Spring Grove Experiment

The Spring Grove Experiment is a series of lysergic acid diethylamide (LSD) studies performed from 1963 to 1976 on patients with psychotic illnesses at the Spring Grove Clinic in Catonsville, Maryland. These patients were sponsored by a federal agency called the National Institute of Mental Health to be part of the first study conducted on the effects of psychedelic drugs on schizophrenics. Then, the Spring Grove Experiments were adapted to study the effect of LSD and psychotherapy on patients including alcoholics, heroin addicts, neurotics, and terminally-ill cancer patients. The research done was largely conducted by the members of the Research Unit of Spring Grove State Hospital. Significant contributors to the experiments included Walter Pahnke, Albert Kurland, Sanford Unger, Richard Yensen, Stanislav Grof, William Richards, Francesco Di Leo and Oliver Lee McCabe. Later, Spring Grove was rebuilt into the Maryland Psychiatric Research Center, where studies continued to be performed for the advancement of psychiatric research. This study on LSD is the largest study on psychedelic drugs to date.
Historical context.
In 1943, Albert Hofmann discovered the hallucinogenic effects of LSD that led to an altered state of consciousness.
In 1947, Gion Condrau and Arthur Stoll observed that people diagnosed as “psychotics” had a stronger tolerance for LSD and that the effects of the drug were similar to the symptoms expressed by psychotics themselves.
In the late 1940s, English researcher Mayer-Gross found connections between schizophrenia and behaviors produced by LSD administration.
In 1950, AK Busch and WC Johnson determined LSD’s stimulative effects and first made the connection of LSD and its potential use in psychotherapy.
In 1951, De Giacomo confirmed that when schizophrenic subjects were given large dosages of LSD by mouth, they experienced a state of catatonia. He also stated that psychotic patients were more tolerant than healthy patients to LSD, and required higher dosages to produce responses.
In 1953, D.W. Liddell and H. Weil-Malherbe studied the effects of LSD on mental processes and adrenaline in the blood and began characterizing the behaviors resulting from LSD administration to patients. They found that “depressive patients,” experienced enhanced symptoms, becoming more depressed; while schizophrenic patients experienced catatonic, or altered, states. They also found that after administering LSD through the patients' veins, adrenaline levels would fluctuate by rising, dropping, and rising, while blood glucose remained unaffected by the drug. Their method of administering LSD through the veins of schizophrenic patients was adopted in later studies.
In 1953, Canadian researchers studied the use of LSD to treat alcoholism. It was found that those who treated their condition with LSD recovered more quickly than those who used a conventional treatment.
In the early 1960s in Psychedelic Research Institute in Prague, Czechoslovakia, Stanislav Grof tested the value of LSD in treatment of psychologically ill patients. His goal was to observe the effect of psychedelics on the psychology of terminally-ill cancer patients. Grof would later be involved in research at the Spring Grove Clinic.
Psychedelic research at Spring Grove.
Experiments at Spring Grove Clinic began in the 1950s at the Spring Grove State Hospital, however the first official Spring Grove Experiment began in 1963. Many of the patients who took part in these experiments federally funded by the National Institute of Mental Health (NIMH) were admitted against their own wishes. Over the course of the experiments, over 700 people were treated with LSD; however, no more than six to eight patients were treated at a time.
Preliminary experiments.
The first psychedelic experiment at the Spring Grove clinic took place in 1955. A small team of researchers including
Albert Kurland, Louis S. Cholden, and Charles Savage set out to analyze the reaction resulting from the administration of LSD to chronic schizophrenic patients. In an attempt to conduct this study with scientific proof, the researchers administered LSD using a double blind procedure. By the end of the first study, the researchers determined that it was not possible to administer LSD using a double blind, because it was obvious to the researchers who had been given LSD. It was, however, found that LSD was unique in its effects on consciousness and unlike other drugs, resulted in rapid tolerance in patients. They determined the effects of LSD to include intense hallucinations and illusions. This work established the foundation for future experiments.
The Spring Grove Experiment: alcoholism and LSD.
In 1963, after observing the initial effects of LSD, the first official experiment included in the “Spring Grove Experiment” series began. This experiment was performed on 69 alcoholic patients. Enthusiastic and hopeful about the possible results of LSD treatment, a team of researchers under Dr. Albert Kurland, Director of Research at State of Maryland Department of Mental Hygiene at the time, Dr. Charles Savage, Director of Research at Spring Grove Hospital, Dr. Shaffer, and Dr. Sanford Unger performed experiments to test LSD with psychotherapy as treatment for alcoholic patients. This work was backed by the State Hospital Alcoholic Rehabilitation Unit. The findings of this experiment were published four years later in 1967.
According to the experimenters themselves, the rationale for using psychedelics to treat alcoholic patients is in the “clinical picture” presented in the features of alcoholic patients. Various personality types such as “neurotic, psychopathic, and schizoid” were thought to have a vulnerability that led to their addiction to alcohol. These individuals were perceived as having a weakened ability to “handle psychological stress, tensions, and frustrations.” They also believed that LSD would allow psychiatrists to open memories and emotions to restore and alter the brain and mind, but only under certain conditions.
The Spring Grove experiment was conducted in Cottage 13, a building on the Spring Grove State Hospital grounds. The environment in Cottage 13 was constructed so that it emitted a positive and optimistic atmosphere to ensure that the patients did not have a negative experience while taking the LSD treatment. Even the sounds, smells, and objects in Cottage 13 were carefully conditioned. Before treatment, the patients were screened after mental breakdowns to determine if they were eligible for LSD treatment. Then they were given a microscopic dose of LSD in Cottage 13. During the 14-hour treatment, the patients underwent psychotherapy so that psychiatrists could attempt to identify underlying conflicts. In addition to the psychotherapy, patients also underwent psychiatric tests so that researchers could determine other effects of LSD, such as changes in IQ scores.
Those who observed the experiments in Cottage 13 encouraged the continuation of it. One such individual was Dr. John Buckman, who claimed that "the treatment procedure seemed to be returning the patients to the human race."
The results show that no patients were harmed. After six months, 33% of patients remained abstinent after LSD treatment, as opposed to the previous statistic of 12% under conventional therapy.
In 1965, the Columbia Broadcasting System (CBS) television network produced a documentary called “LSD: The Spring Grove Experiment.” LSD experimentation on the patients of Spring Grove became a part of the growing conversation on drugs. The success of this documentary led to an insurgence of federal funding that would go into building a new research center in 1969, called the Maryland Psychiatric Research Center.
Expansion.
The success of the trials resulted in an expansion of the treatment to other neurological diseases. The studies expanded to include neurotics and heroin addicts.
In 1966, experiments expanded to treat those suffering from terminal cancers. This type of experimentation arose at the Spring Grove clinic after one of the researchers became a human subject in the same clinic where she worked. Gloria underwent the radical mastectomy procedure to treat her breast cancer, and was subsequently diagnosed with liver cancer. Her resulting depression and anxiety were analogous to psychiatric symptoms, similar to those expressed by patients in the Spring Grove Clinic. After noticing the apparent effectiveness of LSD therapy on alcoholics, Gloria requested that an LSD treatment session be administered on herself. There had been existing studies on the chemotherapeutic analgesic effects of LSD, and the potential of LSD in alleviating the anguish of the dying. These most likely contributed to the permission Gloria received which allowed for the procedure. After consent was acquired, Gloria underwent psychedelic LSD therapy. She was administered a 200 microgram LSD session, and experienced successful results. She stated, “I am still me, but more at peace. My family senses this and we are closer. All who know me well say that this has been a good experience.” Gloria died five weeks later.
The staff at Spring Grove noticed the potential of LSD in treatment and began treating terminally-ill cancer patients to relieve suffering in the time leading up to death. A research study was developed under Dr. Walter N Pahnke, a graduate from Harvard Medicine with a degree in religion and divinity, and Dr. Eric Kast. The thought was that LSD could serve as a narcotic and relieve the pain and suffering caused by cancer. In 1972, the study published a paper concluding that LSD had relieved pain in the terminally ill patients. Thirty one terminally ill patients were treated and statistical results showed that patients received considerable relief from pain. However, flaws in the study invalidated the results including the different psychedelics used an unsystematic study design.
From 1969 to 1972, a variety of experiments were conducted as LSD’s effects on mental health, and heroin addiction were examined. By 1976 the research at Spring Grove, which at that time had been rebuilt and renamed the Maryland Psychiatric Research Psychedelic Clinic, had come to an end.
Psychedelic psychotherapy.
LSD was intravenously injected into patients, and at times was delivered through the form of a pill. In the early experiments, LSD was administered in a single large dose along with a specialized environment, eyeshades, headphones, and selected music. A preparatory period allowed a trained therapist to deeply explore the background of the patient. Doses ranged from 250–800 micrograms sessions, which would last from 8–12 hours. This method was called the “mind-manifesting approach.” By the late 1970s, a more extensive method was developed, called “the extended paradigm,” as named by Stanislav Grof. This involved the administration of several high doses, an increased number of therapeutic sessions, and a greater emphasis on personal dynamics between therapist and patient.
It was not expected that positive results would occur with pure drug administration. Psychedelic therapy involves the use of a hallucinogenic, perception-altering drugs coupled with psychotherapy to treat patients psychologically. The goal of the procedure was to unearth internal conflicts by administering LSD and then use therapy to resolve and work through these emerging latent conflicts. “Mystical peaks” experienced by LSD-treated patients would often give the patient insights and new outlooks on life. Therapy would be used to apply these insights to the individual’s personal life. Musical therapists eventually joined staffing. The main objective of therapy was to provide support and companionship to the patient.
Patients' experiences.
In the original 1955 experiment conducted on schizophrenic patients, there were 20 subjects that received LSD. The experiences and reactions of these subjects were categorized under 3 characteristics covert, which signified a subtle or delayed response; intensification, which pushed the patient’s existing symptoms to extremes; and reversal, which occurred when patients assumed a state opposite to his or her original symptoms.
The following are accounts of patient responses during several experiments conducted at Spring Grove:
In the 1955 trials on chronic Schizophrenics:“This patient seemed most distressed and shaken. Intermittently she would open her mouth as if she were trying desperately to talk or at least to exercise the muscles of her mouth. She also expressed a state of acute anguish with her body movements...A half hour after the crying started, the wails seemed to end in a giggle. Soon the tears diminished, and she had almost continuous waves of laughing for another hour or so. The patient then began to walk about the ward studying the walls and windows as though she were seeing them for the first time. She seemed to respond to hallucinations, for she began to talk to non-present individuals.” A second patient in the 1955 study who was normally aloof, laughing, and idle became uncharacteristically serious 30 minutes after drug administration. She called the doctor by his correct name for the first time, saying:“Dr. X, this is serious business—we are pathetic people—don’t play with us.”In the 1965 CBS documentary, the story of Arthur King, a man experiencing alcoholism and being treated with LSD and psychotherapy, was highlighted. Some of the alcoholic patients who underwent LSD and psychotherapy treatment at Spring Grove felt happier after the treatment and had no more desire to drink. One patient, Arthur King, was admitted into Spring Grove State Hospital as an alcoholic. He underwent the treatment. Afterwards, he reported that he had no more desire to drink—he went back to school and later became an accountant. Years later when he was interviewed, he said that the LSD treatment turned his life around.
In an interview conducted by Richard Yensen, Arthur King stated the following concerning treatment: “There were times when you were very emotional. Yes. That was connected with what was...very unhappy…very! …Thinking about things in the past and very unhappy. Very, very miserable! But then I came to that point everything cleared up... it was like a peace. It was so strange.”The peak experience was defined by the following guidelines1) Unity-the sense that "all is one."2) Transcendence of the time-space boundaries associated with ordinary reality.3) Deeply felt positive mood.4) The sense that this experience is ultimately true or more real than real.5) An experience that the opposites of daily life, rather than conflictual, become instead complementary, two sides of the same coin.6) A sense or feeling of sacredness or of the preciousness of a feeling that the experience is beyond words.7) The experience is transitory.8) Though transitory the experience has profound positive effects in the life of the person having it and is unforgettable
Shortcomings.
The first shortcoming determined early on in experimentation was that no adequate control group could be defined. This occludes the value of the results, and makes it difficult to deduce whether findings in the experiment were due LSD administration or simply just results of intense therapy following the drug administration. Another issue was the inability to conduct the experiment utilizing the blind double-blind procedure. An additional strong criticism of the experiments was that non-drug effects on the subjects were largely underestimated, and the effects of the LSD were possibly overestimated.
Although the overall outcome of the treatment in the Spring Grove Experiments was generally positive, there were also negative effects of LSD treatment in the patient including intense fear, uncontrollable breakdowns, and emotional stress during treatment. LSD was also known to produce feelings of depression, headache, and depersonalization in some cases. In addition, since subjects received LSD treatment and psychotherapy treatment, it is unclear whether the LSD caused the positive outcomes, the psychotherapy, or the carefully prepared combination of LSD and psychotherapy treatment.
These shortcomings demonstrate the possibility that beneficial results in the experiments may not be attributed solely to LSD treatment. Rather, it may be more likely that results occurred out of combination of the effects of social setting, therapy, and drug administration.
Controversy and resistance.
Resistance from the scientific community to psychedelic therapy is thought to have resulted from certain restrictive paradigms about how studies in psychiatry and psychology should be carried out, and which ones are valid. The existing concept supported single solutions to mental health issues, and prescribing pharmaceutical drugs to biologically suppress symptoms of diseases rather than root causes. This focus on pharmaceuticals existed partially because the large amounts of government funding given to pharmaceutical companies.
Controversy on the use of psychedelics as medical treatment was particularly significant considering this time period (1970) constituted the early stages of the declared “war on drugs.” This, along with sensationalized negative LSD cases disseminated by the media, led to a declined attitude toward the usage of LSD as treatment. Other factors such as the accusation that scientists were mismanaging money, and the concern of LSD causing chromosome damage in 1969 led to further negative attitudes toward the study.
Termination.
The studies at Spring Grove State Hospital ended in 1976. Several factors led to the termination of the Spring Grove Experiment.
In 1971 Walter Pahnke, the director of clinical science and leader of the Spring Grove research team at the time, died. His successor had no background in psychedelic research and therefore did not have the experience or drive to continue the experimentation being led by Pahnke before he died. The Maryland Psychiatric Research Center was accused of improper use of public money and not engaging in real treatment that would be beneficial to the public.
When legislation was passed resulting in the detraction of funding from state hospitals, animosity grew between the more privileged researchers and the hospital employees. This discouraged workers from getting involved in experiments, adding to the growing negative atmosphere around LSD research. In addition, controversy surrounding the use of LSD in experiments surfaced. Among these controversies include reports of a suicide in Project MKUltra and treatment with LSD without informed consent at Edgewood Arsenal in the late 1970s. Because the arsenal had ties to the University of Maryland, there was dramatic pressure to discontinue all research involving psychedelics as treatment. The accumulation of these reports, along with general reservations about medicalizing what the media portrayed as strictly deleterious, led to the termination of the psychedelic experiments on human subjects at Spring Grove.
Legacy.
By 1976, more than 700 patients were treated with psychedelic drugs. This produced positive yet equivocal results. Most benefitted, and a minority did not display any response, however, there is no awareness of long-term complications.
By the 1970s, LSD was no longer recognized as having a medical use. It was instead seen as having a great potential for abuse and addiction. In the 1990s, even when Dr. Yensen and Dr. Kurland received FDA approval to continue LSD research, they were unable to acquire the LSD for clinical study in the United States.
Today, LSD research is gradually re-emerging as a focus for clinical researchers. In 2014, there was a study on the effects of LSD and psychotherapy on patients experiencing anxiety. In 2013, studies were being done on patients experiencing Post Traumatic Stress Disorder combining MDMA and psychotherapy; and in 2016, an article was released announcing the FDA’s approval of clinical studies supporting further experiments to devise a drug for treatment of PTSD.
Dr. Kurland's initial hopes to produce "effective therapies that will heal – more quickly and comfortably – the psychic wounds that leave so many people handicapped and alienated" remain.


Michael Joyner

Michael Joseph Joyner is an American anesthesiologist and physiologist who researches exercise physiology. He is the Frank R. and Shari Caywood Professor of Anesthesiology at the Mayo Clinic, where his laboratory has been funded continuously by the National Institutes of Health since 1993. He was Deputy Director and Associate Dean for Research at the Mayo Clinic from 2005 to 2010. He was named a Distinguished Investigator by his colleagues at the Mayo Clinic in 2010, and he received the American Physiological Society’s Walter B. Cannon Award in 2013. A fellow of the American College of Sports Medicine (ACSM), he delivered the Joseph B. Wolffe Memorial Lecture at the ACSM's 2004 annual meeting, received the ACSM Citation Award in 2009, and delivered the opening keynote at their 2018 Conference on Integrative Physiology of Exercise. An outspoken critic of reductionism in science and medicine, he has been called "one of the world's most widely cited experts on the limits of human performance."


Malcolm Jones III

Malcolm Jones III (1959–1996) was an American comic book artist best known as an inker on "The Sandman", where he added his illustrative line and textures to the work of pencillers such as Mike Dringenberg, Kelley Jones, and Colleen Doran. He was also known for inking Denys Cowan's pencils on "The Question".
Early life.
Jones attended the High School of Art and Design with future Milestone Media co-founder Michael Davis. Later, he graduated from Pratt Institute.
Career.
Jones made his professional comics debut inking Dennis Yee's pencils on "Cheap Labor", one of four stories in the DC Comics anthology comic book "New Talent Showcase" #15 (March 1985). His first regular job was as the inker on DC's "Young All-Stars" #1-20, in addition to "Young All-Stars Annual" #1 (1988) (though he did not ink issue #17).
He also pencilled his own work, including a Spider-Man story for "Marvel Comics Presents", and the unpublished "Coldblood" mini-series for Marvel Comics.
Death.
Jones killed himself in 1996.


Janet C. Anderson Gender Resource Center

The Janet C. Anderson Gender Resource Center is located on the Idaho State University campus. The Center addresses topics that deal with equality issues that have an effect on the community regardless of sexual dimorphism, gender, or sexual orientation.
Mission statement.
The mission statement for the Janet C. Anderson Gender Resource Center is:
The Janet C. Anderson Gender Resource Center at Idaho State University serves as the focal point on campus for the consideration of gender issues. The mission of the Center is to increase awareness and promote open dialogue about gender through its resources and services, educational programming and support of gender-related research. In our efforts, we are especially guided by the ideal of diversity, which allows us to envision a future free of the limitations imposed by our culture's standard definitions of gender. Funded through mandatory student fees, the Center’s primary target audience is that of ISU students; the Center also welcomes the interest and participation of prospective students, ISU faculty and staff, and members of the Eastern Idaho community.
History.
The founding of the Janet C. Anderson Gender Resource Center originated in 1996 when members of Idaho State University Professional Women asked President Richard Bowen about establishing a women's center. As a result, Bowen appointed Dr. Janet Anderson, Dean of Student Affairs, to head a committee that would determine if a women's center was a feasible idea for Idaho State University. It was decided that a gender center was an ideal venue for Idaho State University to address women's issues on campus, however the Center was not funded at that time.
In 1998, when Anderson was preparing for her retirement, the Associated Students of ISU (ASISU) was searching for a plan to honor Anderson's service towards the university. As a result, ASISU decided that a center funded through student fees would be an ideal solution to honor Anderson. In October 1998, the Janet C. Anderson Resource Center opened in its permanent space in Gravely Hall.
In December 1999, the Center established the Project Hope Advocacy Program through a grant from the Department of Justice's Office on Violence Against Women. Following a grant renewal, the State Board of Education approved funding for a permanent, full-time advocacy position in 2004. In the spring of 2003, the Idaho Department of Health and Welfare provided a grant to establish the W.I.S.E. Project, an HIV prevention program for women. Also in the spring of 2003, the Center received funding from the Idaho Department of health and Welfare's Rape Prevention and Education Fund, which supports the Center's Project Hope graduate assistant planning programming specifically for men.
The Janet C. Anderson Gender Resource Center has undergone many changes since its founding. On December 9, 2002, President Bowen accepted a proposal by Rebecca Morrow, to amend the Center's official name to the Janet C. Anderson Gender Resource Center. The word "gender" was included to more accurately describe the mission of the Center. The Center believes there should be an open and fair dialogue between both males and females to construct gender. At the Center, hard work has been implemented to make it known as a place that is open to anyone who shares in the curiosity about women's and men's lives in our society.
Services.
The Janet C. Anderson Gender Resource Center provides a number of services that are all geared towards constructing a better understanding of "gender" and how both men and women can affect the word "gender". The Center provides educational programming, the support of gender-related research, and resources that help individuals make important life decisions.
Educational programming.
Each year, the Center takes part in commemorating and celebrating nationally designated months and participates in events designed to draw attention to particular gender-related issues, including:
The Center also hosts discussion groups and sponsors entertainment-oriented events. The Center attempts to maintain a healthy relationship with faculty and staff by giving them the opportunity to host presentations and group discussions surrounding topics such as domestic violence, sexual assault, stalking, healthy relationships, and HIV/AIDS including prevention and cultural diversity.
Support of gender-related research.
The Janet C. Anderson Gender Resource Center sponsors lectures by nationally known figures on an irregular basis.
Resources.
The Janet C. Anderson Gender Resource Center's library holds books, magazines, and pamphlets on a variety of gender-related topics. The library holds material that focuses on everyone no matter what their sex, sexual orientation, ethnic or cultural background, religion, abilities or age are. Materials from the library can be borrowed for a period up to a month.


Martin Halliday

Anthony Martin Halliday (19 August 1926 – 18 March 2008) was a British physician and consultant in clinical neurophysiology. He worked most of his career at the National Hospital for Neurology and Neurosurgery in London.
Career.
Halliday was born on 19 August 1926 in Liverpool to William Reginald Halliday and Edith Hilda (née Macneile Dixon). His family history included numerous ancestors working in the field of medicine. Halliday was schooled at Dauntsey's School, he studied medicine at the University of Glasgow where he graduated in 1949. In 1950 he did his national service where he worked for the British Army physiological section. Halliday worked on finger tremor physiology, which seemed to be linked to sleepiness. His research was valuable as British pilots at times fell asleep while flying round the clock for the Berlin airlift. As such, it was noticed by Arnold Carmichael, the director of the neurophysiology unit of the National Hospital. Carmichael persuaded Halliday to come work at the National when he finished his national service in 1953. At first Halliday joined a research team, in 1961 he became a consultant in clinical neurophysiology and became the head of his own Medical Research Council.
Halliday became interested in changes in brainwave patterns, caused by stimulation of the senses. He became best known for his work on pattern-reversal visual evoked potential. With Ian McDonald he developed a technique which led to laboratory tests for the diagnosis of multiple sclerosis.
In 1989 he became a Fellow of the Royal College of Physicians. He became a foreign member of the Royal Netherlands Academy of Arts and Sciences in 1991.
Halliday died on 28 March 2008, aged 81, after having suffered from pulmonary fibrosis for a long time.


Caroline Latimer

Caroline Wormeley Latimer (March 28, 1860 – 1933) was an American physiologist known for her studies of rigor mortis and the salivary glands, and her popular science writing, which was widely read by women and girls.
Early life.
Latimer was born on March 28, 1860 in Baltimore, Maryland. She was the daughter of English-American author Elizabeth Wormeley Latimer and Randolph Brandt Latimer. Her siblings included Ralph Randolph Latimer and James Brandt Latimer, who worked for the Baltimore and Ohio Railroad and the Chicago, Burlington and Quincy Railroad.
Her paternal grandparents were Caroline (née Preble) Wormeley and Admiral Ralph Randolph Wormeley, a native of Virginia who was an Admiral of the British navy. Her maternal aunts included nurse and author Katherine Prescott Wormeley and Ariana Randolph Wormeley, was married to the American lawyer and banker Daniel Sargent Curtis.
Career.
Unusually, she attended medical school at the Woman's Medical College of Baltimore before she attended an undergraduate institution, and received her M.D. in 1890. She then studied for a bachelor's degree and master's degree in biology at Bryn Mawr College, where she graduated in 1896.
Following her graduation from Bryn Mawr, she became an instructor of biology at Goucher College until 1898, and a physician in Maryland until 1906. She was the associate editor of Appleton's Medical Dictionary beginning in 1915.
Latimer was the author of "Girl and Woman. A Book for Mothers and Daughters", published by D. Appleton & Co. in New York in 1910.


Tetanic stimulation

In neurobiology, a tetanic stimulation consists of a high-frequency sequence of individual stimulations of a neuron. It is associated with potentiation.
High-frequency stimulation causes an increase in release called post-tetanic potentiation (Kandel 2003). This presynaptic event is caused by calcium influx. Calcium-protein interactions then produce a change in vesicle exocytosis. The result of these changes is to make the postsynaptic cell more likely to fire an action potential.
Tetanic stimulation is used in medicine to detect a non-depolarizing block or a depolarizing block on the neuromuscular junction. Lower elicitations of tetanic stimulation in aged muscles were shown to be caused by lower levels of anaerobic energy provision in skeletal muscles.


Man in Tree

Man in Tree refers to a widely viewed standoff between Cody Lee Miller and police on March 22–23, 2016, in Seattle, Washington. Miller scaled a large sequoia tree near a major downtown intersection and remained there for over 24 hours, rebuffing rescue and negotiation attempts and tossing debris at onlookers. The situation disrupted Seattle traffic patterns, became a trending topic across social media, and attracted national attention from news outlets. Miller's treatment by law enforcement and coverage by the media has spurred further debate on the adequacy of mental health care in the USA.
Details.
Miller climbed an sequoia in a Stewart Street traffic island outside the historic former Bon Marché flagship store in downtown Seattle, early on March 22, 2016. He remained there for nearly 25 hours while police forces attempted to coax him down. Miller responded to dialog attempts by throwing sequoia cones, branches he had torn from the crown, and fruit remains, some of which hit passersby. The falling debris and the intervention efforts gridlocked roadways in downtown Seattle’s center, forcing multiple buses to find alternate routes. The event garnered significant media attention, prompting viral Twitter parodies, live streams of negotiation efforts, and national news coverage. After over 24 hours, Miller descended the tree of his own accord at around 11:45 AM on March 23, where he was given food and taken into an ambulance. Miller was subsequently charged with third-degree assault and first-degree malicious mischief but was found incompetent to stand trial after a psychiatric competency evaluation.
Impact.
Man in Tree generated nationwide interest, with news stations feeding live streams of the event and Twitter users elevating the hashtag "#ManInTree" to trending status.
The event also rekindled discussion of the country’s mental health system. After the incident, Miller’s mother said that he was "obviously sick" and that psychiatric care would be more appropriate than jail time. Online periodicals helped spread this perspective in hopes of reorienting the conversation around systemic reform. Miller himself denounced Seattle law enforcement for his alleged mistreatment in the aftermath. Additionally, Congressman Tim Murphy (R, PA) cited Man in Tree when calling for Congressional action on his proposed Helping Families in Mental Health Crisis Act (H.R. 2646).
Tree experts evaluated the sequoia afterward and found that the ordeal inflicted roughly $7,800 worth of damage to the tree.


Lollipop (Lil Wayne song)

"Lollipop" is the first single from rapper Lil Wayne's sixth studio album, "Tha Carter III". The track posthumously features American singer Static Major and is produced by Deezle and Jim Jonsin. It heavily utilizes the Auto-Tune vocal effect. The song was released digitally on March 13, 2008.
"Lollipop" is Lil Wayne's and Static Major's most successful single to date, spending five non-consecutive weeks atop the "Billboard" Hot 100 chart. Static Major died just over two weeks before the release of the song, making the song the eighth to hit number one after the death of a credited artist. There are various versions of the song. The single was certified 5x Platinum by the RIAA for selling five million units in the United States and was ranked the number one hip hop song of 2008 by MTV. The song reached number one on the 2008 issue of "Notarized" by BET. The song was ranked at number five on "Rolling Stone"s list of the 100 Best Songs of 2008. With 9.1 million copies sold as of January 2009, "Lollipop" was named 2008's best-selling digital single worldwide by IFPI.
Music video.
The music video was directed by Gil Green and filmed in Las Vegas at Gavin Maloof's residence on December 31, 2007. The video premiered via BET's "Access Granted" on March 12, 2008. It also reached number one on "TRL" in April on MTV.
The limousine that Wayne and Static get into at the start of the video is based on an International XT pickup truck.
The video is the most-viewed video on Music Choice's video on demand service.
Jim Jonsin, Tyga, Birdman and Mack 10 make cameos in the video.
The final frame of the video is a picture of Static praying with the words "In memory of Stephen "Static Major" Garrett".
Chart performance.
The song won a Grammy Award in February 2009 for Best Rap Song.
Static Major died unexpectedly during a medical procedure on February 25, 2008, sixteen days before the song was released. "Lollipop" jumped 76 spots from number 85 to number 9 on the March 28, 2008 issue of the "Billboard" Hot 100, becoming Lil' Wayne's highest-charting single as a lead artist, along with being his first top ten hit on the chart as a lead artist. His previous highest-charting position as a lead artist was with "Go D.J.", which peaked at number 14 in 2004. The following week, it reached a new peak of number 7 on the Hot 100. The single reached a new peak of number 2 on the "Billboard" Hot 100 on April 17, 2008, making it his highest-charting single as both a lead artist or as a featured performer. (Lil Wayne was a featured artist for Destiny's Child's number 3 (Hot 100) hit, "Soldier".) For the week of May 3, 2008, "Lollipop" reached the number-one spot on the Hot 100, his first number one on the chart. It is also Wayne's first number one on the Hot R&B/Hip-Hop Songs chart and the Hot Rap Tracks chart. On the Hot R&B/Hip-Hop Songs chart, it is the first rap song to reach number one since Ludacris' "Money Maker" in 2006. After one week, it slipped away from top spot, but returned three weeks later, making it the song with the longest break in between peaks in the Hot 100 since Usher's "U Got It Bad."
The week after the release, Wayne and Mariah Carey became the number one most added and greatest gainer at both radio formats with a total of 138 adds. "Lollipop" has become a crossover hit on mainstream radio, as it became his first top 40 hit as a lead artist, entering at number 36, and has so far peaked at number 5. It is his first top ten on the Pop 100, where it has reached number two. It returned to number one on the "Billboard" Hot 100 for the second time on May 22, 2008.
The song has become a top ten success in Canada, peaking at number 10 as of May 29, 2008, and his most successful song in the UK, where it reached number 26 on downloads alone. It reached number 3 on the New Zealand charts and was certified Platinum by the Recording Industry Association of New Zealand.
In 2008, "Lollipop" was the best-selling ringtone in the United States with over 2.3 million copies sold and the second best-selling digital song with over 3.1 million copies.
To date, "Lollipop" sold 4,176,000 digital copies in the United States.
Remixes and covers.
The official remix features Static Major and Kanye West. There is an extended version of the remix that has Wayne talking over the original bridge and singing an altered hook, with Kanye singing adlibs, along with a guitar riff near the end. Other remixes feature Young Jeezy, Gorilla Zoe, Ace Hood, Kurupt, V.I.C., Nicki Minaj, Wiz Khalifa, Tekitek, Rasheeda and Khia, who made a popular female version of the song. Another remix was made commemorating the 2008 NBA champion Boston Celtics. It features the instrumental used in the main song.
David Banner's song "Shawty Say" samples the opening part of the Lil Wayne's second verse for its chorus. JJ uses elements of "Lollipop" in their song "Ecstasy". Drake samples this song on his song "In My Feelings" from his fifth studio album, "Scorpion".
Framing Hanley cover.
The post-hardcore band Framing Hanley covered the song as a bonus track on their album "The Moment". It uses a slight bit of talkbox, but replaces almost all the other sound with electric guitar, and features a hard rock version of the lyrics sung by the band. It was certified Gold by the Recording Industry Association of America for shipping 500,000 units in the United States.


Stephenson Disaster Management Institute

The Stephenson Disaster Management Institute at Louisiana State University is located in the Stephenson National Center for Security Research and Training at LSU.
In February 2007, as a direct result of Hurricane Katrina, LSU alumni Emmet and Toni Stephenson donated $25 million to LSU. Approximately $11 million was allocated to create the Stephenson Disaster Management Institute, as a result of LSU's unique experience and outstanding performance during hurricane relief efforts. The institute enhances LSU’s ability to focus its existing programs and research capacity on the particular problems of disasters, while adding additional capacity with respect to strategic management and decision making. The institute works with its LSU research affiliates to collaborate on projects and research proposals that will improve disaster preparedness and response. Research disciplines span across multiple departments, including engineering, psychology, sociology, information systems & decision sciences, veterinary medicine, economics, and computer science. Serving as the interface between researchers and practitioners, the Stephenson Disaster Management Institute supports projects that encourage partnerships between these communities that inform and improve the quality of research and assure that academic findings are translated into solutions business and emergency managers can use in the field.
SDMI Projects.
Hazard Mitigation Geospatial Updates.
Over the last two years, SDMI has been working aggressively to complete a project that was awarded to SDMI by the Governor's Office of Homeland Security and Emergency Preparedness to collect spatially-correct data for the State's entire inventory of critical infrastructure. The overall goal of this project is to provide data that will assist the State's Hazard Mitigation section and planners at the state and local levels in refining and enhancing their hazard mitigation and emergency operations plans based on accurate geospatial data as well as enhance situational awareness during real-time emergencies. This project has proven to be very important for the planning efforts in updating the State's local hazard mitigation plans. Information collected from this project is being utilized to vastly improve the data, to develop potential damage assessments for specific hazards, and to identify vulnerable infrastructure throughout the parishes. As part of this contract, SDMI has completed projects related to critical infrastructure, high resolution flight imagery, and school safety programs.
Hazard Mitigation Local Plan Updates.
Local governments are required by law under the Disaster Mitigation Act of 2000 and 44 CFR § 201.6 to maintain a hazard mitigation plan and to update it every five years. Louisiana encourages the development of multi-jurisdictional plans, which encompass parish and municipal governments. Between 2015 and 2017 the majority of Louisiana's 64 parishes are due to update their HMPs. To improve the usability of local HMPs and to enhance the data used for the State's Hazard Mitigation Plan (SHMP), SDMI has been chose to assist the local jurisdictions in the update process. Based on the 2014 SHMP template, SDMI will standardize the local HMP layout and utilize its GIS expertise to gather the most recent data for the parish-level hazard analyses and risk assessments.
Division of Administration 9-1-1 Mapping and GIS Portal Project.
SDMI is currently in the final year of a 27-month agreement with the Louisiana Division of Administration's Office of Information Technology to serve as the principal investigator to develop geospatial point data for addresses in rural Louisiana parishes.
The Department of Homeland Security Center for Excellence for Maritime Security.
SDMI was invited by the University of Alaska at Anchorage to participate in an application for an existing DHS Center of Excellence on Maritime Security that was being re-competed following its initial five year award. In an unusual move, DHS decided to issue two awards for this Center, with the incumbent, The Stevens Institute of Technology, being retained and a second Center being awarded to the University of Alaska to focus exclusively on maritime issues in the Arctic environment. DHS was significantly impressed with SDMI's application and determined that SDMI would be joined as a new member of the center. However, instead of partnering with the University of Alaska, SDMI was paired with the Stevens Institute of Technology. SDMI's knowledge and ability to work with inland ports complements the Stevens Institute of Technology on coastal ports. The Center is funded for five years and represents a tremendous growing opportunity for SDMI.
SDMI Initiatives.
The Transformational Technology & Cyber Research Center.
SDMI leadership levied a number of independent circumstances and conditions that presented concurrently to wager the creation of the new Transformational Technology & Cyber Research Center (TTCRC). SDMI saw these conditions as an opportunity toward accomplishing its primary objectives and moved to assemble a joint team to create the TTCRC. Specifically, SDMI has opined for more than a year that cyber and other evolving threats present potential for disasters and represent a blurring of effect in that civilian, military, and government targets are more equally threatened by both natural and man-made disaster. SDMI has also long been advocating for LSU to focus more research through an applied research institute such as SDMI as funders are more often demanding a new capability or decision support function they did not have before.
Louisiana National Guard/SDMI Cyber Lab.
In order to enhance security of cyber networks and minimize the risks of Critical Infrastructure/Key Resources (CIKR) Industrial Control Systems (ICS) and private sector networks, SDMI, in partnership with the Louisiana National Guard, is in the process of building a Cyber Lab that will incorporate the Federal cyber framework and programs with local CIKR industry and private sector training. SDMI is creating this virtual lab for CIKR industry and private sector representatives to use as a test and evaluation center for their ICS and internal networks. The goal of this lab is to replicate industry specific and private sector topology and configurations so that they will be able to conduct tests and Incident Response (IR) procedures in a closed environment without affecting and real-world production. These tests and IR procedures will be evaluated against the Federal frameworks and standards to identify gaps and areas for improvement. SDMI will then develop industry tailored training for that organization's cyber response personnel wherein personnel will be able to attend training and earn certifications for compliance with Federal standards of CIKR Cybersecurity.
SDMI Enhanced School Safety Program.
Recognizing the important role that situational awareness and pre-planning has in responding to School Safety, at the request of the Jefferson Parish School Board, SDMI has developed an enhanced school safety-planning program. As part of an existing contract with GOHSEP, SDMI has been collecting and publishing school floor plans in a secure web based program. The digital floor plans allow first responders to access the schools plans in the event that they are needed to help respond to an active shooter or other emergency that a school may experience. While recognizing the advantage of such a program, Jefferson Parish sought to develop a process in which more information than just floor plans could be obtained.
Animal in Disaster Advisory Group.
The ADAG brings together subject matter experts in the field of animal welfare to improve animal disaster preparation, response and recovery. The strong partnership between SDMI and LDAF who has been a national leader in this area having responded to numerous state emergencies both natural and man-made has been mutually beneficial. LDAF has worked with the LSU Vet School and the Louisiana State Animal Response Team (LSART) and numerous other organizations involved in disaster animal response. They are also represented on the National Alliance of State Animal and Agricultural Emergency Programs board. SDMI, LDAF and our other ADAG members will continue to coordinate these efforts to improve planning, increase resources, develop best practices and willingly share this information with all those interested in animal welfare.
In its first year, the SDMI Animals in Disaster Advisory Group (ADAG) has accomplished two major projects including the development of a Guide focused on "Best Practices for Pet Evacuation and Sheltering" which has been endorsed by FEMA and the creation of a Mobile Pet Animal Shelter that can shelter up to 50 animals and be deployed anywhere in the country through the Emergency Management Assistance Compact (EMAC). The guide and the mobile shelter are the first of several projects that the ADAG has worked on that will make a positive impact in animal rescue and sheltering.
International Disaster Conference and Expo (IDCE).
SDMI and its partners involved in the National Evacuation Conference (NEC) have established a partnership in support of the annual IDCE. The 4-day conference held in New Orleans features nationally and internationally recognized and distinguished leaders presenting information, which informs, educates, and shapes the policies and procedures governing the manner in which the world addresses both man-made and natural disasters. In 2014, IDCE had just over 1,400 registered participants representing 31 countries and 46 states with 256 exhibitors in 98 booths. Emergency Management and Homeland Security Officials, International, Federal, State, and Municipal Government leadership, Military, First Responders, Academia, and various private sector, industry and association leaders attended.
Center for Business Preparedness (CBP).
The CBP is currently involved in several projects involving business continuity and resilience. One project was the conduct of the "Business Preparedness Survey" for the purpose of gaining valuable information on how local, state, and Federal emergency management agencies could best support the private sector in preparing for, responding to, and recovering from all-hazard emergencies. The results of the survey were shared with the emergency management community, and various participating business associations at the Louisiana Emergency Preparedness Association (LEPA) annual conference and at the National Emergency Management Association (NEMA) meeting.
Corporate Membership.
SDMI Center for Business Preparedness (CBP) continues to conduct outreach to the private sector to form relationships that are mutually beneficial and long term and whose passions are aligned with SDMI. Through the Corporate Membership Program SDMI has been able to attract companies at various support levels that are interested in supporting the SDMI mission. SDMI broadened the levels of the program this past year to enable smaller business to participate. Starting memberships at $500 attracted a number of businesses that would not have been interested in supporting SDMI. SDMI is committed to supporting a mutual beneficial relationship. The benefits of membership include information sharing, research, and the opportunity to partner on on-going and future SDMI projects. Corporate members include Waguespack Insurance Agency, SecureNation, Shell Pipeline, Cox Communications, DRC, Witt I. O'Brien's, Entergy, and IXIA.


Jane M. Carlton

Jane M. Carlton is a biologist at New York University whose research centers on the genomics of two groups of single-celled parasites: those which cause malaria (the genus "Plasmodium"), and trichomonads, which include the common sexually transmitted parasite "Trichomonas vaginalis".
Education.
Carlton received her Ph.D. in genetics at the University of Edinburgh, Scotland, and has worked at several scientific institutions in the U.S., including the National Center for Biotechnology Information at the National Institutes of Health and the Institute for Genomic Research (TIGR).
Research.
Carlton is among a group of scientists recording and categorizing changes in all of the malaria parasite's genes at once, with a view toward detecting drug resistance in its earliest stages while it can still be controlled, finding new vulnerabilities in the parasite's genome that can be exploited to fight malaria. As Faculty Director of Genomic Sequencing at NYU's Center for Genomics and Systems Biology, Carlton is examining the genomes of dozens of malaria isolates at a time. Recently her group sequenced several genomes from both a human malaria species ("Plasmodium vivax") and a closely related monkey malaria parasite ("Plasmodium cynomolgi"), producing a more detailed picture of malaria evolution and uncovering a surprising amount of genetic variation in the latter.
Carlton collaborates with scientists at National Institute of Malaria Research in India to develop new research paths and control strategies for the disease there. As Program Director of a seven-year NIH International Center of Excellence in Malaria Research based jointly in New Delhi and NYU, she heads the first pan-Indian genomic survey of malaria parasite strains, along with an in-depth epidemiological study of how the malaria is transmitted and manifests itself in different ecologies and societies in India.
Trichomonads are single-celled parasites that infect humans and other mammals as well as birds. One such parasite is "Trichomonas vaginalis", which causes the most widespread non-viral human STD). Carlton led the group that sequenced the genome of "Trichomonas vaginalis" in 2007 – the first sequencing of any trichomonad genome – and uncovered families of genes that may be responsible for the membrane irritation and damage associated with trichomoniasis. The sequencing project also revealed that the parasite's genome is surprisingly large and composed mostly of highly repetitive ‘mobile’ DNA elements.
Awards and honors.
Carlton has published more than 139 research articles and reviews.
She was the recipient of the Stoll-Stunkard Memorial Lectureship Award from the American Society of Parasitologists in 2010.
She was elected a Fellow of the American Association for the Advancement of Science in 2012.


The Cybersmile Foundation

The Cybersmile Foundation is an international non-profit organisation providing support for victims of cyberbullying and online hate campaigns. The Cybersmile Foundation delivers advice, education and support to those affected and their families whilst promoting positive and productive use of the internet.
History.
The Cybersmile Foundation was the first dedicated cyberbullying charity in the UK. The charity was founded by Scott Freeman and Daniel Raisbeck in 2010 in order to provide a central resource to tackle the issue of cyberbullying, and has since expanded to provide education and support worldwide. The Cybersmile Foundation became a registered charity in 2012. On 19 June 2014 The Cybersmile Foundation officially launched in the U.S. opening their Palo Alto branch. American girl group Fifth Harmony were announced as the official ambassadors on May 30, 2015.
Stop Cyberbullying Day.
The Cybersmile Foundation launched the first international Stop Cyberbullying Day on June 21, 2013 as a day of global positivity online. The day takes place annually on the third Friday in June.
Research.
To coincide with Stop Cyberbullying Day 2015, Cybersmile released original research carried out in partnership with Sugarscape, examining current teen attitudes towards online bullying and social media.
The report revealed that 55% had been cyberbullied while 35% admitted to having suffered up to five separate incidents of online abuse.
Partnerships.
Intel.
Intel launched their 'Diversity in Technology' initiative in 2015, working with a variety of partners, including The Cybersmile Foundation. The company have pledged $300 million over the next several years for the campaign, which focuses on a variety of different strands; Cybersmile are featured as part of the plan to increase inclusivity in the gaming industry and provide support for female gamers. On September 24, 2015 The Cybersmile Foundation launched their 'Gaming Support Centre' in partnership with Intel to "provide practical, emotional and legal support" to victims of abuse when gaming online.
"Sugarscape".
In May 2014, The Cybersmile Foundation became media partners with online teen magazine "Sugarscape", providing content for their young audience focused on online safety and promoting positivity on the internet.
Twitter.
Cybersmile are official partners with Twitter in promoting digital citizenship and to better educate users about being safe online". As part of the partnership, Cybersmile provide the Twitter-only help channel @AskCybersmile, which is listed as a Twitter Trusted Resource.
The Body Shop Foundation.
The Body Shop Foundation supported Cybersmile within their remit to help organisations in the Human Rights category. With their support and funding, Cybersmile have been able to create over 80 downloadable digital programs to educate people about cyberbulliying and online safety worldwide.
"Wicked".
In June 2015, The Cybersmile Foundation were announced as partners in the Wicked for Good program, which fundraises for various causes. The partnership is said to be backed up by strong anti-bullying themes in the stage production and has been supported by the cast in the theatre.
"High School Story".
The Cybersmile Foundation partnered with Pixelberry Studios as part of their game, "High School Story". The game, in which players can create and run their own high school, featured collaborative storylines on the theme of cyberbullying and helped Cybersmile to reach 4 million young people. Pixelberry Studios pledged to raise $100,000 for Cybersmile in 2014 by selling special in-game items and in the end raised over $350,000.
Gaming Initiatives.
In March 2015, Cybersmile announced their plans to tackle "gender inequality and digital abuse within the gaming industry" as part of the Intel Diversity in Technology partnership. As part of this announcement, five long-term goals were established:
In September 2015, Cybersmile launched their Gaming Support Centre, featuring video game specific help and support resources as well as dedicated blog and news feeds from industry professionals.
CPS guidelines.
In December 2012, the Crown Prosecution Service issued guidelines on how cases of cyberbullying will be assessed under the current legislation. The Cybersmile Foundation was consulted as part of the development of these guidelines.


National Drug Evidence Centre

The National Drug Evidence Centre (NDEC) is part of the University of Manchester Faculty of Medical and Human Sciences, located on Oxford Road in Manchester, United Kingdom.
Overview.
NDEC carries out epidemiological, evaluative and policy related research in the field of substance misuse working within the Health Service and Criminal Justice Systems at local, national and European levels. NDEC has strong collaborative links with the European Monitoring Centre on Drugs and Drug Addiction in Lisbon, IFT Germany and IVV Holland. In the UK, the work of the Centre is intrinsically linked to the Department of Health, Home Office and National Treatment Agency (NTA).
NDEC is responsible for analyses and reporting of national government statistics on drug/ alcohol misuse treatment, delivered through a National Statistics hub and is developing a National Data Library for use by policy makers, clinical services and researchers.
The Visualisation Group within NDEC is developing ViewIt-a web visualisation tool with content management and data extraction functions that allow investigation and contextualisation of any dataset in tabular, graphical and map based formats.
History.
NDEC began in The University of Manchester in 1987. Formerly called Drug Misuse Research Unit, it "has developed into an academic research and information centre concerned with understanding the extent and nature of drug/ alcohol problems in communities in the context of public health, alongside evaluation of risk prevention and intervention responses, and has been responsible for the introduction and development of information systems now in use across the whole of the UK and Europe," according to its official website.


Turning Point (charity)

Turning Point is a health and social care organisation that works across mental health, learning disability, substance misuse, primary care, the criminal justice system and employment. In 2017, Turning Point won the contract to deliver sexual health services across 3 London boroughs and Autism Plus joined the Turning Point group. Many of Turning Point services are regulated by the Care Quality Commission.
Organisation.
Turning Point is a social enterprise and registered charity based in the United Kingdom that runs projects in more than 240 locations across England and Wales, making contact in the last year with 130,000 people. In addition to providing direct services, Turning Point also campaigns on behalf of those with social care needs.
It has a turnover of £111m, £60m of which is for the delivery of substance misuse services, £18m for the delivery of mental health services and £34m for the delivery of support to people with a Learning Disability.
The organisation provides services support for a range of people, including those with mental health issues, learning disabilities and/or substance-related disorders.
History.
Turning Point developed out of The Camberwell Alcohol Project in South East London and was founded by Barry Richards, a London businessman, in 1964.
The charity was described as "one of Princess Diana's favourite charities"; she acted as its patron from 1985 to 1997.
In 2001, Lord Victor Adebowale became Chief Executive.
In 2015 the charity denied accusations of "black on black racism" in its appeal against the decision of an earlier employment tribunal that Adebowale had unfairly dismissed the charity's IT director, Ibukun Adebayo. The tribunal did find that Adebayo's actions in accessing lewd emails about her from the charity's deputy chief executive to Adebowale, constituted gross misconduct, but ruled that this did not justify Adebowale's actions. Adebayo's lawyers said that the actions were unfair because the deputy chief executive's behaviour "was more serious than the claimant's by way of his seniority and position as sponsor of Turning Point's equal opportunities policy."
See also.
General:


Going Back to Cali (The Notorious B.I.G. song)

"Going Back to Cali" is a song recorded by rapper The Notorious B.I.G. and Puff Daddy (uncredited) from the album "Life After Death". The song is noted as one of Biggie's popular songs from the album, well known for its catchy hook and beat. The song contains a sample of Zapp hit "More Bounce to the Ounce".
Background.
The song is about Smalls returning to Los Angeles and the West Coast. It begins with Puff Daddy and Smalls in a telephone conversation in which Daddy is telling Smalls that he needs to get ready for a flight to Los Angeles. Smalls sounding like he's just woken up from being asleep. The second verse opens up with Smalls' thoughts on the East Coast–West Coast hip hop rivalry and his relationship with the West Coast:
If I got to choose a coast, I got to choose the EastI live out there, so don't go thereBut that don't mean a nigga can't rest in the WestSee some nice breasts in the WestSmoke some nice sess in the WestY'all niggas is a messThinkin' I'm gon' stop givin' L.A. propsAll I got is beef with those that violate meI shall annihilate thee
Cover versions.
Harlem rapper Mase (who was associated with Biggie) recorded a cover version of the song named "Going Back To Harlem".
The song is heavily sampled in E-40's song "Bust Moves" featuring labelmates Big Omeezy and Droop-E, the latter of whom is E-40's son, from his 2012 album "".


Johannes Zwick

Johannes Zwick (c. 1496, in Konstanz – 23 October 1542, in Bischofszell) was a German Reformer and hymnwriter. He briefly hosted the Anabaptist Johannes Bünderlin in 1529. He died of the plague.


General clinical research center


Calico cat

A calico cat is a domestic cat of any breed with a tri-color coat. The calico cat is most commonly thought of as being typically 25% to 75% white with large orange and black patches (or sometimes cream and grey patches); however, the calico cat can have any three colors in its pattern. They are almost exclusively female except under rare genetic conditions. A calico is not to be confused with a tortoiseshell, which has a mostly mottled coat of black/orange or grey/cream with relatively few to no white markings. However, outside North America, the calico pattern is more usually called "tortoiseshell and white". In the province of Quebec, Canada, they are sometimes called "chatte d'Espagne" (French for '(female) cat of Spain'). Other names include "brindle", "tricolor cat", "mikeneko" (三毛猫) (Japanese for 'triple fur cat'), and "lapjeskat" (Dutch for 'patches cat'); calicoes with diluted coloration have been called "calimanco" or "clouded tiger". Occasionally, the tri-color calico coloration is combined with a tabby patterning; this calico-patched tabby is called a "caliby".
“Calico” refers only to a color pattern on the fur, from colorful printed Calico fabric, not to a cat breed or any reference to any other traits, such as its eyes. Among the breeds whose formal standards allow calico coloration are the Manx cat, American Shorthair, Maine Coon, British Shorthair, Persian cat, Arabian Mau, Japanese Bobtail, Exotic Shorthair, Siberian, Turkish Van, Turkish Angora and Norwegian Forest cat.
Because genetic determination of coat colors in calico cats is linked to the X chromosome, calicos are nearly always female, with one color linked to the maternal X chromosome and a second color linked to the paternal X chromosome. In most cases, males are only one color (for instance, black) as they have only one X chromosome. Male calicoes can happen when a male cat has two X chromosomes (Klinefelter syndrome, with XXY sex chromosomes and generally sterile); is a chimera, with two different cell types; or, rarely, when some skin cells of the developing kitten spontaneously mutate.
Some calico cats can also be overall lighter in color—"dilute calicos". Fairly common among calicos, dilutes are distinguished by having grey (known as blue), cream and gold colors instead of the traditional black, red and brown patches along with their white.
History.
The coat pattern of calico cats does not define any breed, but occurs incidentally in cats that express a range of color patterns; accordingly the effect has no definitive historical background. However, the existence of patches in calico cats was traced to a certain degree by Neil Todd in a study determining the migration of domesticated cats along trade routes in Europe and Northern Africa. The proportion of cats having the orange mutant gene found in calicoes was traced to the port cities along the Mediterranean in Greece, France, Spain and Italy, originating from Egypt. The calico has been Maryland's state cat since October 1, 2001. Calico cats were chosen as the state cat because their white, black, and orange coloring resembles the coloring of the Baltimore oriole (the state bird) and the Baltimore checkerspot butterfly (the state insect).
Genetics.
In genetic terms, calico cats are tortoiseshells in every way, except that in addition they express a white spotting gene. There is however one anomaly: as a rule of thumb the larger the areas of white, the fewer and larger the patches of ginger and dark or tabby coat. In contrast a non-white-spotted tortoiseshell usually has small patches of color or even something like a salt-and-pepper sprinkling. This reflects the genetic effects on relative speeds of migration of melanocytes and X-inactivation in the embryo.
Serious study of calico cats seems to have begun about 1948 when Murray Barr and his graduate student E.G. Bertram noticed dark, drumstick-shaped masses inside the nuclei of nerve cells of female cats, but not in male cats. These dark masses became known as Barr bodies. In 1959, Japanese cell biologist Susumu Ohno determined the Barr bodies were X chromosomes. In 1961, Mary Lyon proposed the concept of X-inactivation: one of the two X chromosomes inside a female mammal shuts off. She observed this in the coat color patterns in mice.
Calico cats are almost always female because the locus of the gene for the orange/non-orange coloring is on the X chromosome. In the absence of other influences, such as color inhibition that causes white fur, the alleles present in those orange loci determine whether the fur is orange or not. Female cats, like all female placental mammals, normally have two X chromosomes. In contrast, male placental mammals, including chromosomally stable male cats, have one X and one Y chromosome. Since the Y chromosome does not have any locus for the orange gene, there is no chance that an XY male could have both orange and non-orange genes together, which is what it takes to create tortoiseshell or calico coloring.
One exception is that in rare cases faulty cell division may leave an extra X chromosome in one of the gametes that produced the male cat. That extra X then is reproduced in each of his cells, a condition referred to as XXY, or Klinefelter syndrome. Such a combination of chromosomes could produce tortoiseshell or calico markings in the male, in the same way as XX chromosomes produce them in the female.
All but about one in three thousand of the rare calico or tortoiseshell male cats are sterile because of the chromosome abnormality, and breeders reject any exceptions for stud purposes because they generally are of poor physical quality and fertility. Even in the rare cases where a male calico is healthy and fertile, most cat registries will not accept them as show animals.
As Sue Hubble stated in her book "Shrinking the Cat: Genetic Engineering Before We Knew About Genes",
The mutation that gives male cats a ginger-colored coat and females ginger, tortoiseshell, or calico coats produced a particularly telling map. The orange mutant gene is found only on the X, or female, chromosome. As with humans, female cats have paired sex chromosomes, XX, and male cats have XY sex chromosomes. The female cat, therefore, can have the orange mutant gene on one X chromosome and the gene for a black coat on the other. The piebald gene is on a different chromosome. If expressed, this gene codes for white, or no color, and is dominant over the alleles that code for a certain color ("i.e." orange or black), making the white spots on calico cats. If that is the case, those several genes will be expressed in a blotchy coat of the tortoiseshell or calico kind. But the male, with his single X chromosome, has only one of that particular coat-color gene: he can be not-ginger or he can be ginger (although some modifier genes can add a bit of white here and there), but unless he has a chromosomal abnormality he cannot be a calico cat.
It is currently very difficult to reproduce the fur patterns of calico cats by cloning. Penelope Tsernoglou wrote "This is due to an effect called x-linked inactivation which involves the random inactivation of one of the X chromosomes. Since all female mammals have two X chromosomes, one might wonder if this phenomenon could have a more widespread impact on cloning in the future."
Calico cats may have already provided findings relating to physiological differences between male and female mammals.
Folklore.
Cats of this coloration are believed to bring good luck in the folklore of many cultures. In Germany, the word for a cat with calico coloring is "Glückskatze" or "lucky cat". In the United States, these are sometimes referred to as "money cats". A cat of the calico coloration is also the state cat of Maryland in the United States. In the late nineteenth century, Eugene Field published "The Duel", a poem for children also known as "The Gingham Dog and the Calico Cat". In Japan, the Maneki-neko figures depict calico cats, bringing good luck; Japanese sailors often had a calico ship's cat to protect against misfortune at sea.


Isaac Walker Hall

Isaac Walker Hall (1868 – 9 October 1953) was a British pathologist and writer.
Hall was educated at Owens College, Manchester. He obtained his M.B. with honours at Victoria University in 1899 and his M.D. in 1902. He studied pathology in Leipzig, Stockholm and Wiesbaden. In 1900, he was appointed senior demonstrator of physiology and lecturer in pathology at Victoria University.
In 1905, he co-authored "Methods of Morbid Histology and Clinical Pathology", with Gotthold Herxheimer. Hall was appointed first honorary pathologist and bacteriologist to the Bristol Royal Infirmary and first professor of pathology at University College, Bristol in 1906.
Hall authored important papers on typhoid fever in 1908 and contributed literature on the bacteriology of public health. He was a member of the British Medical Association for fifty-five years and was vice-president for its Section of Pathology at the Annual Meeting at Belfast in 1909 and at Liverpool in 1912. He was an honorary member of the Association of Clinical Pathologists.
Hall's "The Purin Bodies Of Food Stuffs" was positively reviewed in "The British Medical Journal".
He retired in 1936 and moved to Godalming with his wife.


Nicolle Gonzales

Nicolle Gonzales (born March 15, 1980 in Waterflow, New Mexico) is a Navajo certified midwife. She is currently in the process of opening the nation's first Native American birthing center in her home state, New Mexico.
Biography.
She studied at the University of New Mexico. She first received her bachelors in nursing, followed by a master level midwifery degree. She is a member of the American College of Nurse-Midwives and is certified with the American Midwifery Certification Board.
Gonzales trained as a midwife after traumatic experiences during the birth of her first child. Gonzales lives in Santa Fe, New Mexico.
Changing Woman Initiative (CWI).
Gonzales is the founder of "Changing Woman Initiative", a non-profit organization which aims to improve the experience of childbirth for indigenous women. The cost alone of child birth can range from $13,000 to $17,000, making it less available for rural, indigenous women. Gonzales aims to cut the costs of birth as well as providing other women's health services to help with the cost of women's health in general. Work has not yet started on the clinic, which is intended to cater to women with Medicaid insurance, or women with no insurance at all. Gonzales hopes to open the center on native land.


Pakistan Journal of Pharmaceutical Sciences

The Pakistan Journal of Pharmaceutical Sciences is a bimonthly peer-reviewed open access medical journal covering pharmaceutical sciences. It was established in 1988 and is published by the Faculty of Pharmacy, University of Karachi. The editor-in-chief is Iqbal Azhar (University of Karachi).
According to the "Journal Citation Reports", the journal has a 2015 impact factor of 0.581.


Daniel Duranti

Daniel Duranti (1633 - 1712 or 1713) was an Italian Catholic priest, mostly known for serving as Archbishop of the Roman Catholic Diocese of Skopje and Apostolic Vicar of Roman Catholic Archdiocese of Izmir.
Duranti was born in Arezzo, on 17 September 1633, and ordained priest on 8 March 1664. On 11 December 1690 he was appointed Archbishop of the Diocese of Skopje (ordained Bishop in 1691), position which had remained empty since the death of Pjetër Bogdani. He served in that position until 29 July 1702, when he resigned. Simultaneously, during 7 June 1696 - 1706, and 1708 - 1713, he served as Vicar Apostolic of the Roman Catholic Archdiocese of Izmir. He died from a plague epidemic together with circa 10,000 people in Izmir, most probably in 1712.


Perspectives on Behavior Science

Perspectives on Behavior Science is a semiannual peer-reviewed scientific journal covering behavior analysis. It was established in 1978 and is published by Springer Science+Business Media on behalf of the Association for Behavior Analysis International, of which it is the official journal. It was published as The Behavior Analyst until it obtained its current name in 2018. The editor-in-chief is Donald Hantula (Temple University). According to the "Journal Citation Reports", the journal has a 2016 impact factor of 1.357.


William Miller Ord

William Miller Ord, FRCP (23 September 1834 – 14 May 1902) was a British medical scientist. He was a surgeon at St. Thomas Hospital in London, where he worked for 50 years.
Biography.
Ord was born in 1834, the son of George Ord, MRCS, a surgeon who practiced in Brixton. He received his medical education at St Thomas' Hospital, where he entered in 1852, and at London University. He became a member of the Royal College of Surgeons in 1855, and a member of the Royal College of Physicians in 1869 (later elected a Fellow in 1875).
At St. Thomas′, he was successively surgical registrar, house surgeon, lecturer in comparative anatomy, lecturer in physiology, assistant physician lecturer in medicine, and physician. He was also elected Dean of the Medical School.
In 1879 he described Ord's thyroiditis.
He was an active member of the Medical Society of London, and was president of the society in 1885.
Ord died at The Hall, in Salisbury, residence of his son, on 14 May 1902.


Marine Drugs

Marine Drugs is a peer-reviewed open-access medical journal publishing reviews and regular research papers on the research, development, and production of therapeutic agents from marine natural products. It is published by MDPI and was established in 2003. The editor-in-chief is Prof. Orazio Taglialatela-Scafati (Università degli Studi di Napoli Federico II, Italy).
Abstracting and indexing.
The journal is abstracted and indexed in:
According to the "Journal Citation Reports", the journal has a 2017 impact factor of 4.379.


June Hartley

June Hartley (born 1967) is a California woman who faced charges for assisting in the suicide of her brother, Jimmy, after he suffered a series of strokes.
Death and criminal charges.
Jimmy Hartley, a blues musician and lead singer for the Studebaker Blues Band, was found dead in his family's home in Lodi, California on December 8, 2008. A helium tank and a copy of an instructional book by Derek Humphry, the chairman of Final Exit Network, were found near his body. He had previously been left paralyzed and lost his speech and hearing after a series of strokes in 2006. Over the next two years, he had repeatedly asked police and others to help him die.
On February 23, 2009, San Joaquin County prosecutors charged June Hartley with assisted suicide, an offense for which she faced six years in prison if convicted. She pleaded not guilty and was freed on bail on February 28, 2009. She later changed her plea to guilty on a lesser charge and received a sentence of probation and community service without jail time.
Opinion and reaction.
The case generated a response from both supporters and critics of assisted suicide. Brian Johnston, executive director of the California Pro-Life Council, stated that Hartley's case underscored the need for laws to keep "emotionally vulnerable people" from "taking lethal action" into their own hands. However, Barbara Coombs Lee, the president of Compassion and Choices, defended Hartley. She explained that a case like Hartley's "cries out for humane and rational legislation, but lawmakers are unwilling to embrace it." Assisted suicide advocate Jacob Appel expressed concerns that the case might have significant repercussions. He wrote that "family members and friends of similarly suffering individuals in California...may now shy away from helping their loved ones die if they fear reprisals from overzealous district attorneys."


Human Performance (journal)

Human Performance is a quarterly peer-reviewed scientific journal covering industrial and organizational psychology as it relates to job performance. It was established in 1988, with Frank Landy (Pennsylvania State University) as its founding editor-in-chief. It is published by Taylor & Francis and the current editor-in-chief is David J. Woehr (University of North Carolina at Charlotte). According to the "Journal Citation Reports", the journal has a 2016 impact factor of 1.302, ranking it 49th out of 80 journals in the category "Psychology, Applied".


John of Capistrano

John of Capistrano ("Italian": San Giovanni da Capestrano, "Hungarian": Kapisztrán János, "Polish": Jan Kapistran, "Croatian": Ivan Kapistran", Serbian": Јован Капистран, Jovan Kapistran) (24 June 1386 – 23 October 1456) was a Franciscan friar and Catholic priest from the Italian town of Capestrano, Abruzzo. Famous as a preacher, theologian, and inquisitor, he earned himself the nickname 'the Soldier Saint' when in 1456 at age 70 he led a crusade against the invading Ottoman Empire at the siege of Belgrade with the Hungarian military commander John Hunyadi.
Elevated to sainthood, he is the patron saint of jurists and military chaplains, as well as the namesake of the Franciscan missions San Juan Capistrano in Southern California and San Juan Capistrano in San Antonio, Texas.
Early life.
As was the custom of this time, John is denoted by the village of Capestrano, in the Diocese of Sulmona, in the Abruzzi region, Kingdom of Naples. His father had come to Italy with the Angevin court of Louis I of Anjou, titular King of Naples. He studied law at the University of Perugia.
In 1412, King Ladislaus of Naples appointed him Governor of Perugia, a tumultuous and resentful papal fief held by Ladislas as the pope's champion, in order to effectively establish public order. When war broke out between Perugia and the Malatestas in 1416, John was sent as ambassador to broker a peace, but Malatesta threw him in prison. It was during this imprisonment that he began to think more seriously about his soul. He decided eventually to give up the world and become a Franciscan friar, owing to a dream he had in which he saw Francis of Assisi and was warned by him to enter the Franciscan Order. He had married before the war, but asserted the marriage was never consummated and received permission to take holy orders.
Friar and preacher.
Together with James of the Marches, John entered the Order of Friars Minor at Perugia on 4 October 1416. Along with James, he studied theology at Fiesole, near Florence, under Bernardine of Siena. He soon gave himself up to the most rigorous asceticism, violently defending the ideal of strict observance and orthodoxy, following the example set by Bernardine. From 1420 onwards, he preached with great effect in numerous cities and eventually became well known. He was ordained in 1425.
Unlike most Italian preachers of repentance in the 15th century, John was effective in northern and central Europe—in German states of Holy Roman Empire, Bohemia, Moravia, Austria, Hungary, Croatia and the Kingdom of Poland. The largest churches could not hold the crowds, so he preached in the public squares—at Brescia in Italy, he preached to a crowd of 126,000.
Reformer.
When he was not preaching, John was writing tracts against heresy of every kind. This facet of his life is covered in great detail by his early biographers, Nicholas of Fara, Christopher of Varese and Girlamo of Udine. While he was thus evangelizing, he was actively engaged in assisting Bernardine of Siena in the reform of the Franciscan Order, largely in the interests of a more rigorous discipline in the Franciscan communities. Like Bernardine, he strongly emphasized devotion to the Holy Name of Jesus, and, together with Bernardine, was accused of heresy on this account. In 1429, these Observant friars were called to Rome to answer charges of heresy, and John was chosen by his companions to speak for them. They were both acquitted by the Commission of Cardinals appointed to judge the accusations.
He was frequently deployed to embassies by Popes Eugene IV and Nicholas V: in 1439, he was sent as legate to Milan and Burgundy, to oppose the claims of the Antipope Felix V; in 1446, he was on a mission to the King of France; in 1451 he went at the request of the emperor as Apostolic Nuncio to Austria. During the period of his nunciature, John visited all parts of the Empire, preaching and combating the heresy of the Hussites; he also visited Poland at the request of Casimir IV Jagiellon. As legate, or inquisitor, he prosecuted the last Fraticelli of Ferrara, the Jesuati of Venice, the Crypto-Jews of Sicily, Moldavia and Poland, and, above all, the Hussites of Germany, Hungary and Bohemia; his aim in the last case was to make talks impossible between the representatives of Rome and the Bohemians, for every attempt at conciliation seemed to him to be conniving at heresy.
John, in spite of this tireless life, found time to work—both during the lifetime of his mentor, Bernardine, and afterwards—on the reform of the Order of Friars Minor. He also upheld, in his writings, speeches and sermons, theories of papal supremacy rather than the theological wranglings of councils (see Conciliar Movement). John, together with his teacher, Bernardine, his colleague, James of the Marche, and Albert Berdini of Sarteano, are considered the four great pillars of the Observant reform among the Friars Minor.
Anti-Jewish incitement.
John was known as the "Scourge of the Jews" for his inciting of antisemitic violence. Like some other Franciscans, he ranged over a broad area on both sides of the Alps, and his preaching to mass open-air congregations often led to pogroms. In 1450 the Franciscan "Jew-baiter" arranged a forced disputation at Rome with a certain Gamaliel called "Synagogæ Romanæ magister". Between 1451 and 1453, his fiery sermons against Jews persuaded many southern German regions to expel their entire Jewish population, and in Silesia, then Kingdom of Bohemia, at Wroclaw many were burned at the stake.
The soldier saint.
After the Fall of Constantinople in 1453, the Ottoman Empire, under Sultan Mehmed II, threatened Christian Europe. That following year Pope Callixtus III sent John, who was already aged seventy, to preach a Crusade against the invading Turks at the Imperial Diet of Frankfurt. Gaining little response in Bavaria and Austria, he decided to concentrate his efforts in Hungary. John succeeded in gathering together enough troops to march onto Belgrade, which at that time was under siege by Turkish forces. In the summer of 1456, these troops, together with John Hunyadi, managed to raise the siege of Belgrade; the old and frail friar actually led his own contingent into battle. This feat earned him the moniker of 'the Soldier Priest'.
Although he survived the battle, John fell victim to the bubonic plague, which flourished in the unsanitary conditions prevailing among armies of the day. He died on 23 October 1456 at the nearby town of Ilok (now a Croatian border town on the Danube).
Sainthood and feast day.
The year of John of Capistrano's canonization is variously given as 1690, by Pope Alexander VIII or as 1724 by Pope Benedict XIII. In 1890, his feast day was included for the first time in the General Roman Calendar and assigned to 28 March. In 1969, Pope Paul VI moved his feast day to 23 October, the day of his death. Where Mass and the Office are said according to the 1962 Roman Missal and its concomitant calendar, his feast day remains on March 28.
Eponym.
As a Franciscan reformer preaching simplicity, John became the eponym of two Spanish missions founded by the Franciscan friars in the north of the then-Spanish Americas: Mission San Juan Capistrano in present-day Southern California and Mission San Juan Capistrano just outside the city center of present-day San Antonio in Texas.
Patron saint.
He is the patron saint of military chaplains and jurists.


Derek Richter

Derek Richter (14 January 1907 – 15 December 1995), English neuroscientist, was one of the founding fathers of the science of brain chemistry. Identifying monoamine oxidase and demonstrating its function in the brain early in his career, he became a prime mover in his field. In 1968 he was involved in the foundation of the British Brain Research Organization (BRA). Prior to this he helped to establish the Mental Health Research Fund, later renamed The Mental Health Foundation,(1949). He also established the Journal of Neurochemistry (1956), of which he was one of the chief editors from 1956 to 1969. He was involved in the foundation of the International Brain Research Organization (IBRO) (1960), of which he became secretary-general, and the International Society for Neurochemistry (ISN) (1967). After leading a research unit at Whitchurch Psychiatric Hospital (1947–1960), he became director of the Medical Research Council Neuropsychiatric Research Unit in Carshalton (1960–1971). Throughout his life he promoted international collaboration in research.
Biography.
Richter was born in Bath, Somerset, third child of Charles A Richter, co-founder of the family firm, Bath Cabinet Makers. From Oundle School he won a scholarship to Magdalen College, Oxford, where he gained a first-class honour's degree in Chemistry. At Munich University he worked under Nobel Prize-winning Heinrich Wieland. In 1931 he gained a PhD (magna cum laude) for the autoxidation of aldehydes.
He then moved to Sir Frederick Gowland Hopkins Biochemical Laboratory at Cambridge alongside Nobel laureates Ernst Chain, Richard Synge, Frederick Sanger, Hans Krebs and Archer Martin. This was a defining period, working with on monoamines that have great physiological interest.
A year before the outbreak of World War II, he took a post at the Maudsley Hospital to work on amphetamines. Married to Beryl Ailsa Griffiths, with whom he had three children, he set up a wartime research laboratory for treating shell-shock in the Mill Hill Emergency Hospital. Despite taxing commitments, he simultaneously qualified in medicine at St Bartholomew's Hospital.
In 1947 Richter received a Rockefeller Foundation grant to set up a laboratory in the Whitchurch Psychiatric Hospital, Cardiff. Four years later, with one of the first Geiger counters to measure radioisotopes in the country, he and RMC Dawson had isolated nuclei from the cells of the cerebral cortex and demonstrated changes in brain metabolism with changes in brain function. With Linford Rees he carried out early work on biochemical changes concerning epilepsy and electroconvulsive therapy (ECT) and collaborated with W. Grey-Walter in EEG studies. With Miki Gaitonde, he worked on the metabolic activity of proteins of the brain.
At Carshalton, Richter gathered a multidisciplinary international group of scientists with a global approach to their research. He became involved with the World Health Organization, and Amnesty International. In retirement he was elected a fellow of the Royal College of Psychiatrists, and wrote a series of humanitarian books. Typically, his last book was intended for foreign visitors.
Concern for the childless women prompted him, through medical colleague Bertold Wiesner to become one of the first sperm donors at Mary Barton (Wiesner's wife)'s insemination clinic in London.
Some of these children have been identified by DNA markers. Between April 1945 and 1951 he made weekly contributions at a time when AID was strictly anonymous and very controversial. It was a precursor to modern developments in reproductive technology such as IVF, that are leading to changes in the structure of families.
He continued to write and edit enlightened books, gardened passionately and joined his second wife, Molly Bullock, in establishing South Lodge, a refuge in Epsom for discharged mental patients.


Nanocarriers

A nanocarrier is nanomaterial being used as a transport module for another substance, such as a drug. Commonly used nanocarriers include micelles, polymers, carbon-based materials, liposomes and other substances. Nanocarriers are currently being studied for their use in drug delivery and their unique characteristics demonstrate potential use in chemotherapy.
Characterization.
Nanocarriers range from sizes of diameter 1–1000 nm, however due to the width of microcapillaries being 200 nm, nanomedicine often refers to devices <200 nm. Because of their small size, nanocarriers can deliver drugs to otherwise inaccessible sites around the body. Since nanocarriers are so small, it is oftentimes difficult to provide large drug doses using them. The emulsion techniques used to make nanocarriers also often result in low drug loading and drug encapsulation, providing a difficulty for the clinical use.
Types.
Nanocarriers discovered thus far include polymer conjugates, polymeric nanoparticles, lipid-based carriers, dendrimers, carbon nanotubes, and gold nanoparticles. Lipid-based carriers include both liposomes and micelles. Examples of gold nanoparticles are gold nanoshells and nanocages.
Different types of nanomaterial being used in nanocarriers allows for hydrophobic and hydrophilic drugs to be delivered throughout the body. Since the human body contains mostly water, the ability to deliver hydrophobic drugs effectively in humans is a major therapeutic benefit of nanocarriers. Micelles are able to contain either hydrophilic or hydrophobic drugs depending on the orientation of the phospholipid molecules. Some nanocarriers contain nanotube arrays allowing them to contain both hydrophobic and hydrophilic drugs.
One potential problem with nanocarriers is unwanted toxicity from the type of nanomaterial being used. Inorganic nanomaterial can also be toxic to the human body if it accumulates in certain cell organelles. New research is being conducted to invent more effective, safer nanocarriers. Protein based nanocarriers show promise for use therapeutically since they occur naturally, and generally demonstrate less cytotoxicity than synthetic molecules.
Targeted drug delivery.
Nanocarriers are useful in the drug delivery process because they can deliver drugs to site-specific targets, allowing drugs to be delivered in certain organs or cells but not in others. Site-specificity is a major therapeutic benefit since it prevents drugs from being delivered to the wrong places. Nanocarriers show promise for use in chemotherapy because they can help decrease the adverse, broader-scale toxicity of chemotherapy on healthy, fast growing cells around the body. Since chemotherapy drugs can be extremely toxic to human cells, it is important that they are delivered to the tumor without being released into other parts of the body. Four methods in which nanocarriers can deliver drugs include passive targeting, active targeting, pH specificity, and temperature specificity.
Passive targeting.
Passive targeting refers to a nanocarrier's ability to travel down a tumor's vascular system, become trapped, and accumulate in the tumor. This accumulation is caused by the enhanced permeability and retention effect which refers to the poly(ethylene oxide) (PEO) coating on the outside of many nanocarriers. PEO allows nanocarriers to travel through the leaky vasculature of a tumor, where they are unable to escape. The leaky vasculature of a tumor is the network of blood vessels that form in a tumor, which contain many small pores. These pores allow nanocarriers in, but also contain many bends that allow the nanocarriers to become trapped. As more nanocarriers become trapped, the drug accumulates at the tumor site. This accumulation cause large doses of the drug to be delivered directly to the tumor site. PEO may also have some adverse effects on cell-nanocarrier interactions, weakening the effects of the drug, since many nanocarriers must be incorporated into the cells before the drugs can be released.
Active targeting.
Active targeting involves the incorporation of targeting modules such as ligands or antibodies on the surface of nanocarriers that are specific to certain types of cells around the body. Nanocarriers have such a high surface-area to volume ratio allowing for multiple ligands to be incorporated on their surfaces. These targeting modules allow for the nanocarriers to be incorporated directly inside of cells, but also have some drawbacks. Ligands may cause nanocarriers to become slightly more toxic due to non-specific binding, and positive charges on ligands may decrease drug delivery efficiency once inside of cells. Active targeting has been shown to help overcome multi-drug resistance in tumor cells.
pH specificity.
Certain nanocarriers will only release the drugs they contain in specific pH ranges. pH specificity also allows nanocarriers to deliver drugs directly to a tumor site. Tumors are generally more acidic than normal human cells, with a pH around 6.8. Normal tissue has a pH of around 7.4. Nanocarriers that only release drugs at certain pH ranges can therefore be used to release the drug only within acidic tumor environments. High acidic environments cause the drug to be released due to the acidic environment degrading the structure of the nanocarrier. These nanocarriers will not release drugs in neutral or basic environments, effectively targeting the acidic environments of tumors while leaving normal body cells untouched. This pH sensitivity can also be induced in micelle systems by adding copolymer chains to micelles that have been determined to act in a pH independent manor.
These micelle-polymer complexes also help to prevent cancer cells from developing multi-drug resistance. The low pH environment triggers a quick release of the micelle polymers, causing a majority of the drug to be released at once, rather than gradually like other drug treatments. This quick release mechanism significantly decreases the time it takes for anticancer drugs to kill a tumor, effectively preventing the tumor from having time to undergo mutations that would render it drug resistant.
Temperature specificity.
Some nanocarriers have also been shown to deliver drugs more effectively at certain temperatures. Since tumor temperatures are generally higher than temperatures throughout the rest of the body, around 40 °C, this temperature gradient helps act as safeguard for tumor-specific site delivery.
Uses.
Most of research on nanocarriers is being applied to their potential use in drug delivery, especially in chemotherapy. Since nanocarriers can be used to specifically target the small pores, lower pH's, and higher temperatures of tumors, they have the potential to lower the toxicity of many chemotherapy drugs. Also, since almost 75% of anticancer drugs are hydrophobic, and therefore demonstrate difficulty in delivery inside human cells, the use of micelles to stabilize, and effectively mask the hydrophobic nature of hydrophobic drugs provides new possibilities for hydrophobic anticancer drugs.