Org. Chem. 2007, 72, 7720) reported advances in this area. In a close competition, Jin-Quan Yu, now at Scripps/La Jolla (J. Am. Chem. Soc. 2007, 129, 3510) and Olafs Daugulis of the University of Houston (J. Am. Chem. Soc. 2007, 129, 9879) both reported that a carboxyl group can activate an ortho H for direct functionalization.
Substituted Benzenes: The Alvarez-Manzaneda Synthesis of (-)-Taiwaniquinone G
Authors: Taber Douglass
Published: November 2020

Continuing efforts toward the direct functionalization of aromatic C-H bonds, Nobutaka Fujii and Hiroaki Ohno of Kyoto University described (Chem. Commun. 2009, 3413) a Pd-mediated protocol for the ortho hydroxylation of aryl tetrahydropyrimidines such as 1. To use a boronic acid as an activating/directing group, Michinori Suginome, also of Kyoto University, devised (J. Am. Chem. Soc. 2009, 131, 7502) the pyrazolylpyridyl derivative 3. The product 4 could be returned to the boronic acid or carried on to the borate ester, in each case with recovery of the directing group. Eiichi Nakamura of the University of Tokyo established (Angew. Chem. Int. Ed. 2009, 49, 2925) that ortho arylation of 5 could be accomplished even in the presence of a reactive aryl halide. In a complementary approach, Matthew J. Gaunt of the University of Cambridge developed (Science 2009, 323, 1593) a procedure for C-H arylation of anilides such as 7 that showed good meta selectivity. Mamoru Tobisu and Naoto Chatani of Osaka University have found (Chem. Lett. 2009, 38, 710) for the conversion of aryl ethers such as 9 to the tertiary amine. Masahito Ochiai of the University of Tokushima observed (J. Am. Chem. Soc. 2009, 131, 8392) the remarkable inversion of an arene sulfonamide such as 11 to the protected aniline 12. Matthias Beller of the Universität Rostock established (Angew. Chem. Int. Ed. 2009, 49, 918) a Pd-mediated procedure for the conversion of even a congested aryl halide 13 to the phenol 14. The first C-C bond formations with phenols used very reactive, but expensive, leaving groups such as triflates. With improving ligand design, conditions have been found that work well even with inexpensive mesylates. Now, Zhang-Jie Shi of Peking University (J. Am. Chem. Soc. 2008, 130, 14468) and Neil K. Garg of UCLA (J. Am. Chem. Soc. 2008, 130, 14422), working independently, developed similar procedures for the Ni-mediated arylation of esters such as 15. Both groups found that pivalates worked particularly well. For some highly-substituted benzene derivatives, construction of the aromatic ring can be an economical approach.
Transition Metal Catalyzed Construction of Carbocyclic Rings: (-)-Hamigeran B
Authors: Taber Douglass
Published: November 2020

Several elegant methods for the enantioselective transformation of preformed prochiral rings have been put forward. Derek R. Boyd of Queen’s University, Belfast devised (Chem. Commun. 2008, 5535) a Cu catalyst that effected allylic oxidation of cyclic alkenes such as 1 with high ee. Christoph Jaekel of the Ruprecht-Karls-Universität Heidelberg established (Adv. Synth. Cat. 2008, 350, 2708) conditions for the enantioselective hydrogenation of cyclic enones such as 3. Marc L. Snapper of Boston College developed (Angew. Chem. Int. Ed. 2008, 47, 5049) a Cu catalyst for the enantioselective allylation of activated cyclic enones such as 5. Alexandre Alexakis of the University of Geneva showed (Angew. Chem. Int. Ed. 2008, 47, 9122) that dienones such as 8 could be induced to undergo 1,4 addition, again with high ee. Tsutomu Katsuki of Kyushu University originated (J. Am. Chem. Soc. 2008, 130, 10327) an Ir catalyst for the addition of diazoacetate 11 to alkenes such as 10 to give the cyclopropane 12 with high chemo-, enantio- and diastereoselectivity. Weiping Tang of the University of Wisconsin found (Angew. Chem. Int. Ed. 2008, 47, 8933) a silver catalyst that rearranged cyclopropyl diazo esters such as 13 to the cyclobutene 14 with high regioselectivity. Zhang-Jie Shi of Peking University demonstrated (J. Am. Chem. Soc. 2008, 130, 12901) that under oxidizing conditions, a Pd catalyst could cyclize 15 to 16. Sergio Castillón of the Universitat Rovira i Virgili, Tarragona devised (Organic Lett. 2008, 10, 4735) a Rh catalyst for the enantioselective cyclization of 17 to 18. Virginie Ratovelomanana-Vidal of the ENSCP Paris and Nakcheol Jeong of Korea University established (Adv. Synth. Cat. 2008, 350, 2695) conditions for the enantioselective intramolecular Pauson-Khand cyclization of 19 to give, after hydrolysis, the cyclopentenone 20. Quanrui Wang of Fudan University, Several elegant methods for the enantioselective transformation of preformed prochiral rings have been put forward. Derek R. Boyd of Queen’s University, Belfast devised (Chem. Commun. 2008, 5535) a Cu catalyst that effected allylic oxidation of cyclic alkenes such as 1 with high ee.