Target Health Presenting at CBI Meeting on eSource Data in Clinical Investigations


Target Health Inc. is pleased to announce that Dr. Jules T. Mitchel, President of Target Health, will present at the CBI conference on eSource Data in Clinical Investigations. Dr. Mitchel’s presentation, entitled “eSource Methodology – Investigate the Impact on the Industry,“ will use results and experiences from completed and ongoing clinical trials performed by Target Health to:


1. Identify ways eSource methodologies are integrated with risk-based monitoring

2. Examine the impact on the clinical research enterprise and stakeholders


The conference will be held on May 4-5, 2015 at the Wyndham Philadelphia Historic District, Philadelphia, Pa. General topics include industry models for implementation, data integration, and change management to enable eSource adoption. The conference will allow attendees to:


1. Benchmark against industry trailblazers to overcome the top challenges of eSource implementation and integration,

2. Develop best practices for change management to enable eSource adoption

3. Walk away with actionable strategies to effectively utilize eSource within their own organizations


Mention promo code UJB969 for $300 off your registration. If you want a bigger discount, respond to the newsletter with a request. For more information please visit


Participants include:

Jonathan Helfgott, Formerly Associate Director, FDA; Now at Stage 2 Innovations

Debbie Profit, Director, Corporate Projects, Otsuka Pharmaceuticals

Mohammed Ali, Global Program Manager, Global Clinical Operations, Novartis

Ed Kellar, Director, Global Management, Operational Support, Astellas

Johann Proeve, Global Strategy and Development, Bayer HealthCare

Fabian Sandoval, Emerson Clinical Research Institute, LLC

Peggy Siemon-Hryczyk, Senior Director, Eisai Inc.

Deborah Baretz, Senior Director, Harvard Clinical Research Institute


Sunset Over Pilot Mountain, NC


Another spectacular photograph from our friend and colleague James Farley, Clinical Data Manager, TransTech Pharma


For centuries Pilot Mountain has served as a landmark for Native Americans, early explorers, and migrating wildlife. This iconic peak is the most recognizable mountain in North Carolina and forms the centerpiece of Pilot Mountain State Park. Rising to an elevation of 2,421 feet, this solitary quartzite mountain, part of the ancient Sauratown Mountain range, was dedicated a National Natural Landmark.



Sunset From Pilot Mountain ©JFarley Photagraphy


ON TARGET is the newsletter of Target Health Inc., a NYC-based, full-service, contract research organization (eCRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services to the pharmaceutical and device industries, including the paperless clinical trial.


For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.


Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor



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What You Always Wanted to Know About the Hippocampus


The hippocampus is located in the medial temporal lobe of the brain. In this lateral view of the human brain, the frontal lobe is at left, the occipital lobe at right, and the temporal and parietal lobes have largely been removed to reveal the hippocampus underneath.



RI coronal view of a hippocampus


The hippocampus was named after its resemblance to the seahorse, from the Greek hippos, “horse“ and kampos, “sea monster.“


The hippocampus is a major component of the brains of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. The hippocampus is located under the cerebral cortex; and in primates it is located in the medial temporal lobe, underneath the cortical surface. It contains two main interlocking parts: Ammon’s horn and the dentate gyrus. In Alzheimer’s disease, the hippocampus is one of the first regions of the brain to suffer damage. Memory loss and disorientation are included among the early symptoms. Damage to the hippocampus can also result from oxygen starvation (hypoxia), encephalitis, or medial temporal lobe epilepsy. People with extensive, bilateral hippocampal damage may experience anterograde amnesia – the inability to form or retain new memories.


In rodents, the hippocampus has been studied extensively as part of a brain system responsible for spatial memory and navigation. Many neurons in the rat and mouse hippocampus respond as place cells: that is, they fire bursts of action potentials when the animal passes through a specific part of its environment. Hippocampal place cells interact extensively with head direction cells, whose activity acts as an inertial compass or GPS, and conjecturally with grid cells in the neighboring entorhinal cortex. Since different neuronal cell types are neatly organized into layers in the hippocampus, it has frequently been used as a model system for studying neurophysiology. The form of neural 1) ___ known as long-term potentiation (LTP) was first discovered to occur in the hippocampus and has often been studied in this structure. LTP is widely believed to be one of the main neural mechanisms by which memory is stored in the brain.




The human hippocampus and fornix compared with a seahorse (preparation by Laszlo Seress in 1980)


The earliest description of the ridge running along the floor of the temporal horn of the lateral ventricle comes from the Venetian anatomist Julius Caesar Aranzio (1587), who likened it first to a silkworm and then to a seahorse (Latin: hippocampus from Greek, “horse“ and “sea monster“). The German anatomist Duvernoy (1729), the first to illustrate the structure, also wavered between “seahorse“ and “silkworm.“ “Ram’s horn“ was proposed by the Danish anatomist Jacob Winslow in 1732; and a decade later his fellow Parisian, the surgeon de Garengeot, used “cornu Ammonis“ – horn of (the ancient Egyptian god) Amun. Another mythological reference appeared with the term pes hippocampi, which may date back to Diemerbroeck in 1672, introducing a comparison with the shape of the folded back forelimbs and webbed feet of the classical hippocampus a Greek sea monster with a horse’s forequarters and a fish’s tail. The hippocampus was then described as pes hippocampi major, with an adjacent bulge in the occipital horn, the calcar avis, being named pes hippocampi minor.


The renaming of the hippocampus as hippocampus major, and the calcar avis as hippocampus minor, has been attributed to Felix Vicq-d’Azyr systematizing nomenclature of parts of the brain in 1786. Mayer mistakenly used the term hippopotamus in 1779, and was followed by some other authors until Karl Friedrich Burdach resolved this error in 1829. In 1861 the hippocampus minor became the center of a dispute over human evolution between Thomas Henry Huxley and Richard Owen, satirized as the Great Hippocampus Question. The term hippocampus minor fell from use in anatomy textbooks, and was officially removed in the Nomina Anatomica of 1895. Today, the structure is called the hippocampus rather than hippocampus major, with pes hippocampi often being regarded as synonymous with De Garengeot’s “cornu Ammonis“, a term that survives in the names of the four main histological divisions of the hippocampus: CA1, CA2, CA3, and CA4.




Nissl-stained coronal section of the brain of a macaque monkey, showing hippocampus (circled). Source:


In terms of anatomy, the hippocampus is an elaboration of the edge of the cerebral 2) ___. The structures that line the edge of the cortex make up the so-called limbic system (Latin limbus =border): These include the hippocampus, cingulate cortex, olfactory cortex, and amygdala. Paul MacLean once suggested, as part of his triune brain theory, that the limbic structures comprise the neural basis of emotion. Some neuroscientists no longer believe that the concept of a unified “limbic system“ is valid, however. Yet, the hippocampus is anatomically connected to parts of the brain that are involved with emotional behavior – the septum, the hypothalamic mammillary body, and the anterior nuclear complex in the thalamus – therefore its role as a limbic structure cannot be completely dismissed.


The hippocampus as a whole has the shape of a curved tube, and can be distinguished as a zone where the cortex narrows into a single layer of densely packed pyramidal 3) ___ 3 to 6 cells deep in rats, which curl into a tight U shape; one edge of the “U,“ field CA4, is embedded into a backward-facing, strongly flexed, V-shaped cortex, the dentate gyrus. It consists of ventral and dorsal portions, both of which are of similar composition but are parts of different neural circuits. This general layout holds across the full range of mammalian species, from hedgehog to human, although the details vary. In human or monkey brains, the portion of the hippocampus down at the bottom, near the base of the temporal lobe, is much broader than the part at the top. One of the consequences of this complex geometry is that cross-sections through the hippocampus can show a variety of shapes, depending on the angle and location of the cut.




Basic circuit of the hippocampus, as drawn by Santiago Ramon y Cajal. DG: dentate gyrus. Sub: subiculum. EC: entorhinal cortex.


The entorhinal cortex (EC), located in the parahippocampal gyrus, is considered to be part of the hippocampal region because of its anatomical connections. The EC is strongly and reciprocally connected with many other parts of the cerebral cortex. The main output pathway (perforant path, first described by Ramon y Cajal) of EC axons comes from the large pyramidal cells in layer II that “perforate“ the subiculum and project densely to the granule cells in the dentate gyrus. The perforant path establishes the EC as the main “interface“ between the hippocampus and other parts of the cerebral cortex. The dentate granule cell axons (called mossy fibers) pass on the information from the EC on thorny spines that exit from the proximal apical dendrite of CA3 pyramidal cells. Then, CA3 axons exit from the deep part of the cell body and loop up into the region where the apical dendrites are located, then extend all the way back into the deep layers of the entorhinal cortex – the Shaffer collaterals completing the reciprocal circuit. Within the hippocampus, the flow of information from the EC is largely unidirectional, with signals propagating through a series of tightly packed 4) ___ layers, first to the dentate gyrus, then to the CA3 layer, then to the CA1 layer, then to the subiculum, then out of the hippocampus to the EC, mainly due to collateralization of the CA3 axons. Each of these layers also contains complex intrinsic circuitry and extensive longitudinal connections. Several other connections play important roles in hippocampal function. Beyond the output to the EC, additional output pathways go to other cortical areas including the prefrontal cortex. A very important large output goes to the lateral septal area and to the mammillary body of the hypothalamus. The hippocampus receives modulatory input from the serotonin, norepinephrine, and dopamine systems. The inputs from the septal area play a key role in controlling the physiological state of the hippocampus. Destruction of the septal area abolishes the hippocampal theta rhythm and severely impairs certain types of 5) ___. The cortical region adjacent to the hippocampus is known collectively as the parahippocampal gyrus (or parahippocampus). It includes the EC and also the perirhinal cortex, which plays an important role in visual recognition of complex objects. There is also substantial evidence that it makes a contribution to memory, which can be distinguished from the contribution of the hippocampus. It is apparent that complete amnesia occurs only when both the hippocampus and the parahippocampus are damaged.




Hippocampus (animation)


Historically, the earliest widely held hypothesis was that the hippocampus is involved in olfaction. This idea was cast into doubt by a series of anatomical studies that did not find any direct projections to the hippocampus from the olfactory bulb. However, later work did confirm that the olfactory bulb does project into the ventral part of the lateral entorhinal cortex, and field CA1 in the ventral hippocampus sends axons to the main olfactory bulb, the anterior olfactory nucleus, and to the primary olfactory cortex. There continues to be some interest in hippocampal olfactory responses, in particular the role of the hippocampus in memory for odors, but few specialists today believe that olfaction is its primary function. Over the years, three main ideas of hippocampal function have dominated the literature: inhibition, memory, and space. The behavioral inhibition theory (caricatured by O’Keefe and Nadel as “slam on the brakes!“) was very popular up to the 1960s. It derived much of its justification from two observations: first, that animals with hippocampal damage tend to be hyperactive; second, that animals with hippocampal damage often have difficulty learning to inhibit responses that they have previously been taught, especially if the response requires remaining quiet as in a passive avoidance test. Jeffrey Gray developed this line of thought into a full-fledged theory of the role of the hippocampus in anxiety. The inhibition theory is currently the least popular of the three. The second major line of thought relates the hippocampus to memory. Although it had historical precursors, this idea derived its main impetus from a famous report by William Beecher Scoville and Brenda Milner describing the results of surgical destruction of the hippocampi (in an attempt to relieve 6) ___ seizures), in Henry Molaison, known until his death in 2008 as “Patient H.M.“ The unexpected outcome of the surgery was severe anterograde and partial retrograde amnesia; Molaison was unable to form new episodic memories after his surgery and could not remember any events that occurred just before his surgery, but he did retain memories of events that occurred many years earlier extending back into his childhood. This case attracted such widespread professional interest that Molaison became the most intensively studied subject in medical history. In the ensuing years, other patients with similar levels of hippocampal damage and amnesia (caused by accident or disease) have also been studied, and thousands of experiments have studied the physiology of activity-driven changes in synaptic connections in the hippocampus. There is now almost universal agreement that the hippocampi play some sort of important role in memory; however, the precise nature of this role remains widely debated. The third important theory of hippocampal function relates the hippocampus to space. The spatial theory was originally championed by O’Keefe (Nobel Laureate for this research) and Nadel, who were influenced by E.C. Tolman’s theories about “cognitive maps“ in humans and animals. O’Keefe and his student Dostrovsky in 1971 discovered neurons in the rat hippocampus that appeared to them to show activity related to the rat’s location within its environment. Despite skepticism from other investigators, O’Keefe and his co-workers, especially Lynn Nadel, continued to investigate this question, in a line of work that eventually led to their very influential 1978 book “The Hippocampus as a Cognitive Map.“ As with the memory theory, there is now almost universal agreement that spatial coding plays an important role in hippocampal function, but the details are widely debated.


Psychologists and neuroscientists generally agree that the hippocampus plays an important role in the formation of new memories about experienced events (episodic or autobiographical memory). Part of this function is hippocampal involvement in the detection of novel events, places and stimuli. Some researchers regard the hippocampus as part of a larger medial temporal lobe memory system responsible for general declarative memory (memories that can be explicitly verbalized – these would include, for example, memory for facts in addition to episodic memory). Due to bilateral 7) ___ the brain has a hippocampus in each cerebral hemisphere, so every normal brain has two of them. If damage to the hippocampus occurs in only one hemisphere, leaving the structure intact in the other hemisphere, the brain can retain near-normal memory functioning. Severe damage to the hippocampi in both hemispheres results in profound difficulties in forming new memories (anterograde amnesia) and often also affects memories formed before the damage occurred (retrograde amnesia). Although the retrograde effect normally extends many years back before the brain damage, in some cases older memories remain. This retention of older memories leads to the idea that consolidation over time involves the transfer of memories out of the hippocampus to other parts of the brain. Damage to the hippocampus does not affect some types of memory, such as the ability to learn new skills (playing a musical instrument or solving certain types of puzzles, for example). This fact suggests that such abilities depend on different types of memory (procedural memory) and different brain regions. Furthermore, amnesic patients frequently show “implicit“ memory for experiences even in the absence of conscious knowledge. For example, patients asked to guess which of two faces they have seen most recently may give the correct answer most of the time in spite of stating that they have never seen either of the faces before. Some researchers distinguish between conscious recollection, which depends on the hippocampus, and familiarity, which depends on portions of the medial temporal cortex.




Spatial firing patterns of 8 place cells recorded from the CA1 layer of a rat. The rat ran back and forth along an elevated track, stopping at each end to eat a small food reward. Dots indicate positions where action potentials were recorded, with color indicating which neuron emitted that action potential.


Studies conducted on freely moving rats and mice have shown that many hippocampal neurons have “place fields“, that is, they fire bursts of action potentials when a rat passes through a particular part of the environment. Evidence for place cells in primates is limited because it is difficult to record brain activity from freely moving monkeys. Place-related hippocampal neural activity has been reported in monkeys moving around inside a room while seated in a restraint chair. On the other hand, Edmund Rolls and his colleagues instead described hippocampal cells that fire in relation to the place a monkey is looking at, rather than the place where its body is located. In humans, cells with location-specific firing patterns have been reported in a study of patients with drug-resistant epilepsy who were undergoing an invasive procedure to localize the source of their seizures, with a view to surgical resection. The patients had diagnostic electrodes implanted in their hippocampus and then used a computer to move around in a virtual 8) ___ town.


Place responses in rats and mice have been studied in hundreds of experiments over four decades, yielding a large quantity of information. Place cell responses are shown by pyramidal cells in the hippocampus proper, and granule cells in the dentate gyrus. These constitute the great majority of neurons in the densely packed hippocampal layers. Inhibitory interneurons, which make up most of the remaining cell population, frequently show significant place-related variations in firing rate that are much weaker than those displayed by pyramidal or granule cells. There is little if any spatial topography in the representation; in general, cells lying next to each other in the hippocampus have uncorrelated spatial firing patterns. Place cells are typically almost silent when a rat is moving around outside the place field but reach sustained rates as high as 40 Hertz when the rat is near the center. Neural activity sampled from 30 to 40 randomly chosen place cells carries enough information to allow a rat’s location to be reconstructed with high confidence. In some cases, the firing rate of rat hippocampal cells depends not only on place but also on the direction a rat is moving, the destination toward which it is traveling, or other task-related variables. The discovery of place cells in the 1970s led to a theory that the hippocampus might act as a cognitive map – a neural representation of the layout of the environment. Several lines of evidence support the hypothesis. It is a frequent observation that without a fully functional hippocampus, humans may not remember where they have been and how to get where they are going: Getting lost is one of the most common symptoms of amnesia.


Studies with animals have shown that an intact hippocampus is required for initial learning and long-term retention of some spatial memory tasks, in particular ones that require finding the way to a hidden goal. The “cognitive map hypothesis“ has been further advanced by recent discoveries of head direction cells, grid cells, and border cells in several parts of the rodent brain that are strongly connected to the hippocampus. Brain 9) ___ shows that people have more active hippocampi when correctly navigating, as tested in a computer-simulated “virtual“ navigation task. Also, there is evidence that the hippocampus plays a role in finding shortcuts and new routes between familiar places. For example, London’s taxi drivers must learn a large number of places and the most direct routes between them (they have to pass a strict test, The Knowledge, before being licensed to drive the famous black cabs). A study at University College London by Maguire, et al.. (2000) showed that part of the hippocampus is larger in taxi drivers than in the general public, and that more experienced drivers have bigger hippocampi. Whether having a bigger hippocampus helps an individual to become a better cab driver, or if finding shortcuts for a living makes an individual’s hippocampus grow is yet to be elucidated. However, in that study, Maguire et al. examined the correlation between size of the grey matter and length of time that had been spent as a taxi driver, and found a positive correlation between the length of time an individual had spent as a taxi driver and the volume of the right hippocampus. It was found that the total volume of the hippocampus remained constant, from the control group vs. taxi drivers. That is to say that the posterior portion of a taxi driver’s hippocampus is indeed increased, but at the expense of the anterior portion. There have been no known detrimental effects reported from this disparity in hippocampal proportions.


Various sections of the hippocampal formation are shown to be functionally and anatomically distinct. The dorsal (DH), ventral (VH) and intermediate regions of the hippocampal formation serve different functions, project with differing pathways, and have varying degrees of place field neurons. The dorsal region of the hippocampal formation serves for spatial memory, verbal memory, and learning of conceptual information. The intermediate hippocampus has overlapping characteristics with both the ventral and dorsal hippocampus. The ventral hippocampus functions in fear conditioning and affective processes. Anagnostaras et al. (2002) showed that alterations to the ventral hippocampus reduced the amount of information sent to the amygdala by the dorsal and ventral hippocampus, consequently altering fear conditioning in rats.


The hippocampus shows two major “modes“ of activity, each associated with a distinct pattern of neural population activity and waves of electrical activity as measured by an 10) ___ (EEG). These modes are named after the EEG patterns associated with them: theta (awake behavior) and large irregular activity (during slow wave sleep) (LIA). The main characteristics described below are for the rat, which is the animal most extensively studied. The theta mode appears during states of active, alert behavior (especially locomotion), and also during REM (dreaming) sleep. In the theta mode, the EEG is dominated by large regular waves with a frequency range of 6 to 9 Hertz, and the main groups of hippocampal neurons (pyramidal cells and granule cells) show sparse population activity, which means that in any short time interval, the great majority of cells are 11) ___, while the small remaining fraction fire at relatively high rates, up to 50 spikes in one second for the most active of them. An active cell typically stays active for half a second to a few seconds. As the rat behaves, the active cells fall silent and new cells become active, but the overall percentage of active cells remains more or less constant. In many situations, cell activity is determined largely by the spatial location of the animal, but other behavioral variables also clearly influence it. The LIA mode appears during slow-wave (non-dreaming) sleep, and also during states of waking immobility such as resting or eating. In the LIA mode, the EEG is dominated by sharp waves, that are randomly-timed large deflections of the EEG signal lasting for 25-50 milliseconds. Sharp waves are frequently generated in sets, with sets containing up to 5 or more individual sharp waves and lasting up to 500 ms.


Age-related conditions such as 12) ___ disease (for which hippocampal disruption is one of the earliest signs) have a severe impact on many types of cognition, but even normal aging is associated with a gradual decline in some types of memory, including episodic memory and working memory (or short-term memory). Because the hippocampus is thought to play a central role in memory, there has been considerable interest in the possibility that age-related declines could be caused by hippocampal deterioration. Some early studies reported substantial loss of neurons in the hippocampus of elderly people, but later studies using more precise techniques found only minimal differences. Similarly, some MRI studies have reported shrinkage of the hippocampus in elderly people, but other studies have failed to reproduce this finding. There is, however, a reliable relationship between the size of the hippocampus and memory performance ? meaning that not all elderly people show hippocampal shrinkage, but those who do, tend to perform less well on some memory tasks. There are also reports that memory tasks tend to produce less hippocampal activation in elderly than in young subjects. Furthermore, a randomized-control study published in 2011 found that aerobic exercise could increase the size of the hippocampus in adults aged 55 to 80 and also improve spatial memory.


The hippocampus contains high levels of glucocorticoid receptors, which make it more vulnerable to long-term stress than most other brain areas. Stress-related steroids affect the hippocampus in at least three ways: first, by reducing the excitability of some hippocampal neurons; second, by inhibiting the genesis of new neurons in the dentate gyrus; third, by causing atrophy of dendrites in pyramidal cells of the CA3 region. There is evidence that humans having experienced severe, long-lasting traumatic stress show atrophy of the hippocampus more than of other parts of the brain. These effects show up in post-traumatic stress 13) ___ (PTSD), and they may contribute to the hippocampal atrophy reported in schizophrenia and severe depression. A recent study has also revealed atrophy as a result of depression, but this can be stopped with anti-depressants even if they are not effective in relieving other symptoms. Hippocampal atrophy is also frequently seen in Cushing’s syndrome, a disorder caused by high levels of cortisol in the bloodstream. At least some of these effects appear to be reversible if the stress is discontinued. There is, however, evidence derived mainly from studies using rats that stress occurring shortly after birth can affect hippocampal function in ways that persist throughout life. Gender-specific responses to stress have also been demonstrated to have an effect on the hippocampus. During situations in which adult male and female rats were exposed to chronic stress the females were shown to be better able to cope.


ANSWERS: 1) plasticity; 2) cortex; 3) neurons; 4) cell; 5) memory; 6) epileptic; 7) symmetry; 8) reality; 9) imaging; 10) electroencephalogram; 11) silent; 12) Alzheimer’s; 13) disorder


Julius Caesar Aranzi MD (1530-1589) Brainman & More


Julius Caesar Aranzi (Julius Caesar Arantius in Latin) was a leading figure in the history of the science of human anatomy and is one of the pioneer anatomists and surgeons of the 16th century who discovered the different anatomical structures of the human body. One of his prominent discoveries is the hippocampus. Aranzi has not received full acclaim for his achievements in the field of anatomy and surgery and for some reason remains relatively unknown. Some of his anatomical books (all in Latin) are: Observationes Anatomicas, and De Humano Foetu Opusculum and surgical books De Tumoribus Secundum Locos Affectos and Hippocratis librum de vulneribus capitis commentarius brevis.


Aranzi originated the term hippocampus, from the Greek word for seahorse [hippos “horse“] and kampos [“sea monster“]. Arantius published his description of the hippocampus in 1587, in the first chapter of his work titled De Humano Foetu Liber. Numerous nomenclatures of this structure, including “white silkworm,“ “Ammon’s horn,“ and “ram’s horn“ were proposed by different scholars at that time. However, the term hippocampus has become the most widely used in the literature.


Aranzi was born in Bologna, the son of Ottaviano di Jacopo and Maria Maggi. Owing to the poverty of the family, he studied with his uncle Bartolomeo Maggi, (1477-1552), a famous surgeon who was a lecturer at the University of Bologna as well as court physician to Julius III. He held this uncle in such high esteem that he assumed his surname, calling himself Giulio Cesare Aranzi Maggio. Aranzi was admitted to the University of Padua where he made his first discovery in 1548, at the age of nineteen, when he described the elevator muscle of the upper eyelid. Later, at the University of Bologna, he received a doctorate in medicine in 1556 and was appointed a lecturer in medicine and surgery shortly thereafter at the age of twenty-seven. In 1570, surgery and anatomy were separated into separate professorships at his instigation and he held the newly created chair in anatomy for thirty-three years until his death at Bologna in 1589.


From Aranzi came the first correct account of the anatomical peculiarities of the fetus, and he was the first to show that the muscles of the eye do not, as was previously imagined, arise from the dura mater but from the margin of the optic hole. He also, after considering the anatomical relations of the cavities of the heart, the valves and the great vessels, corroborated the views of Realdo Colombo regarding the course which the blood follows in passing from the right to the left side of the heart.


Aranzi was also the first anatomist to describe distinctly the inferior cornua of the ventricles of the cerebrum and other brain parts. He recognized the objects that these brain parts resembled and named them accordingly in 1564. They are still known by his names as in hippocampus. His observations were more accurate than that of others in subsequent centuries. He wrote at length of the choroid plexus, and gave a detailed description of the fourth ventricle, under the name of cistern of the cerebellum, his own discovery. He also was the first to discover that the blood of mother and fetus remain separate during pregnancy.


As Professor of Anatomy and Surgery at the University of Bologna from 1556, he established anatomy as a major branch of medicine for the first time. Aranzi combined anatomy with a description of pathological processes, based largely on his own research, Galen, and the work of his contemporary Italians. Aranzi discovered the ?Nodules of Aranzi’ in the semilunar valves of the heart and wrote the first description of the superior levator palpebral and the coracobrachialis muscles. His books (in Latin) covered surgical techniques for many conditions, including hydrocephalus, nasal polyp, goitre and tumors to phimosis, ascites, haemorrhoids, anal abscess and fistulae and much more. Aranzi had an extensive knowledge in surgery and anatomy based in part on the ancient Greek and his contemporaries in the 16th century but essentially on his personal experience and practice. Sources: Wikipedia; Journal of Medical Biography (2011)


Molecule Hijacks Enzyme to Boost Alcohol Metabolism


After alcohol is consumed, it is first metabolized into acetaldehyde, a toxic chemical that can cause DNA damage and cancer. In the liver, aldehyde dehydrogenase 2 (ALDH2) is the main enzyme responsible for breaking down acetaldehyde into acetate, a nontoxic metabolite. It also removes other toxic aldehydes that can accumulate in the body. An estimated 560 million people in East Asia, and many people of East Asian descent, carry a genetic mutation that produces an inactive form of ALDH2. When individuals with the ALDH2 mutation drink alcohol, acetaldehyde accumulates in the body, resulting in facial flushing, nausea, and rapid heartbeat. People with the ALDH2 mutation are also at increased risk for cancers of the mouth, esophagus, and other areas of the upper aerodigestive tract.


According to an article published online in the Proceedings of the National Academy of Sciences (PNAS) (23 February 2015), an experimental compound has been shown to empower an enzyme to help process acetaldehyde, a toxic metabolite of alcohol. The findings might lead to new treatments to help people with impaired ability to metabolize acetaldehyde and other toxic substances. This class of small molecules is called aldehyde dehydrogenase activators, or Aldas, that in previous studies have been found to increase the activity of the ALDH2 enzyme. In the current study, the authors tested a new compound, Alda-89, which could provide another aldehyde dehydrogenase enzyme – ALDH3A1 — with accelerated acetaldehyde-metabolizing powers that it ordinarily does not possess.


The authors targeted the ALDH3A1 enzyme because it metabolizes acetaldehyde poorly and is highly expressed in the upper airway, stomach and gut. These aforementioned tissues are prone to cancer development in people who drink alcohol in excess. The hypothesis is that by recruiting ALDH3A1 to metabolize acetaldehyde, it could be possible to accelerate the elimination of acetaldehyde from tissues that are more vulnerable to its carcinogenic effects.”


Results showed that Alda-89 increased acetaldehyde metabolism both in normal mice and in mice carrying the ALDH2 mutation found in the East Asian population. The authors also showed that, in test tube analyses, acetaldehyde removal was faster when they combined Alda-89 with Alda-1, a compound previously shown to activate ALDH2, compared with activating each ALDH alone. It was also showed in animal studies that mice treated with the combination of Alda-89 and Alda-1 exhibit accelerated recovery from alcohol intoxication.


Neuropsychiatric Symptoms, APOE e4, and the Risk of Incident Dementia


A study published in Neurology (2015; 84:935-943), was performed to investigate the population-based interaction between a biological variable (APOE e4), neuropsychiatric symptoms, and the risk of incident dementia among subjects with prevalent mild cognitive impairment (MCI).


The study, entitled the Mayo Clinic Study of Aging, was a prospective study of 332 participants, presenting with prevalent MCI (aged 70 years and older). Study participation was a median of 3 years. The diagnoses of MCI and dementia were made by an expert consensus panel based on published criteria, after reviewing neurologic, cognitive, and other pertinent data. Neuropsychiatric symptoms were determined at baseline using the Neuropsychiatric Inventory Questionnaire. Cox proportional hazards models, with age as a time scale, was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Models were adjusted for gender, education, and medical comorbidity.


Results showed that baseline agitation, nighttime behaviors, depression, and apathy significantly increased the risk of incident dementia. Additive interactions were also observed between APOE e4 and depression (joint effect HR = 2.21; test for additive interaction, p < 0.001); and between APOE e4 and apathy (joint effect HR = 1.93; p = 0.031). Anxiety, irritability, and appetite/eating were not associated with increased risk of incident dementia.


According to the authors, among prevalent MCI cases, baseline agitation, nighttime behaviors, depression, and apathy elevated the risk of incident dementia, and there was a synergistic interaction between depression or apathy and APOE e4 in further elevating the risk of incident dementia.


FDA Approves First Biosimilar Product




The U.S. FDA has approved Zarxio (filgrastim-sndz), the first biosimilar product approved in the United States.


Biological products are generally derived from a living organism. They can come from many sources, including humans, animals, microorganisms or yeast. A biosimilar product is a biological product that is approved based on a showing that it is highly similar to an already-approved biological product, known as a reference product. The biosimilar also must show it has no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products.


Sandoz, Inc.’s Zarxio is biosimilar to Amgen Inc.’s Neupogen (filgrastim), which was originally licensed in 1991. Zarxio is approved for the same indications as Neupogen, and can be prescribed by a health care professional for patients:


1. with cancer receiving myelosuppressive chemotherapy;

2. with acute myeloid leukemia receiving induction or consolidation chemotherapy;

3. with cancer undergoing bone marrow transplantation;

4. undergoing autologous peripheral blood progenitor cell collection and therapy

5. with severe chronic neutropenia.


The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed as part of the Affordable Care Act that President Obama signed into law in March 2010. The BPCI Act created an abbreviated licensure pathway for biological products shown to be “biosimilar“ to or “interchangeable“ with an FDA-licensed biological product, called the “reference product.“ This abbreviated licensure pathway under section 351(k) of the Public Health Service Act permits reliance on certain existing scientific knowledge about the safety and effectiveness of the reference product, and enables a biosimilar biological product to be licensed based on less than a full complement of product-specific preclinical and clinical data. A biosimilar product can only be approved by the FDA if it has the same mechanism(s) of action, route(s) of administration, dosage form(s) and strength(s) as the reference product, and only for the indication(s) and condition(s) of use that have been approved for the reference product. The facilities where biosimilars are manufactured must also meet the FDA’s standards.


The FDA’s approval of Zarxio is based on review of evidence that included structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates Zarxio is biosimilar to Neupogen. Zarxio has been approved as biosimilar, not as an interchangeable product. Under the BPCI Act, a biological product that that has been approved as an “interchangeable“ may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.


The most common expected side effects of Zarxio are aching in the bones or muscles and redness, swelling or itching at injection site. Serious side effects may include spleen rupture; serious allergic reactions that may cause rash, shortness of breath, wheezing and/or swelling around the mouth and eyes; fast pulse and sweating; and acute respiratory distress syndrome, a lung disease that can cause shortness of breath, difficulty breathing or increase the rate of breathing.


For this approval, the FDA has designated a placeholder nonproprietary name for this product as “filgrastim-sndz.“ The provision of a placeholder nonproprietary name for this product should not be viewed as reflective of the agency’s decision on a comprehensive naming policy for biosimilar and other biological products. While the FDA has not yet issued draft guidance on how current and future biological products marketed in the United States should be named, the agency intends to do so in the near future.


Sandoz, a Novartis company, is based in Princeton, New Jersey. Neupogen is marketed by Amgen, based in Thousand Oaks, California.


Easy Blueberry Cake, Rum Optional


A moist delicious cake ©Joyce Hays, Target Health Inc.




1.5 sticks margarine

3/4 cup Splenda

1.5 cups almond flour

1.5 teaspoon baking powder

1 teaspoon vanilla extract

5 eggs

6 oz. fresh blueberries




All ingredients together ©Joyce Hays, Target Health Inc.




1. Preheat oven to 350

2. With Canola oil, grease a springform cake pan

3. In a small bowl, put the almond flour and the baking powder and with a spoon, mix them together

4. Over a low flame, slowly melt the margarine



First beat the eggs, then add Splenda slowly with beaters on. ©Joyce Hays, Target Health Inc.


5. Now, in your electric mixer, add the eggs, and with the beaters on, slowly add all of the Splenda.

6. With beaters on, add the vanilla

7. With beaters on, add the melted margarine

8. With beaters on, very slowly add the flour and baking powder mixture. After each addition of flour, wait until it’s totally absorbed, before you add the next small amount of almond flour.


Be sure to add these dry ingredients last.



After beating all ingredients, take beaters out, get the batter off the beaters with a small spatula and add the blueberries. Just stir them in with a spoon and pour the batter into an oiled spring pan. You can see me, reflected in the beaters, taking this photo ©Joyce Hays, Target Health Inc.


9. Without beaters on, add the (wash and dry first) blueberries.

10. Finally, pour the cake batter into the oiled cake pan and put in the oven




Going into the oven. ©Joyce Hays, Target Health Inc.


When cake is done, take out of oven and run a knife around the cake pan, but leave cake in pan until it cools for about 10 minutes. Serve while still warm and if you don’t have a weight problem, serve with vanilla ice cream, otherwise, consider fat-free Cool Whip.




With a simple cake like this one, you might want to consider serving it without rum the first time. It will be very good. Then for variety, you could try adding as much rum all over the cake, as you like, depending on your taste. After adding the rum, you will find that overnight, the flavor infuses the entire cake and is even better the next day.


If you wanted to use butter instead of margarine, go ahead. It seems like after many years of hearing how heart-unhealthy, fat is, we’re now hearing that it’s okay to eat. I’m still going to try to make this cake with either coconut oil or canola oil, instead of butter or margarine, because no matter what anyone says, there are more calories in butter or margarine.


This is a simple cake to make and delicious with coffee in the morning, lunch, snack or dessert at dinner time. You might want to save half of the cake for breakfast (without adding anything) and the other half for dinner, soaked in rum or whatever your favorite liqueur is.


This weekend we had the opportunity to see one of the most political plays we have ever seen, at The Manhattan Theater Club’s Stage One. We recommend highly, The World of Extreme Happiness.



World premiere play by Frances Ya-Chu Cowhig


Unwanted from the moment she’s born, Sunny is determined to escape her life in rural China and forge a new identity in the city. As na?ve as she is ambitious, Sunny views her new job in a grueling factory as a stepping stone to untold opportunities. When fate casts her as a company spokeswoman at a sham PR event, Sunny’s bright outlook starts to unravel in a series of harrowing and darkly comic events, as she begins to question a system enriching itself by destroying its own people.


Although, we’re patrons at this theater club, we wouldn’t recommend a play in our newsletter, unless we thought our friends and colleagues would enjoy it.


The Big Apple offers the opportunity to see much theater with political overtones. This play and the recently seen, Disgraced, are two fine examples of this. Go to both if you can.


Over dinner after the play, we agreed that the United States missed a golden opportunity, after the Soviet Union fell, to continue as a close ally of China. But back then, we only saw China as giving us leverage with the Soviet Union. Hopefully there is time to repair, but already Russia and China share a certain paranoia regarding our motives.


We had a wonderful weekend. Hope you did too!




Back to enjoying Paul Hobbs (Napa Valley) Cabernet Sauvignon, always excellent wines from this vineyard. ©Joyce Hays, Target Health Inc.



From Our Table to Yours!


Bon Appetit!