Ice crystals form in the beautifully symmetric tetrahedral shapes seen in snowflakes and on the surface of frozen ponds. Such geometries can persist at very high pressures, even if the underlying structure undergoes phase changes both subtle and dramatic with varying pressure. This certainly applies to unconstrained water. When confined between other materials, however, the behaviour of water is influenced by atomic interactions with material surfaces. The more usual ice crystals can then morph into something quite different.
When water is confined at high pressure between sheets of graphene — a single-atom-thick arrangement of carbon atoms in a hexagonal lattice — its molecules adopt a square configuration. This is the surprise finding of researchers in Germany, the UK and China.
Published in the journal Nature, the results of the study, funded in part by the Graphene Flagship, could improve our understanding of water transport through nanometre-scale channels in natural and artificial membranes. For example, the aquaporin protein-mediated flow of water across biological cell membranes is down to a balance between hydrophobic and hydrophilic interactions with channel surfaces. Such interactions are dependent on chemical bonds between hydrogen atoms.
With graphene ‘pores’ the situation is different, in that the cross section is planar rather than circular. Also, the pressure exerted on the water is so high that hydrogen bond interactions with the graphene surface are overcome by the attractive van der Waals atomic interaction that draws together the graphene planes. Still, the comparison is pertinent, and should add to the scientific debate around water flow through nanoscale channels and across membranes.
Ulm University physicists Gerardo Algara-Siller and Ossi Lehtinen carried out the latest experiment, in which a graphene monolayer was first deposited on an electron microscope grid. This graphene layer was then exposed to a small amount of water, and covered with another layer of graphene. Much of the water was squeezed out of the graphene sandwich by the van der Waals force; the remainder was trapped in pockets less than a millionth of a metre across.
“Gerardo Algara-Siller and Ossi Lehtinen carried out the experiment, and imaged the unknown ice structure between graphene sheets,” said Ulm University professor Ute Kaiser, who led the German side of the collaboration. “We did not know at first what we were seeing, and only in discussion with our Manchester colleagues was the idea of square ice born. A detailed structural and elemental analysis then proved this structure to be real.”
The Manchester connection is significant, not least owing to participation in the research by Irina Grigorieva, who has a special interest in molecular and particle transport across membranes formed of layered materials such as graphene. Scientists have long sought to understand the structure and behaviour of water confined within narrow channels. The study has until now only been possible in computer simulations, the results of which seldom agree with each other.
Grigorieva’s Manchester colleague Andre Geim, who shared the 2010 Nobel Prize in Physics for his pioneering work on graphene, is another co-author of the new Naturepaper. Geim and others had previously speculated that observations of ultrafast water flow through graphene nanocapillaries could be due to two-dimensional square ice. The new research appears to confirm the hypothesis, even if the detailed origins of this strange structure remain a mystery.
- G. Algara-Siller, O. Lehtinen, F. C. Wang, R. R. Nair, U. Kaiser, H. A. Wu, A. K. Geim, I. V. Grigorieva. Square ice in graphene nanocapillaries. Nature, 2015; 519 (7544): 443 DOI: 10.1038/nature14295
Graphene Flagship. “New form of ice: Square ice filling for a graphene sandwich.” ScienceDaily. ScienceDaily, 25 March 2015. <www.sciencedaily.com/releases/2015/03/150325140221.htm>.
New kind of ‘tandem’ solar cell: Two types of photovoltaic material combined to make a cell that harnesses more sunlight
The new cell uses a layer of silicon — which forms the basis for most of today’s solar panels — but adds a semi-transparent layer of a material called perovskite, which can absorb higher-energy particles of light. Unlike an earlier “tandem” solar cell reported by members of the same team earlier this year — in which the two layers were physically stacked, but each had its own separate electrical connections — the new version has both layers connected together as a single device that needs only one control circuit.
The new findings are reported in the journal Applied Physics Letters by MIT graduate student Jonathan Mailoa; associate professor of mechanical engineering Tonio Buonassisi; Colin Bailie and Michael McGehee at Stanford; and four others.
“Different layers absorb different portions of the sunlight,” Mailoa explains. In the earlier tandem solar cell, the two layers of photovoltaic material could be operated independently of each other and required their own wiring and control circuits, allowing each cell to be tuned independently for optimal performance.
By contrast, the new combined version should be much simpler to make and install, Mailoa says. “It has advantages in terms of simplicity, because it looks and operates just like a single silicon cell,” he says, with only a single electrical control circuit needed.
One tradeoff is that the current produced is limited by the capacity of the lesser of the two layers. Electrical current, Buonassisi explains, can be thought of as analogous to the volume of water passing through a pipe, which is limited by the diameter of the pipe: If you connect two lengths of pipe of different diameters, one after the other, “the amount of water is limited by the narrowest pipe,” he says. Combining two solar cell layers in series has the same limiting effect on current.
To address that limitation, the team aims to match the current output of the two layers as precisely as possible. In this proof-of-concept solar cell, this means the total power output is about the same as that of conventional solar cells; the team is now working to optimize that output.
Perovskites have been studied for potential electronic uses including solar cells, but this is the first time they have been successfully paired with silicon cells in this configuration, a feat that posed numerous technical challenges. Now the team is focusing on increasing the power efficiency — the percentage of sunlight’s energy that gets converted to electricity — that is possible from the combined cell. In this initial version, the efficiency is 13.7 percent, but the researchers say they have identified low-cost ways of improving this to about 30 percent — a substantial improvement over today’s commercial silicon-based solar cells — and they say this technology could ultimately achieve a power efficiency of more than 35 percent.
They will also explore how to easily manufacture the new type of device, but Buonassisi says that should be relatively straightforward, since the materials lend themselves to being made through methods very similar to conventional silicon-cell manufacturing.
One hurdle is making the material durable enough to be commercially viable: The perovskite material degrades quickly in open air, so it either needs to be modified to improve its inherent durability or encapsulated to prevent exposure to air — without adding significantly to manufacturing costs and without degrading performance.
This exact formulation may not turn out to be the most advantageous for better solar cells, Buonassisi says, but is one of several pathways worth exploring. “Our job at this point is to provide options to the world,” he says. “The market will select among them.”
- Jonathan P. Mailoa, Colin D. Bailie, Eric C. Johlin, Eric T. Hoke, Austin J. Akey, William H. Nguyen, Michael D. McGehee and Tonio Buonassisi. A 2-terminal perovskite/silicon multijunction solar cell enabled by a silicon tunnel junction. Appl. Phys. Lett., 2015 DOI: 10.1063/1.4914179
Massachusetts Institute of Technology. “New kind of ‘tandem’ solar cell: Two types of photovoltaic material combined to make a cell that harnesses more sunlight.” ScienceDaily. ScienceDaily, 24 March 2015. <www.sciencedaily.com/releases/2015/03/150324120824.htm>.
Gulf Stream system: Atlantic Ocean overturning, responsible for mild climate in northwestern Europe, is slowing
“It is conspicuous that one specific area in the North Atlantic has been cooling in the past hundred years while the rest of the world heats up,” says Stefan Rahmstorf of the Potsdam Institute for Climate Impact Research, lead author of the study to be published inNature Climate Change. Previous research had already indicated that a slowdown of the so-called Atlantic meridional overturning circulation might be to blame for this. “Now we have detected strong evidence that the global conveyor has indeed been weakening in the past hundred years, particularly since 1970,” says Rahmstorf.
Because long-term direct ocean current measurements are lacking, the scientists mainly used sea-surface and atmospheric temperature data to derive information about the ocean currents, exploiting the fact that ocean currents are the leading cause of temperature variations in the subpolar north Atlantic. From so-called proxy data — gathered from ice-cores, tree-rings, coral, and ocean and lake sediments — temperatures can be reconstructed for more than a millennium back in time. The recent changes found by the team are unprecedented since the year 900 AD, strongly suggesting they are caused by human-made global warming.
“The melting Greenland ice sheet is likely disturbing the circulation”
The Atlantic overturning is driven by differences in the density of the ocean water. From the south, the warm and hence lighter water flows northwards, where the cold and thus heavier water sinks to deeper ocean layers and flows southwards. “Now freshwater coming off the melting Greenland ice sheet is likely disturbing the circulation,” says Jason Box of the Geological Survey of Denmark and Greenland. The freshwater is diluting the ocean water. Less saline water is less dense and has therefore less tendency to sink into the deep. “So the human-caused mass loss of the Greenland ice sheet appears to be slowing down the Atlantic overturning — and this effect might increase if temperatures are allowed to rise further,” explains Box.
The observed cooling in the North Atlantic, just south of Greenland, is stronger than what most computer simulations of the climate have predicted so far. “Common climate models are underestimating the change we’re facing, either because the Atlantic overturning is too stable in the models or because they don’t properly account for Greenland ice sheet melt, or both,” says Michael Mann of Pennsylvania State University in the US. “That is another example where observations suggest that climate model predictions are in some respects still overly conservative when it comes to the pace at which certain aspects of climate change are proceeding.”
No new ice-age — but major negative effects are possible
The cooling above the Northern Atlantic would only slightly reduce the continued warming of the continents. The scientists certainly do not expect a new ice age, thus the imagery of the ten-year-old Hollywood blockbuster ‘The Day After Tomorrow’ is far from reality. However, it is well established that a large, even gradual change in Atlantic ocean circulation could have major negative effects.
“If the slowdown of the Atlantic overturning continues, the impacts might be substantial,” says Rahmstorf. “Disturbing the circulation will likely have a negative effect on the ocean ecosystem, and thereby fisheries and the associated livelihoods of many people in coastal areas. A slowdown also adds to the regional sea-level rise affecting cities like New York and Boston. Finally, temperature changes in that region can also influence weather systems on both sides of the Atlantic, in North America as well as Europe.”
If the circulation weakens too much it can even break down completely — the Atlantic overturning has for long been considered a possible tipping element in the Earth System. This would mean a relatively rapid and hard-to-reverse change. The latest report by the Intergovernmental Panel on Climate Change (IPCC) estimates there to be an up to one-in-ten chance that this could happen as early as within this century. However, expert surveys indicate that many researchers assess the risk to be higher. The study now published by the international team of researchers around Rahmstorf provides information on which to base a new and better risk assessment.
The above story is based on materials provided by Potsdam Institute for Climate Impact Research (PIK). Note: Materials may be edited for content and length.
- Stefan Rahmstorf, Jason E. Box, Georg Feulner, Michael E. Mann, Alexander Robinson, Scott Rutherford, Erik J. Schaffernicht. Exceptional twentieth-century slowdown in Atlantic Ocean overturning circulation. Nature Climate Change, 2015; DOI: 10.1038/nclimate2554
Potsdam Institute for Climate Impact Research (PIK). “Gulf Stream system: Atlantic Ocean overturning, responsible for mild climate in northwestern Europe, is slowing.” ScienceDaily. ScienceDaily, 23 March 2015. <www.sciencedaily.com/releases/2015/03/150323132746.htm>.
Electronic Informed Consent Joins Target Health’s Software Suite
Target Health Inc., the innovator of the paperless clinical trial, has incorporated the electronic informed consent (Target e*Informed Consent™) into Target e*Studio®. Interestingly, at the same time we were finishing up the software, our colleagues at FDA released a draft guidance on electronic informed consent. We are doing some minor modifications to the software based on the draft guidance and plan to meet with FDA shortly and show them what we have.
First Day of Spring in NYC – View From 88th Street
The Big Apple had a snowy Winter in 2014-2015 and the first day of Spring offered no let up. Look carefully as there are trees, cars, tables, benches and air conditioners covered with snow.
Late Snow in NYC©target Health Inc. 2015
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
The Limbic System
Emotion involves the entire nervous system, of course. But there are two parts of the nervous system that are especially significant: The limbic system and the 1) ___nervous system. The limbic system is the collective name for structures in the human brain involved in emotion, motivation, and emotional association with memory. The limbic system plays its role in the formation of memory by integrating emotional states with stored memories of physical sensations. The limbic system is a complex set of structures that lies on both sides of the thalamus, just under the cerebrum. It includes the hypothalamus, the hippocampus, the amygdala, and several other nearby areas. In this drawing, you are looking at the brain cut in half, but with the brain stem intact. The part of the limbic system shown is that which is along the left side of the thalamus (hippocampus and amygdala) and just under the front of the thalamus (hypothalamus):
The hypothalamus is a small part of the brain located just below the thalamus on both sides of the third ventricle. (The ventricles are areas within the cerebrum that are filled with cerebrospinal fluid, and connect to the fluid in the spine.) It sits just inside the two tracts of the optic nerve, and just above (and intimately connected with) the pituitary gland. The hypothalamus is one of the busiest parts of the brain, and is mainly concerned with homeostasis. Homeostasis is the process of returning something to some set point. It works like a 2) ___. The hypothalamus is responsible for regulating hunger, thirst, pain responses, pleasure levels, sexual satisfaction, anger, aggressive behavior, and more. It also regulates the functioning of the autonomic nervous system, which in turn, regulates pulse, blood pressure, breathing, and arousal in response to emotional circumstances.
The hypothalamus receives inputs from a number of sources. From the vagus nerve, it gets information about blood pressure and the distension of the gut (stomach satisfaction, fullness). From the reticular formation in the brainstem, it gets information about skin temperature. From the optic nerve, it gets information about light and darkness. From unusual neurons lining the ventricles, it gets information about the contents of the cerebrospinal 3) ___, including toxins that lead to vomiting. And from the other parts of the limbic system and the olfactory nerves, it gets information that helps regulate eating and sexuality. The hypothalamus also has some receptors of its own, that provide information about ion balance and temperature of the blood. In one of the more recent discoveries, there is a protein called leptin which is released by fat cells when overeating The hypothalamus apparently senses the levels of leptin in the bloodstream and responds by decreasing appetite. Some people have a gene mutation which produces 4) ___, and their bodies can’t tell the hypothalamus that they have had enough to eat. However, many overweight people do not have this mutation, so there is still a lot of research to do!
The hypothalamus sends instructions to the rest of the body in two ways. The first is to the autonomic nervous system. This allows the hypothalamus to have ultimate control of things like blood pressure, heartrate, breathing, digestion, sweating, and all the sympathetic and parasympathetic functions. The other way the hypothalamus controls things is via the pituitary gland. It is neurally and chemically connected to the pituitary, which in turn pumps hormones called releasing factors into the bloodstream. As you know, the pituitary is the so-called master gland, and these hormones are vitally important in regulating growth and metabolism.
The hippocampus consists of two horns that curve back from the amygdala. It appears to be very important in converting things that are in your mind at the moment (in short-5) ___ memory) into things that you will remember for the long run (long-term memory). If the hippocampus is damaged, a person cannot build new memories, and lives instead in a strange world where everything they experience just fades away, even while older 6) ___ from the time before the damage are untouched! This very unfortunate situation is fairly accurately portrayed in the wonderful movie Memento, as well as in a more light-hearted movie, 50 First Dates. But there is nothing light-hearted about it: Most people who suffer from this kind of brain damage end up institutionalized.
The amygdalas are two almond-shaped masses of neurons on either side of the thalamus at the lower end of the hippocampus. When it is stimulated electrically, animals respond with aggression. And if the amygdala is removed, animals get very tame and no longer respond to things that would have caused rage before. But there is more to it than just anger: When removed, animals also become indifferent to stimuli that would have otherwise have caused fear and even sexual responses.
Besides the hypothalamus, hippocampus, and 7) ___, there are other areas in the structures near to the limbic system that are intimately connected to it: The cingulate gyrus is the part of the cerebrum that lies closest to the limbic system, just above the corpus collosum. It provides a pathway from the thalamus to the hippocampus, seems to be responsible for focusing attention on emotionally significant events, and for associating memories to smells and to pain. The ventral tegmental area of the brain stem (just below the thalamus) consists of dopamine pathways that seem to be responsible for pleasure. People with damage here tend to have difficulty getting 8) ___ in life, and often turn to alcohol, drugs, sweets, and gambling.
The basal ganglia (including the caudate nucleus, the putamen, the globus pallidus, and the substantia nigra) lie over and to the sides of the 9) ___ system, and are tightly connected with the cortex above them. They are responsible for repetitive behaviors, reward experiences, and focusing attention. The prefrontal cortex, which is the part of the frontal lobe which lies in front of the motor area, is also closely linked to the limbic system. Besides apparently being involved in thinking about the future, making plans, and taking action, it also appears to be involved in the same dopamine pathways as the ventral tegmental area, and plays a part in pleasure and addiction. When we look more closely at the areas of the brain involved with laughter, the limbic system seems to be central. The limbic system is a network of structures located beneath the cerebral cortex. This system is important because it controls some behaviors that are essential to the life of all 10) ___ (finding food, self-preservation).
ANSWERS: 1) autonomic; 2) thermostat; 3) fluid; 4) leptin; 5) -term; 6) memories; 7) amygdala; 8) pleasure; 9) limbic; 10) mammals
Pierre Paul Broca MD (1824-1880)
Pierre Paul Broca was a French physician, surgeon, anatomist, and anthropologist. He is best known for his research on Broca’s area, a region of the frontal lobe that has been named after him. Broca’s Area is involved with articulated language. His work revealed that the brains of patients suffering from aphasia contained lesions in a particular part of the cortex, in the left frontal region. This was the first anatomical proof of the localization of brain function. Broca’s work also contributed to the development of physical anthropology, advancing the science of anthropometry.
Paul Broca was born on June 28, 1824, in Sainte-Foy-la-Grande, Bordeaux, France, the son of Benjamin Broca, a medical practitioner and former surgeon in Napoleon’s service. Broca’s mother was the daughter of a Protestant preacher. Broca received basic education in his hometown school, earning a bachelor’s degree at the age of 16. He entered medical school in Paris when he was 17, and graduated at 20, when most of his contemporaries were just beginning as medical students. After graduating, Broca undertook an extensive internship, first with the urologist and dermatologist Philippe Ricord (1800-1889) at the Hopital du Midi, then in 1843 with the psychiatrist Fran?ois Leuret (1797-1851) at the Bicetre. In 1844, he became an intern with Pierre Nicolas Gerdy (1797-1856), a great anatomist and surgeon. After two years with Gerdy, Broca became his assistant.
In 1848, Broca founded a society of free-thinkers, sympathetic to Charles Darwin’s theories. Broca was fascinated by the concept of evolution and once remarked, I would rather be a transformed ape than a degenerate son of Adam. This brought him into conflict with the church, which regarded him as a subversive, materialist, and a corrupter of the youth. The church’s animosity toward him continued throughout his lifetime, resulting in numerous confrontations between Broca and the ecclesiastical authorities.
In 1848, Broca became Prosector of anatomy at the University of Paris Medical School. He was also appointed secretary to the Societe Anatomique. In 1849, he was awarded a medical doctorate. In 1859, in association with Etienne Eugene Azam, Charles-Pierre Denonvilliers, Francois Anthime Eugene Follin, and Alfred Armand Louis Marie Velpeau, Broca performed the first experiments in Europe using hypnotism as surgical anesthesia. In 1853, Broca became professor agrege, and was appointed surgeon of the hospital. He was elected to the chair of external pathology at the Faculty of Medicine in 1867, and one year later professor of clinical surgery. In 1868, he was elected a member of the Academie de medicine, and appointed the Chair of clinical surgery. He served in this capacity until his death. He worked for the Hopital St. Antoine, the Pitie, the Hotel des Clinques, and the Hopital Necker. In parallel with his medical career, Broca pursued his interest in anthropology. In 1859, he founded the Society of Anthropology of Paris. He served as the secretary of the society from 1862. In 1872, he founded the journal Revue d’anthropologie, and in 1876, the Institute of Anthropology. The Church opposed the development of anthropology in France, and in 1876 organized a campaign to stop the teaching of the subject at the Anthropological Institute. Near the end of his life, Paul Broca was elected a lifetime member of the French Senate. He was also a member of the Academie francaise and held honorary degrees from many learned institutions, both in France and abroad.
Broca died on July 9, 1880, at the age of 56 due to a brain hemorrhage. His two sons both became distinguished professors of medical science.
Broca’s early scientific works dealt with the histology of cartilage and bone, but he also studied cancer pathology, the treatment of aneurysms, and infant mortality. One of his major concerns was the comparative anatomy of the brain. As a neuroanatomist he made important contributions to the understanding of the limbic system and rhinencephalon. Olfaction was for him a sign of animality. He wrote extensively on biological evolution, then known as transformism in France (the term was also adopted in English at the time but is today used little in either language). In his later career, Broca wrote on public health and public education. He engaged in the discussion on the health care for the poor, becoming an important figure in the Assistance Publique. He also advocated secular education for women and famously opposed Felix-Antoine-Philibert Dupanloup (1802-1878), Roman Catholic bishop of Orleans, who wanted to keep control of women’s education. One of Broca’s major areas of expertise was the comparative anatomy of the brain. His research on the localization of speech led to entirely new research into the lateralization of brain function. Broca is celebrated for his discovery of the speech production center of the brain located in the ventroposterior region of the frontal lobes (now known as Broca’s area). He arrived at this discovery by studying the brains of aphasic patients (persons with speech and language disorders resulting from brain injuries). This area of study began for Broca with the dispute between the proponents of cerebral localization – whose views derived from the phrenology of Franz Joseph Gall (1758-1828) – and their opponents led by Pierre Flourens (1794-1867) – who claimed that, by careful ablation of various brain regions, he had disproved Gall’s hypotheses. However, Gall’s former student, Jean-Baptiste Bouillaud (1796-1881), kept the localization of function hypothesis alive (especially with regards to a language center), although he rejected much of the rest of phrenological thinking. Bouillaud challenged professionals of the time to disprove him by finding a case of frontal lobe damage unaccompanied by a disorder of speech. His son-in-law, Ernest Aubertin (1825-1893), began seeking out cases to either support or disprove the theory, and he found several in support of it.
Broca’s Society of Anthropology of Paris became the new platform for the localization of function controversy when several experts of head and brain anatomy joined, including Aubertin. Most of these experts still supported Flourens argument, but Aubertin was persistent in presenting new patients to counter their views. However, it was Broca, not Aubertin, who finally put the localization of function existence issue to rest. In 1861, Broca heard of a patient, named Leborgne, in the Bicetre Hospital who had a 21-year progressive loss of speech and paralysis but not a loss of comprehension nor mental function. He was nicknamed Tan due to his inability to clearly speak any words other than tan. When Leborgne died just a few days later, Broca performed an autopsy. He determined that, as predicted, Leborgne did in fact have a lesion in the frontal lobe of the left cerebral hemisphere. From a comparative progression of Leborgne’s loss of speech and motor movement, the area of the brain important for speech production was determined to lie within the third convolution of the left frontal lobe, next to the lateral sulcus. For the next two years, Broca went on to find autopsy evidence from 12 more cases in support of the localization of articulated language. Although history credits this discovery to Broca, another French neurologist, Marc Dax, made similar observations a generation earlier, but he died before he had the time to do the research to further his evidence. Today the brains of many of Broca’s aphasic patients are still preserved in the Musee Dupuytren, and his collection of casts in the Musee d’Anatomie Delmas-Orfila-Rouviere. Broca presented his study on Leborgne in 1861 in the Bulletin of the Societe Anatomique.
Patients with damage to Broca’s area and/or to neighboring regions of the left inferiorfrontal lobe are often categorized clinically as having Expressive aphasia (also known as Broca’s aphasia). This type of aphasia, which often involves impairments in speech output, can be contrasted with Receptive aphasia, (also known as Wernicke’s aphasia), named for Karl Wernicke, which is characterized by damage to more posterior regions of the left temporal lobe, and is often characterized by impairments in language comprehension. Broca first became acquainted with anthropology through the works of Isidore Geoffroy-Saint Hilaire (1805-1861), Antoine Etienne Reynaud Augustin Serres (1786-1868) and Jean Louis Armand de Quatrefages de Breau (1810-1892), and anthropology soon became his lifetime interest. He spent much time at his Anthropological Institute, studying skulls and bones. In that sense, Broca was a pioneer in the study of physical anthropology. He advanced the science of cranial anthropometry by developing many new types of measuring instruments (craniometers) and numerical indices. Broca also contributed significantly to the field of comparative anatomy of primates. He was interested in the relationship between anatomical features of the brain and mental capabilities, such as intelligence. He believed, as did many in his time, that man’s intellectual qualities could be measured by the size of his brain.
New research has found that dysfunction in the Broca area may lead to other speech disorders such as stuttering and apraxia of speech. Recent anatomical neuroimaging studies have shown that the pars opercularis of Broca’s area is anatomically smaller in individuals who stutter whereas the pars triangularis appears to be normal.
Paul Broca’s name is one of the 72 names inscribed on the Eiffel Tower.
Biogen Idec Presents Positive Interim Results from Phase 1B Study of Investigational Alzheimer’s Disease Treatment Aducanumab (BIIB037)
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and behavioral disturbances that eventually result in a person’s inability to perform daily activities. In 2010, it was estimated that 25 million individuals were living with AD worldwide. Evidence suggests that pathophysiological changes typically begin years prior to the symptoms that lead to a clinical diagnosis. As the disease progresses, cognitive impairments, behavioral changes and functional disability commonly associated with AD begin to manifest.
Aducanumab (BIIB037) is an investigational compound being developed for the treatment of AD. Aducanumab is a human recombinant monoclonal antibody (mAb) selected from a population of elderly, healthy donors and cognitively stable patients using Neurimmune’s technology platform called Reverse Translational Medicine (RTM). Biogen Idec licensed aducanumab from Neurimmune under a collaborative development and license agreement. Aducanumab targets aggregated forms of beta amyloid including soluble oligomers and insoluble fibrils deposited into the amyloid plaque in the brain of AD patients. Based on pre-clinical and interim Phase 1b data, treatment with aducanumab has been shown to reduce amyloid plaque levels.
Biogen Idec announced data from a pre-specified interim analysis of PRIME, the Phase 1b study of aducanumab, in which aducanumab demonstrated an acceptable safety profile and positive results on radiologic and clinical measurements in patients with prodromal or mild AD. Treatment with aducanumab produced a dose- and time-dependent reduction of amyloid plaque in the brain. Amyloid plaque is believed to play a key role in the development of the symptoms of AD. In exploratory analyses, a dose-dependent, statistically significant effect of slowing clinical decline was observed on the Mini Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) scales.
PRIME is an ongoing Phase 1b randomized, double-blind, placebo-controlled, multiple-dose study evaluating the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of aducanumab in patients with prodromal or mild AD. This interim analysis of PRIME reflects data for 166 patients, up to week 54 in the placebo (n=40), 1 mg/kg (n=31), 3 mg/kg (n=33) and 10 mg/kg (n=32) dose arms, and up to week 30 data for the 6 mg/kg (n=30) dose arm.
Radiology Results: In patients receiving aducanumab, a dose- and time-dependent reduction of amyloid plaque was observed over 54 weeks of treatment. PET imaging using the radiotracer florbetapir, which binds to amyloid plaque, was used to measure plaque levels in the brain. A composite standardized uptake value ratio (SUVR) of six regions of the brain -frontal, parietal, lateral temporal, sensorimotor, anterior and posterior cingulate – was calculated at baseline, at 26 weeks and at 54 weeks using whole cerebellum as a reference. In the placebo arm, the SUVR was virtually unchanged at 26 and 54 weeks. Aducanumab treatment resulted in a statistically significant reduction of amyloid plaque in the 3 mg/kg [average change of -0.087, p<0.01)], 6 mg/kg [-0.143 (p<0.001)] and 10 mg/kg [-0.205 (p<0.001)] dose arms compared to placebo at 26 weeks. Amyloid plaque levels were reduced by -0.030 in the 1 mg/kg arm, which was not significant. At week 54, a statistically significant reduction of amyloid plaque was observed in the 3 mg/kg [-0.139 (p<0.001)] and 10 mg/kg [-0.266 (p<0.001)] dose arms. The reduction of amyloid plaque in the 1 mg/kg (-0.056) arm was not significant. The 6 mg/kg arm is ongoing and the week 54 data will become available at a later date.
Clinical Results: The effect of aducanumab on AD-related impairment was measured using the MMSE and Clinical Dementia Rating sum of boxes (CDR-SB). The MMSE is used to assess a patient’s cognitive status and the CDR-SB characterizes a patient’s cognitive and functional performance. On the MMSE, patients in the placebo group worsened by an average of 3.14 at one year, whereas the decline was 2.21 in the 1 mg/kg arm, 0.75 in the 3 mg/kg arm and 0.58 in the 10 mg/kg arm. Relative to placebo, the 3 mg/kg and 10 mg/kg doses demonstrated a statistically significant slowing of cognitive decline on the MMSE, both with p-values <0.05. On the CDR-SB, patients in the placebo group worsened by an average of 2.04 at one year. In comparison, the worsening was 1.70 in the 1 mg/kg arm, 1.33 in the 3 mg/kg arm and 0.59 in the 10 mg/kg arm. Relative to placebo, the 10 mg/kg showed a statistically significant slowing of clinical decline on the CDR-SB with p-value <0.05.
Safety Results: Based on the sponsor, Aducanumab demonstrated an acceptable safety and tolerability profile in this analysis. The most frequently reported treatment-related serious adverse event (SAE) and adverse event (AE) was ARIA (amyloid-related imaging abnormalities). Based on MRI scans, the incidence of ARIA-E (edema) was dose- and apolipoprotein E4-(ApoE4) status-dependent. In general, the onset of ARIA-E was observed early in the course of treatment and was asymptomatic or with mild, transient symptoms. The majority of patients with ARIA-E continued treatment and did so at a lower dose. In ApoE4 carriers, the incidence of ARIA-E was 5% in the 1 mg/kg and 3 mg/kg arms, 43% in the 6 mg/kg arm and 55% in the 10 mg/kg arm. In ApoE4 non-carriers, the incidence of ARIA-E was 9%, 11% and 17% in the 3 mg/kg, 6 mg/kg and 10 mg/kg aducanumab arms, respectively; no cases were reported in the 1 mg/kg arm. In ApoE4 carriers, the incidence of patients who developed ARIA-E and discontinued treatment was 5% in the 1 mg/kg arm, 10% in the 6 mg/kg arm, and 35% in the 10 mg/kg arm. There were no discontinuations in the 3 mg/kg arm. In ApoE4 non-carriers, the incidence of patients who developed ARIA-E and discontinued treatment was 11% in the 6 mg/kg arm and 8% in the 10 mg/kg arm. There were no discontinuations in the 1 mg/kg and 3 mg/kg arms. Headache occurred in 22% of patients receiving aducanumab compared to 5% in the placebo groups and appeared to be dose-dependent. Three deaths were reported in the time period of this analysis, two in the placebo group and one in the 10 mg/kg study arm; none were considered to be treatment related. Other AEs and SAEs were consistent with what is typically observed in the study population.
Association of Aspirin and NSAID Use with Risk of Colorectal Cancer According to Genetic Variants
As we wrote last week, the new pharmaceutical industry will focus on mechanisms of actions and potential therapies and old drugs may be part of the new therapies.
Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to be associated with lower risk of colorectal cancer. As a result, a study published in the Journal of the American Medical Association (2015;313:1133-1142) was performed to identify common genetic markers that may confer differential benefit from aspirin or NSAID chemoprevention. For the study, gene/environment interactions were tested between regular use of aspirin and/or NSAIDs and single-nucleotide polymorphisms (SNPs) in relation to risk of colorectal cancer.
The investigation was a case-control study using data from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia, and Germany, and included colorectal cancer cases (n=8634) and matched controls (n=8553) ascertained between 1976 and 2011. Participants were all of European descent. Data included Genome-wide SNP data and information on regular use of aspirin and/or NSAIDs and other risk factors.
Results showed that regular use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer (prevalence, 28% vs 38%; 6.2×10-28) compared with nonregular use. In the conventional logistic regression analysis, the SNP rs2965667 at chromosome 12p12.3 near the MGST1 gene showed a genome-wide significant interaction with aspirin and/or NSAID use (P = 4.6×10-9 for interaction). Aspirin and/or NSAID use was associated with a lower risk of colorectal cancer among individuals with rs2965667-TT genotype (prevalence, 28% vs 38%; OR, 0.66; P = 7.7×10-33) but with a higher risk among those with rare (4%) TA or AA genotypes (prevalence, 35% vs 29%; P = 0.002). In case-only interaction analysis, the SNP rs16973225 at chromosome 15q25.2 near the IL16 gene showed a genome-wide significant interaction with use of aspirin and/or NSAIDs (P = 8.2×10-9 for interaction). Regular use was associated with a lower risk of colorectal cancer among individuals with rs16973225-AA genotype (prevalence, 28% vs 38%; P = 1.9×10-30) but was not associated with risk of colorectal cancer among those with less common (9%) AC or CC genotypes (prevalence, 36% vs 39%; P = 0.76).
In this genome-wide investigation of gene/environment interactions, use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer, and this association differed according to genetic variation at 2 SNPs at chromosomes 12 and 15. Validation of these findings in additional populations may facilitate targeted colorectal cancer prevention strategies.
Genetically Engineered Arctic Apples and Innate Potatoes are Safe for Consumption
Foods derived from genetically engineered plants must meet the same legal standards, including safety standards, as foods derived from traditional plant breeding methods. To help developers of foods derived from genetically engineered plants comply with their obligations under the Federal Food, Drug, and Cosmetic Act and FDA regulations, the FDA encourages them to participate in a voluntary consultation process with the agency prior to commercial distribution.
The FDA has completed its evaluation for two varieties of apples genetically engineered by Okanagan Specialty Fruits, Inc., and for six varieties of potatoes genetically engineered by J. R. Simplot Company and concluded that these foods are as safe and nutritious as their conventional counterparts. Okanagan’s Granny Smith and Golden Delicious varieties of apples, known collectively by the trade name Arctic Apples, are genetically engineered to resist browning associated with cuts and bruises by reducing levels of enzymes that can cause browning. Simplot’s varieties of Ranger Russet, Russet Burbank and Atlantic potatoes are collectively known by the trade name Innate and are genetically engineered to reduce the formation of black spot bruises by lowering the levels of certain enzymes in the potatoes. In addition, they are engineered to produce less acrylamide by lowering the levels of an amino acid called asparagine and by lowering the levels of reducing-sugars. Acrylamide is a chemical that can form in some foods during high-temperature cooking, such as frying, and has been found to be carcinogenic in rodents.
As part of its consultation process, both Okanagan, of British Columbia, Canada, and Simplot, of Boise, Idaho, submitted to the FDA a summary of their safety and nutritional assessments. The consultation process includes a review of information provided by a company about the nature of the molecular changes and the nutritional composition of the food compared to traditionally bred varieties. At present, FDA has no additional food safety questions at this time concerning food from these plant varieties. It is a company’s continuing responsibility to ensure that food it markets is safe and otherwise in compliance with all applicable legal and regulatory requirements. In certain circumstances, characteristics of these varieties of apples and potatoes that differ from their conventional counterparts may require disclosure to the consumer. Both companies are encouraged to consult with the FDA about potential labeling requirements.
Blueberry Muffins and/or Pudding
These warm, just out of the oven blueberry muffins are easy to make, healthy and good with coffee ©Joyce Hays, Target Health Inc.
Blueberry puddings in various size individual dishes ©Joyce Hays, Target Health Inc.
The moist Blueberry Pudding went fast ©Joyce Hays, Target Health Inc.
You can add whipped cream or cool whip (or ice cream) to the warm pudding ©Joyce Hays, Target Health Inc.
2 cups almond flour
1.5 teaspoons baking powder
1/4 teaspoon baking soda
1/3 cup brown sugar (or Splenda)
1/2 cup Agave
1 stick butter
1/4 cup canola oil
1 teaspoon vanilla extract
1 cup almond milk
Zest of 2 lemons
6 ounces fresh blueberries, washed well
Garnishes optional: whipped cream, cool whip, vanilla ice cream (you decide)
1. Preheat oven to 300 degrees
2. In a small pan, melt the butter over a low flame, then remove and let cool. Add the canola oil to the melted butter and stir.
3. Dip a pastry brush into the butter/oil and lightly brush any baking dishes of muffin tins you’re using with the butter mixture. I used one muffin tin with six holes and 8 little individual ramekins. The ramekins are for pudding. If you want only muffins then use another muffin tin or 2 and forget about the ramekins.
4. Combine the first 4 dry ingredients together and set aside.
5. In a large mixing bowl beat the eggs, add the milk and beat. Gradually add the brown sugar (or brown Splenda) to the eggs and hand whisk (or use electric beaters). Next add the cooled down butter mixture. Then add the agave, vanilla, zest and beat or whisk.
6. Finally, add the blueberries. Fold them into the mixture; do not beat them.
7. Now fill up your muffin tin cups half full. Fill the ramekins half full and put them into the oven for 20 minutes.
8. Remove after 20 minutes and if serving the ramekins pudding serve right away with garnish (optional). For muffins: after you take them out of the oven, run a knife around the outside of each muffin, just to loosen them a bit. Set aside to cool, then dig in.
Whisk the wet ingredients together first. Notice the modern whisk from a dear friend. ©Joyce Hays, Target Health Inc.
Add the blueberries to the mixture, last ©Joyce Hays, Target Health Inc.
We still love that Sexy Beast cabernet from Australia by Two Hands Vineyards ©Joyce Hays, Target Health Inc.
Luckily, I made these delicious blueberry treats during the week, since by Friday afternoon, I was feeling, not so good; dunno what it was. Spring arrived this week and I had a slight fever. Would like to call it Spring fever, but nausea was also a part of it. No doubt a slight case of the flu which is going around here in the Big Apple. Our usual wonderful weekend was disrupted. We gave away our opera tickets to Manon at the MetOpera and stayed home eating light and playing Scrabble. (we each won a game). We’ll watch a movie tonight. C’est la vie.
Hope your weekend was better than ours. However, I must say, here, the company is always the best!
From Our Table to Yours!