Meetings – Medical Device Clinical Trials 2014 (Chicago) and DIA (San Diego)

 

Warren Pearlson, Target Health’s Director of Business Development will be attending the Medical Device Clinical Trials 2014 meeting in Chicago on June 3rd and 4th. Please contact Warren atwpearlson@targethealth.com if you will be attending or interested in our experience with Medical Devices.

 

Target Health will also be at DIA in San Diego this year (Booth 1935) so please let us know if you will be attending.

 

20140527-11

Cormorants Resting by the Central Park Reservoir ©Target Health Inc.

 

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

 

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

 

Joyce Hays, Founder and Chief Editor of On Target
Jules Mitchel, Editor

 

New Stem Cell Finding Bodes Well for Future Medical Use in Humans

 

20140527-10

New bone formation (stained bright green under ultra-violet light) was seen in monkeys given their own reprogrammed stem cells. Credit: Nature magazine

 

Stem cells are undifferentiated biological cells that can differentiate into specialized cells and can divide (through mitosis) to produce more stem cells. They are found in multicellular organisms. In mammals, there are two broad types of stem cells: embryonic stem cells, which are isolated from the inner cell mass of blastocysts, and adult stem cells, which are found in various tissues. In adult organisms, stem cells and progenitor cells act as a repair system for the 1) ___, replenishing adult tissues. In a developing embryo, stem cells can differentiate into all the specialized cells – ectoderm, endoderm and mesoderm but also maintain the normal turnover of regenerative organs, such as blood, skin, or intestinal tissues.

 

There are three known accessible sources of autologous adult stem cells in humans: bone marrow, lipid cells and 2) ___. Stem cells can also be taken from umbilical cord blood just after birth. Of all stem cell types, autologous harvesting involves the least risk. By definition, autologous cells are obtained from one’s own body, just as one may bank his or her own blood for elective surgical procedures.

 

Adult stem cells are frequently used in medical therapies, for example in bone 3) ___ transplantation. Stem cells can now be artificially grown and transformed (differentiated) into specialized cell types with characteristics consistent with cells of various tissues such as muscles or nerves. Embryonic cell lines and autologous embryonic stem cells generated through Somatic-cell nuclear transfer or dedifferentiation have also been proposed as promising candidates for future therapies. Induced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from adult cells. The iPSC technology was pioneered by Shinya Yamanaka’s lab in Kyoto, Japan, who showed in 2006 that the introduction of four specific genes could convert adult cells into pluripotent stem cells. He was awarded the 2012 Nobel Prize along with Sir John Gurdon “for the discovery that mature cells can be reprogrammed to become pluripotent.“

 

Pluripotent stem cells hold great promise in the field of 4) ___ medicine. Because they can propagate indefinitely, as well as give rise to every other cell type in the body (such as neurons, heart, pancreatic, and liver cells), they represent a single source of cells that could be used to replace those lost to damage or disease. The most well-known type of pluripotent stem cell is the embryonic stem cell. However, since the generation of embryonic stem cells involves destruction (or at least manipulation) of the pre-implantation stage embryo, there has been much controversy surrounding their use. Further, because embryonic stem cells can only be derived from embryos, it has so far not been feasible to create patient-matched embryonic stem cell lines. Since iPSCs can be derived directly from adult tissues, they not only bypass the need for 5) ___, but can be made in a patient-matched manner, which means that each individual could have their own pluripotent stem cell line. These unlimited supplies of autologous cells could be used to generate transplants without the risk of immune rejection. While the iPSC technology has not yet advanced to a stage where therapeutic transplants have been deemed safe, iPSCs are readily being used in personalized drug discovery efforts and understanding the patient-specific basis of disease. Depending on the methods used, reprogramming of adult cells to obtain iPSCs may pose significant risks that could limit their use in humans. For example, if viruses are used to genomically alter the cells, the expression of cancer-causing genes “oncogenes“ may potentially be triggered.

 

In February 2008, scientists announced the discovery of a technique that could remove oncogenes after the induction of pluripotency, thereby increasing the potential use of iPS cells in human diseases. In April 2009, it was demonstrated that generation of iPS cells is possible without any genetic alteration of the adult cell: a repeated treatment of the cells with certain proteins channeled into the cells via poly-arginine anchors was sufficient to induce pluripotency. The acronym given for those iPSCs is piPSCs (protein-induced pluripotent stem cells).

 

A major concern over using stem cells is the risk of tumors: but now a new study shows that It takes a lot of effort to get induced pluripotent stem (iPS) cells to grow into 6) ___ after they have been transplanted into a monkey. The findings will bolster the prospects of one day using such cells clinically in humans. Making iPS cells from an animal’s own skin cells and then transplanting them back into the creature also does not trigger an inflammatory response as long as the cells have first been coaxed to 7) ___ towards a more specialized cell type. Both observations, published in May 2014, Cell Reports, bode well for potential cell therapies.

 

“It’s important because the field is very controversial right now,“ says Ashleigh Boyd, a stem-cell researcher at University College London, who was not involved in the work. “It is showing that the weight of evidence is pointing towards the fact that the cells won’t be rejected.“

 

Pluripotent 8) ___ cells, can be differentiated into many different specialized cell types in culture – and so are touted for their potential as therapies to replace tissue lost in diseases such as Parkinson’s and some forms of diabetes and blindness. iPS cells, which are made by reprogramming adult cells, have an extra advantage because transplants made from them could be genetically matched to the recipient. Researchers all over the world are pursuing therapies based on iPS cells, and a group in Japan began enrolling patients for a human study last year. But work in mice has suggested controversially that even genetically matched iPS cells can trigger an immune 9) ____, and pluripotent stem cells can also form slow-growing tumors, another safety concern. Cynthia Dunbar, a stem-cell biologist at the National Institutes of Health in Bethesda, Maryland, who led the new study, decided to evaluate both concerns in healthy rhesus macaques. Human stem cells are normally only studied for their ability to form tumors in mice – as a test of pluripotency – if the animals’ immune systems are compromised, she says. “We really wanted to set up a model that was closer to 10) ___. It was somewhat reassuring that in a normal monkey with a normal immune system you had to give a whole lot of immature cells to get any kind of tumor to grow, and they were very slow growing.“ Dunbar and her team made iPS cells from skin and white blood cells from two rhesus macaques, and transplanted the iPS cells back into the monkeys that provided them. It took 20 times as many iPS cells to form a tumor in a monkey, compared with the numbers needed in an immunocompromised mouse. Such information will be valuable for assessing safety risks of potential therapies, Dunbar says. And although the iPS cells did trigger a mild immune response – attracting white blood 11) ___ and causing local inflammation – iPS cells that had first been differentiated to a more mature state did not. Although this was the first study to look at undifferentiated iPS cells transplanted back into the 12) ___ they came from, it is not the first primate study to monitor how cells differentiated from iPS cells fare when transplanted. Scientists at Kyoto University in Japan found that monkey iPS cells that had been differentiated into dopaminergic neurons (the type of neuron that dies in Parkinson’s disease) and transplanted into the brain survived for months without forming tumors. Researchers at RIKEN in Kobe, Japan, got similar results when transplanting iPS cells first coaxed into forming retinal pigment epithelial cells, cells that support the photoreceptors at the back of the 13) ___. Neither study observed tumors forming, and both found that transplants are not rejected when animals receive their own cells. However, both of the sites involved normally have a fairly weak capacity to trigger immune responses.

 

Dunbar, by contrast, differentiated iPS cells into bone precursor cells and placed them into small scaffolds just under the skin, a location with a robust immune 14) ___. The transplants did not cause irritation or inflammation, probably because the differentiated cells do not express embryonic proteins absent in mature tissues. By eight weeks, new bone had formed. Almost a year later no tumors had formed, and bone formation persisted.

 

More work is needed because evidence from other studies suggests that the bone precursor cells themselves may damp down the immune system, says Dunbar. She is hoping to repeat these studies using iPS cells that have been coaxed into making heart and liver cells.

Sources: Nature.com, May 16, 2014; Wikipedia

 

ANSWERS: 1) body; 2) blood; 3) marrow; 4) regenerative; 5) embryos; 6) tumors; 7) differentiate; 8) stem; 9) response; 10) human; 11) cells; 12) monkey; 13) eye; 14) response

 

Stem Cells

 

20140527-7

 

Stem cells have an interesting history that has been somewhat tainted with debate and controversy. In the mid-1800s it was discovered that cells were basically the building blocks of life and that some cells had the ability to produce other cells. Attempts were made to fertilize mammalian eggs outside of the human body and in the early 1900s, it was discovered that some cells had the ability to generate blood cells. In 1968, the first bone marrow transplant was performed to successfully treat two siblings with severe combined immunodeficiency. Other key events in stem cell research include:

 

a. 1978: Stem cells were discovered in human cord blood

b. 1981: First in vitro stem cell line developed from mice

c. 1988: Embryonic stem cell lines created from a hamster

d. 1995: First embryonic stem cell line derived from a primate

e. 1997: Cloned lamb from stem cells

f. 1997: Leukemia origin found as hematopoietic stem cell, indicating possible proof of cancer stem cells

 

In 1998, Thompson, from the University of Wisconsin, isolated cells from the inner cell mass of early embryos and developed the first embryonic stem cell lines. During that same year, Gearhart, from Johns HopkinsUniversity, derived germ cells from cells in fetal gonad tissue; pluripotent stem cell lines were developed from both sources. Then, in 1999 and 2000, scientists discovered that manipulating adult mouse tissues could produce different cell types. This meant that cells from bone marrow could produce nerve or liver cells and cells in the brain could also yield other cell types. These discoveries were exciting for the field of stem cell research, with the promise of greater scientific control over stem cell differentiation and proliferation.

 

Below are a few research achievements, that show a history of stem cell research over the past 100 years:

 

1908: The term “stem cell” was proposed for scientific use by the Russian histologist Alexander Maksimov (1874-1928) at congress of hematologic society in Berlin. It postulated existence of hematopoietic stem cells.

 

1960s: Joseph Altman and Gopal Das present scientific evidence of adult neurogenesis, ongoing stem cell activity in the brain; their reports contradict Cajal’s “no new neurons” dogma and are largely ignored.

 

1963: McCulloch and Till illustrate the presence of self-renewing cells in mouse bone marrow.

 

1968: Bone marrow transplant between two siblings successfully treats SCID.

 

1978: Hematopoietic stem cells are discovered in human cord blood.

 

1981: Mouse embryonic stem cells are derived from the inner cell mass by scientists Martin Evans, Matthew Kaufman, and Gail R. Martin. Gail Martin is attributed for coining the term “Embryonic Stem Cell”.

 

1992: Neural stem cells are cultured in vitro as neurospheres.

 

1995: Dr. B.G. Matapurkar pioneers in adult stem-cell research with clinical utilization of research in the body and neo-regeneration of tissues and organs in the body. Received International Patent from US Patent Office (USA) in 2001 (effective from 1995). Clinical utilization in human body also demonstrated and patented in 60 patients (World Journal of Surgery-1999 and 1991).

 

1997: Dr. B.G. Matapurkar’s surgical technique on regeneration of tissues and organs is published. Regeneration of fallopian tube and uterus is published.

 

1997: Leukemia is shown to originate from a hematopoietic stem cell, the first direct evidence for cancer stem cells.

 

1998: James Thomson and coworkers derive the first human embryonic stem cell line at the University of Wisconsin-Madison.

 

1998: John Gearhart (Johns Hopkins University) extracted germ cells from fetal gonadal tissue (primordial germ cells) before developing pluripotent stem cell lines from the original extract.

 

2000s: Several reports of adult stem cell plasticity are published.

 

2001: Scientists at Advanced Cell Technology clone first early (four- to six-cell stage) human embryos for the purpose of generating embryonic stem cells.

 

2003: Dr. Songtao Shi of NIH discovers new source of adult stem cells in children’s primary teeth.

 

2005: Researchers at Kingston University in England claim to have discovered a third category of stem cell, dubbed cord-blood-derived embryonic-like stem cells (CBEs), derived from umbilical cord blood. The group claims these cells are able to differentiate into more types of tissue than adult stem cells.

 

2005: Researchers at UC Irvine’s Reeve-Irvine Research Center are able to partially restore the ability of rats with paralyzed spines to walk through the injection of human neural stem cells.

 

 

20140527-8

Yong Zhao, University of Illinois at Chicago

 

April 2006 Scientists at the University of Illinois at Chicago identified cells from the umbilical cord blood with embryonic and hematopoietic characteristics.

 

August 2006: Mouse Induced pluripotent stem cells: the journal Cell publishes Kazutoshi Takahashi and Shinya Yamanaka.

 

November 2006: Yong Zhao et al. revealed the immune regulation of T lymphocytes by Cord Blood-Derived Multipotent Stem Cells (CB-SCs).

 

October 2006: Scientists at Newcastle University in England create the first ever artificial liver cells using umbilical cord blood stem cells.

 

January 2007: Scientists at Wake Forest University led by Dr. Anthony Atala and Harvard report discovery of a new type of stem cell in amniotic fluid. This may potentially provide an alternative to embryonic stem cells for use in research and therapy.

 

June 2007: Research reported by three different groups shows that normal skin cells can be reprogrammed to an embryonic state in mice. In the same month, scientist Shoukhrat Mitalipov reports the first successful creation of a primate stem cell line through somatic cell nuclear transfer

 

 

20140527-9

Martin Evans, a co-winner of the Nobel Prize in recognition of his gene targeting work.

 

October 2007: Mario Capecchi, Martin Evans, and Oliver Smithies win the 2007 Nobel Prize for Physiology or Medicine for their work on embryonic stem cells from mice using gene targeting strategies producing genetically engineered mice (known as knockout mice) for gene research.

 

November 2007: Human induced pluripotent stem cells: Two similar papers released by their respective journals prior to formal publication: in Cell by Kazutoshi Takahashi and Shinya Yamanaka, “Induction of pluripotent stem cells from adult human fibroblasts by defined factors”, and in Science by Junying Yu, et al., from the research group of James Thomson, “Induced pluripotent stem cell lines derived from human somatic cells”: pluripotent stem cells generated from mature human fibroblasts. It is possible now to produce a stem cell from almost any other human cell instead of using embryos as needed previously, albeit the risk of tumorigenesis due to c-myc and retroviral gene transfer remains to be determined.

 

January 2008: Robert Lanza and colleagues at Advanced Cell Technology and UCSF create the first human embryonic stem cells without destruction of the embryo

 

January 2008: Development of human cloned blastocysts following somatic cell nuclear transfer with adult fibroblasts

 

February 2008: Generation of pluripotent stem cells from adult mouse liver and stomach: these iPS cells seem to be more similar to embryonic stem cells than the previously developed iPS cells and not tumorigenic, moreover genes that are required for iPS cells do not need to be inserted into specific sites, which encourages the development of non-viral reprogramming techniques.

 

March 2008-The first published study of successful cartilage regeneration in the human knee using autologous adult mesenchymal stem cells is published by clinicians from Regenerative Sciences

 

October 2008: Sabine Conrad and colleagues at Tubingen, Germany generate pluripotent stem cells from spermatogonial cells of adult human testis by culturing the cells in vitro under leukemia inhibitory factor (LIF) supplementation.

 

30 October 2008: Embryonic-like stem cells from a single human hair.

 

January 2009: Yong Zhao and colleagues confirmed the reversal of autoimmune-caused type 1 diabetes by Cord Blood-Derived Multipotent Stem Cells (CB-SCs) in an animal experiment.

 

1 March 2009: Andras Nagy, Keisuke Kaji, et al. discover a way to produce embryonic-like stem cells from normal adult cells by using a novel “wrapping” procedure to deliver specific genes to adult cells to reprogram them into stem cells without the risks of using a virus to make the change. The use of electroporation is said to allow for the temporary insertion of genes into the cell.

 

28 May 2009 Kim et al. announced that they had devised a way to manipulate skin cells to create patient specific “induced pluripotent stem cells” (iPS), claiming it to be the ‘ultimate stem cell solution’.

 

11 October 2010 First trial of embryonic stem cells in humans.

 

25 October 2010: Ishikawa et al. write in the Journal of Experimental Medicine that research shows that transplanted cells that contain their new host’s nuclear DNA could still be rejected by the individual’s immune system due to foreign mitochondrial DNA. Tissues made from a person’s stem cells could therefore be rejected, because mitochondrial genomes tend to accumulate mutations.

 

2011: Israeli scientist Inbar Friedrich Ben-Nun led a team which produced the first stem cells from endangered species, a breakthrough that could save animals in danger of extinction.

 

January 2012: The human clinical trial of treating type 1 diabetes with lymphocyte modification using Cord Blood-Derived Multipotent Stem Cells (CB-SCs) achieved an improvement of C-peptide levels, reduced the median glycated hemoglobin A1C (HbA1c) values, and decreased the median daily dose of insulin in both human patient groups with and without residual beta cell function. Yong Zhao’s Stem Cell Educator Therapy appears “so simple and so safe”

 

October 2012: Positions of nucleosomes in mouse embryonic stem cells and the changes in their positions during differentiation to neural progenitor cells and embryonic fibroblasts are determined with single-nucleotide resolution.

 

2012: Katsuhiko Hayashi used mouse skin cells to create stem cells and then used these stem cells to create mouse eggs. These eggs were then fertilized and produced healthy baby offspring. These latter mice were able to have their own babies.

 

2013: First time lab grown meat made from muscle stem-cells has been cooked and tasted.

 

2013: First time mice adult cells were reprogrammed into stem cells in vivo.

 

2013: Scientists at Scotland’s Heriot-Watt University developed a 3D printer that can produce clusters of living human embryonic, potentially allowing complete organs to be printed on demand in the future.

 

2014: Adult mouse cells reprogrammed to pluripotent stem cells using stimulus-triggered acquisition of pluripotency (STAP); a process which involved bathing blood cells in an acid bath (pH 5.7) for 30minutes at 37 ?C.

 

In early 2007, researchers led by Dr. Anthony Atala discovered a new type of stem cell isolated in amniotic fluid. This finding is particularly important because these stem cells could prove to be a viable alternative to the controversial use of embryonic stem cells. Over the last few years, national policies and debate amongst the public as well as religious groups, government officials and scientists have led to various laws and procedures regarding stem cell harvesting, development and treatment for research or disease purposes. The goals of such policies are to safeguard the public from unethical stem cell research and use while still supporting new advancements in the field.

 

In March 2009, President Barack Obama reversed a Bush-era policy which had limited funding of embryonic stem cell research and pledged to develop “strict guidelines” on the research. Under Obama, stem cell research has flourished. Stem cell research has now progressed dramatically and there are countless research studies published each year in scientific journals. Adult stem cells are already being used to treat many conditions such as heart disease and leukemia. Researchers still have a long way to go before they completely control the regulation of stem cells. The potential is overwhelmingly positive and with continued support and research, scientists will ideally be able to harness the full power of stem cells to Treat Diseases that you or a loved one may suffer from one day. Sources:  Cell.com; NIH.gov; Wikipedia

Key Factor in Early Auditory System Development

 

The human ear can detect a wide range of frequencies, from the low rumble of distant thunder to the high-pitched whine of a mosquito. The sensory cells that detect these sounds are called hair cells, named for the hair-like strands that cluster on their tops. Hair cells are spread across a flat surface called the basilar membrane, which rolls up like a carpet and tucks into a snail shell-shaped structure in the inner ear called the cochlea.

 

Part of what accounts for our remarkable range of hearing is that hair cells have different specializations. Rather than working to sense all audible frequencies, each of our roughly 16,000 hair cells is dedicated to a narrow range. Hair cells are ordered along the basilar membrane’s length, or axis, according to the frequency they detect. Those that sense low pitches are at one end and those that detect high-frequency sounds are at the opposite end. The cells in between, step through the mid-range pitches.

 

This spatial arrangement of hair cells on the basilar membrane, also known as the tonotopic map, has been known for years. What hasn’t been known is how each hair cell learns to “hear“ specific frequencies.

 

According to an article published online in the May 20, 2014 issue of Nature Communications, a molecule has been uncovered in an animal model that acts as a key player in establishing the organization of the auditory system. The molecule, a protein known as Bmp7, is produced during embryonic development and acts to help sensory cells find their ultimate position on the tonotopic map, which is the fundamental principle of organization in the auditory system. The tonotopic map groups sensory cells by the sound frequencies that stimulate them. The study is the first to identify one of the molecular mechanisms that determines position. An additional study, appearing in the same edition, revealed that another signaling molecule, retinoic acid, acts in concert with Bmp7 to position cells.

 

According to the authors, during development, hair cells at each position along the axis need to figure out where they are so that they know what frequency they should be listening to; this is called positional identity. As a result, the goal of the study was to determine how hair cells figure out their position.

 

The authors suspected that, like numbers on a ruler, the positions of hair cells along the basilar membrane were marked by stepwise differences in the level of a signaling molecule that would determine position. Molecular concentration gradients of this sort have been shown to steer the positioning of other cell types in the body during development. To see if such a signaling molecule might be involved in the structural organization of the cochlea, the authors examined the basilar papilla from six-day old chick embryos. The basilar papilla in chickens is similar to the cochlea in mammals, with hair cells arranged along the length of its basilar membrane in a similar fashion according to frequency. The authors reasoned that if a molecular concentration gradient were involved in positioning hair cells, the molecule’s level would be higher at one end of the basilar papilla than the other.

 

When the basilar papilla was split in half looking for molecules, one stood out because of the striking difference in its level between the two halves of Bmp7, the signaling protein known to play a role in the development of bone and kidneys. Additional experiments revealed a gradual gradient in the level of Bmp7 across the length of the basilar papilla. It was next shown that Bmp7 promotes the development of low-frequency-sensing hair cells. When developing basilar papillas were bathed in a solution containing Bmp7, it was observed that all the hair cells developed characteristics of low-frequency-sensing hair cells, even those at the high-frequency end. These findings suggest that during embryonic development, high levels of Bmp7 at one end of the basilar papilla signal the formation of low-frequency-sensing hair cells. Decreasing levels of Bmp7 along the length of the basilar papilla map with a gradual change towards tuning to higher frequencies.

 

In future work, the authors aim to use a mouse model to understand the role of Bmp7 in specifying the positioning of hair cells in a mammalian organism. Bmp7 is known to be present in cells of the inner ear in mammals, suggesting a possible role for the molecule in tuning. The researchers hope to be able to outline its precise role in patterning parts of the auditory system.

 

According to the authors, complex sounds like music or speech that consist of many different frequencies are split into individual frequencies in the ear, processed through separate channels, and then reassembled in the brain. By revealing the part played by Bmp7 in patterning hair cells in the inner ear, a broader role for the molecule in the auditory system as a whole may have been uncovered.

 

High Cholesterol Levels Linked To Lower Fertility

 

Cholesterol is a waxy, fat-like substance found in all cells of the body. It’s used to make a number of substances, including hormones and vitamin D. High blood cholesterol levels typically do not cause any signs or symptoms, but can increase the chances for heart disease.

 

According to an article published online in the Journal of Endocrinology and Metabolism (20 May 2014), high cholesterol levels may impair fertility in couples trying to achieve a pregnancy. Couples in which each partner had a high cholesterol level took the longest time to reach pregnancy. Moreover, couples in which the woman had a high cholesterol level and the man did not, also took longer to achieve pregnancy when compared to couples in which both partners had cholesterol levels in the acceptable range.

 

For the current analysis, the authors studied couples who were not being treated for infertility but who were trying to conceive a child. A total of 501 couples from four counties in Michigan and 12 counties in Texas were enrolled from 2005 to 2009. The couples were part of the Longitudinal Investigation of Fertility and the Environment (LIFE) study, established to examine the relationship between fertility and exposure to environmental chemicals and lifestyle. The women taking part in the study ranged from 18 to 44 years of age, and the men were over 18. The couples were followed until pregnancy or for up to one year of trying.

 

Study volunteers provided blood samples, which were tested for free cholesterol. The measurement of free cholesterol is used in research and differs from the cholesterol test given in doctors’ offices. Cholesterol tests administered by physicians measure the cholesterol subtypes: HDL cholesterol, LDL cholesterol and triglycerides. For the study, the authors relied on a test to measure the total amount of cholesterol in the blood, but which did not distinguish between cholesterol subtypes. The authors theorized that blood cholesterol might be related to fertility as the body uses cholesterol to manufacture hormones like testosterone and estrogen.

 

For the study, the authors calculated the probability that a couple would achieve pregnancy by using a statistical measure called the fecundability odds ratio (FOR). The measure estimates couples’ probability of pregnancy each cycle, based on their serum cholesterol concentrations. Results showed that on average, those couples in which the female did not become pregnant during the study duration had the highest free cholesterol levels. In general, high free cholesterol levels were correlated with longer times to pregnancy and lower fecundability odds ratios. Couples in which the female had a high cholesterol level and the male did not also took longer to achieve pregnancy when compared to couples in which both partners had cholesterol levels in the acceptable range. In their analysis, the study authors accounted for potential racial differences, as well as differences by age, body mass index, and education. Among study participants, Hispanic males had the highest free cholesterol levels.

 

TARGET HEALTH excels in Regulatory Affairs. Each week we highlight new information in this challenging area.

 

FDA Approves First Molecular (Gene-Based) Test to Determine Red Blood Cell Types in Transfusion Medicine

 

The surfaces of red blood cells display minor blood group antigens in addition to the major ABO blood group antigens. Some people develop antibodies to non-ABO antigens following transfusion or pregnancy. This is especially true in people who may receive repeated blood transfusions, such as those with sickle cell disease. The development of such antibodies can cause red blood cell destruction if red blood cells with the corresponding antigens are later transfused. Development of antibodies to non-ABO antigens can be prevented by selecting blood that is better matched to the patient?s non-ABO antigens. In addition, when a potential transfusion recipient has a known antibody that causes red blood cell destruction, red blood cells that are negative for the corresponding antigen must be found. The identification of red blood cell antigens has traditionally been performed by serological typing. This involves testing blood with reagents (antisera) that are specific for the antigens for which the blood is being tested. However, specific antisera may be scarce or unavailable.

 

The FDA has approved the Immucor PreciseType Human Erythrocyte Antigen (HEA) Molecular BeadChip Test – the first FDA-approved molecular assay used in transfusion medicine to assist in determining blood compatibility. The assay can be used to determine donor and patient non-ABO/non-RhD (non-ABO) red blood cell types in the United States.

 

The Immucor PreciseType HEA Molecular BeadChip Test works by detecting genes that govern the expression of 36 antigens that can appear on the surface of red blood cells. The test uses thousands of coded beads that bind with the genes coding for non-ABO red blood cell antigens that are present in a blood sample. A light signal is generated from each bead that has captured a specific gene. Accompanying computer software decodes the light signals and reports which antigens are predicted to be present on the red cells based on the genes that are detected.

 

A study was conducted to compare the typing results of the PreciseType HEA Molecular BeadChip Test with licensed serological reagents and DNA sequencing. The results demonstrated comparable performance between the methods.

 

The product was brought before the FDA’s Blood Products Advisory Committee on March 18, 2014. After reviewing the relevant information, the committee concluded that the data provided reasonable assurance that the Immucor PreciseType HEA Molecular BeadChip Test is safe and effective for its intended use.

 

The Immucor PreciseType HEA Molecular BeadChip Test is manufactured by BioArray Solutions Ltd. of Warren, New Jersey.

 

Asparagus Soup

20140527-1

©Joyce Hays, Target Health Inc.                             Ready to ladle into bowls

 

Asparagus is still in season, so I wanted to take advantage of that by experimenting with a new soup recipe. Here in Manhattan Spring has been glorious and cool, so hot soup remained a little pleasure. I made this soup a couple of times while my husband was away on business. The first time, I put more than a pinch of cayenne, resulting in a near disaster. I had one bowl and gave the rest away. I also discovered that one bunch of asparagus was not enough to give a full rich flavor. I tried two bunches and then three and found that three bunches was the best for this recipe, and not asparagus by the pound, unless your local grocer sells small bunches. I also included celery root, because it’s healthy and adds a certain depth to any soup or stew, like a potato, only more healthy

 

Ingredients

6 cans chicken broth (5 calories per broth serving, in low-fat, low sodium version)

1-3 pounds fresh, locally-grown asparagus or 3 bunches (figure about 1 pound per bunch

1 onion, in thick slices

2 cloves garlic, juiced

1 carrot, cut into chunks

4 whole stalks celery

1/4 celery root

Zest of 1/2 lemon

1 teaspoon turmeric

Pinch salt

Pinch black pepper

Pinch cayenne (optional)

1/2 fresh lemon squeezed

 

 

20140527-2

©Joyce Hays, Target Health Inc.                        Delicious fresh ingredients

 

20140527-3

©Joyce Hays, Target Health IncYou can weight each bunch at a time, if you care about the weight. However, a guesstimate is fine.

 

 

20140527-4

©Joyce Hays, Target Health Inc.

 

After simmering all veggies in chicken stock (or broth from a can), till soft (20 to 30 minutes), remove from stock with a large slotted spoon and put into a bowl. Next, and in phases, fill your food processer 1/2 to 3/4 full of the veggies and pulse until everything is pureed. After each pulsing, use a spatula to scrape the pureed veggies out, and back into the chicken stock. Now, sample the soup, and adjust seasonings to your taste. Go easy on the cayenne (optional). You don’t want to overpower the fresh taste of the asparagus. Add the fresh lemon juice a little at a time, sampling each time, until you get it right. I love the lemon, so the juice of 1/2 lemon works for me.

 

 

20140527-5

©Joyce Hays, Target Health Inc. Serve hot or cold with a thin slice of lemon, or a dollop of creme fraiche (or sour cream), or croutons

 

 

20140527-6

©Joyce Hays, Target Health Inc.

 

Because my dear hub had been traveling on business for 10 days, one of his “welcome home“ treats, was to break open this lovely red Tuscan wine. A little pricey, but hey, if not now, when? If you like complex flavors swirling on your tongue, from start to finish, I think you’ll find that, with this 2010 Ornellaia. BTW, we’re not investors in this vineyard, just interested in new taste experiences.

 

We started dinner toasting with this wine; then came the asparagus soup with some Turkish bread, I had left-over and heated. I had the soup with lemon slice, he preferred a dollop of sour cream. We had hummus with the Turkish bread and freshly made kale patties with an avocado topping. Jules had just come home, so hunger was not an issue . . . these light veggie dishes were just right and the special wine was perfect for the occasion. We had my fresh (pureed) blueberry/yogurt/sugar-free jello/wheat germ dessert and left the table glowing. Nice to have him back home!

 

We wish our friends and colleagues a relaxing long weekend, with serious thoughts and appreciation for our men and women who volunteer for military service, to protect us and our hope to preserve democracy.

 

Here’s a toast to our, “Sweet land of liberty“ may it always be so.

 

Bon Appetit !

 

Regulatory Affairs Expertise at Target Health

 

No matter what happens in the discovery phase, innovators of drugs, devices and biologics will always need to amass data and have expertise in regulatory affairs. While Target Health is well-known in the data and software space, and is the champion of the paperless clinical trial, we are also quite known and respected in the regulatory space. Our esteemed head of regulatory affairs is Glen Park, PharmD, and yes, he is the only Park at Target Health who is not of Korean descent. Glen joined us 9 years ago and has been a major asset of our company. Glen had over 20 years of experience at AVENTIS PHARMA (FORMERLY HOECHST MARION ROUSSEL), SANKYO PHARMA DEVELOPMENT and the UNIVERSITY OF IOWA, and now leads the regulatory team at Target Health which represents 36 clients at FDA. The following are major Target Health accomplishments where we made significant contributions to the regulatory approval process:

 

1. NDA  –  Gaucher Disease (orphan disease)

2. NDA  –  Cystic Fibrosis (orphan disease)

3. NDA  –  Head Lice (2)

4. NDA  –  Emergency Contraception

5. BLA  –  Auto-inflammatory diseases (orphan disease)

6. PMA  –  Surgical Adhesions

7. PMA  –  Periodontal Disease

8. PMA  –  Companion Diagnostic

9. 510(k) – Heart Rate Variability (2)

 

In addition to regulatory approvals, we obtained orphan drug designation for the following indications:

 

1.   Gaucher Disease – NDA Approved

2.   Hereditary angioedema – NDA Approved

3.   Debridement in hospitalized patients with 3rd degree burns – EMA approved

4.   Growth Hormone

5.   Scleroderma

6.   Alagille Syndrome

7.   Burn progression in hospitalized patients

8.   Caries prevention, head and neck cancer

9.   Cushing’s syndrome secondary to ectopic ACTH secretion

10. Edema-related effects in hospitalized patients with 3rd degree burns

11. Osteonecrosis of the jaw

 

As a biologist, Dr. Mitchel is fascinated by the fauna and flora of Central Park, the heart and lungs of New York City. How brilliant it was to put a park right in the middle of it all. Every week we will try to share the breath of wildlife in NYC.

 

Springtime in NYC – Central Park ©Target Health Inc.

20140519-13

Nesting Pair of Canadian Geese                                               Black Crowned Night Heron

 

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

 

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

 

Joyce Hays, Founder and Chief Editor of On Target

Jules Mitchel, Editor

Battlefield Medicine

20140519-10

Arterial bleed controlled by a tourniquet

 

20140519-11

Practicing IV procedures in dark conditions.

 

20140519-12

This photo shows the back of an armored personnel carrier set up as an ambulance. Given that this vehicle is designed to withstand attack from rockets, much of the equipment is concealed from view.

 

A medical corps is generally a military branch or officer corps responsible for medical care for serving military personnel. Such officers are typically military physicians. Since 90% of combat 1) ___ occur on the battlefield before the casualty ever reaches a medical treatment facility, Tactical Combat Casualty Care (TCCC) focuses on training major hemorrhaging, and airway complications such as a tension-pneumonthorax. This has driven the casualty fatality rate down drastically since the Vietnam conflict to less than 9%. Today, TCCC is quickly becoming the standard of care for the tactical management of combat casualties within the Department of Defense and is the sole standard of care dually endorsed by both the American College of Surgeons and the National Association of EMT’s for casualty management in tactical environments. TCCC is built around three definitive phases of casualty care: 1) Care Under Fire; 2) Tactical Field Care; 3) Tactical Evacuation Care.

 

Combat medics (also known as medics) are military personnel who have been trained to at least an EMT-Basic level (16 week course in the U.S. Army), and who are responsible for providing first 2) ___ and frontline trauma care on the battlefield. They are also responsible for providing continuing medical care in the absence of a readily available physician, including care for disease and battle injury. Combat medics are normally co-located with the combat troops they serve in order to easily move with the troops and monitor ongoing health. An eight-year process to transform the training and skills of Army combat medics culminated recently, as all members of the old 91B Military Occupational Specialty (MOS) became qualified as 68W Healthcare Specialists. A group of past and present leaders of Army Medicine gathered at Fort Sam Houston, Texas, to celebrate this event. This Corp was originally established in 1887.

 

68W medics all qualify as emergency 3) ___ technicians. They are trained in advanced airway skills, hemorrhage control techniques, shock management and evacuation. All Soldiers in the new MOS must re-certify their skills every two years, and must earn 72 hours of continuing education credits during those two years. Retired Lt. Gen. James B. Peake, former Army surgeon general and former Secretary of the Department of Veterans Affairs, spoke recently, “When you see a Soldier without a leg, and with an external fixator on his other leg, and he says, ?I was lucky that day because I was with my medic in my vehicle, that’s why I’m here,’ that’s what it boils down to,“ Peake said. Peake began the process that led to the 68W MOS when he commanded the Army Medical Department Center and School. He discussed the process of improving training, adding simulation technology and re-engineering the second-largest MOS in the Army. “This was an opportunity to take medical care much farther forward than we had been able to before, with a higher level of technical enablement and skill,“ Peake said. Peake added that the process of improving training continues. “It is made better by continually listening to Soldiers, continually shaping the way that training is done,“ he said. “When you talk to those who have earned the Silver Star or the Distinguished Service Cross, and we’ve had those in medics, they say, ?I was just doing my job. I was just doing what I was trained to do,’“ he said

 

Soldiers of the 232nd Medical Battalion stage practice events, which demonstrate the 68W’s advanced ability to save 4) ___ on the battlefield. Soldiers portray a modern squad treating a thigh wound. The 68W quickly applied a Combat Application Tourniquet and prepared the casualty for evacuation by a Stryker armored ambulance. The 68W medic’s patient was well on his way to advanced care at a combat support hospital. On today’s modern battlefield, medical care has made remarkable strides in saving the lives of the wounded. Soldiers and Marines who would have perished in yesterday’s wars are returning home in spite of devastating injuries. Our troops are equipped to stabilize their own injuries and those of their buddies, even in the absence of medical personnel. Medics and corpsmen are armed with advances in technology as they emerge, and our experience helps set new standards of trauma 5) ___.

 

Front-loading definitive medical care at the point of injury makes obvious sense. The patient’s own well-oxygenated blood, circulating in a system of relatively intact blood vessels, is the gold standard of perfusion. Does it make sense to lie still on the battlefield, bleeding and yelling “Medic!“ when the means exist for the injured to stop his own bleeding? Does it make sense for the casualty with a patched-up circulatory system to arrive at the hospital without an airway, suffering from irreversible hypoxic 6) ___ injury? Of the many advances in battlefield medicine, some of the most beneficial are also the simplest. Consider the tourniquet. The military has adopted newer tourniquets, manufactured with a sturdy nylon strap and an attached windlass instead of a stick. Today, every soldier is issued this one-handed 7) ___ to apply to their own injured limbs, stopping the loss of blood before significant hemorrhage occurs. These are much quicker and simpler to apply than yesterday’s homemade strip of cloth and a stick foraged from the woods. When penetrating trauma with significant 8) ___ occurs, the combat medic approach is often defined by the simultaneous efforts of more than one EMT. In this arrangement, one rescuer might well be spared to do nothing but provide direct pressure, elevation and squeeze a pressure point, while others tend to the airway. In the case of the military medic, however, they’re often presented with multiple casualties, many of whom may simultaneously suffer from severe penetrating extremity trauma with uncontrolled hemorrhage and airway compromise. Battlefield triage differs as well: sometimes, it’s necessary to return the most troops to the fight as quickly as possible in order to prevent the loss of additional lives. It is sometimes necessary to treat and return the lesser-injured to the fight first, so that they may defend the medics, while they attend to the more serious casualties. There are even times when the combat 9) ___ may save the most lives by taking up his own weapons and jump into the fight personally. This is a vastly different proposition from the civilian EMT staging at a safe distance while law enforcement makes the scene safe. In this setting, rapid application of the tourniquet makes good sense. The newer tourniquets are quick to apply, and every soldier carries one. Even with a compromised 10) ___, patients can survive a brief hypoxic event. Most can survive for the time it takes to apply the tourniquet. In deciding whether to address airway or bleeding first, the significance of the injury is considered. While penetrating trauma to an artery may require the rapid application of a tourniquet, one is often not needed in the case of a slower venous bleed. If there are numerous critical patients awaiting medical attention, however, the tourniquet may be the quickest way to stabilize the patient with the venous bleed, permitting a medic to move on to the next case and ultimately save the most life.

 

An experienced U.S. medic recounts:

After a 20-year career in EMS, during which I went on to become a registered nurse and worked part-time in an emergency department, I was deployed to Ramadi, Iraq, as a combat medic with the Vermont National Guard. Aside from my weapons, I found my three most useful tools were tourniquets, the new trauma dressings with built-in elastic bandages, and my laryngoscope. The new one-handed tourniquets are designed to be used by the casualty, and every soldier has one. When I was in Iraq, however, we did not have these in sufficient quantity to use them frequently on other people. Instead, we used simple ratchet straps cut down to size. These are inexpensive and available at any neighborhood hardware store. While they require two hands to apply, they are effective at controlling bleeding and cheap enough to be disposable. My next favorite innovation was the “Israeli“ dressing, consisting of a thick gauze pad sewn into an elastic bandage. Developed and manufactured in Israel, it is remarkably effective, simple to apply and inexpensive to manufacture. The thick gauze is held tight to the injury by the attached bandage. The more significant the hemorrhage, the tighter the bandage is applied. There were other tools at our disposal. The simple tampon does a phenomenal job of stopping the bleeding in a bullet hole or stab wound. The Asherman Chest Seal comes with a flutter valve and is used for sucking chest wounds, with or without a 14-gauge IV needle to decompress a pneumothorax. In addition to the traditional IV catheters and tubing, the military medic carries a spring-loaded device called a FAST1 to initiate intraosseous infusions in the upper part of the adult sternum when venous access is impossible.

 

The fluids we carried were also different. Subscribing to the logic of controlled hypotension, we no longer ran large volumes of Ringer’s lactate wide open in every case of trauma. I carried equal quantities of normal saline and Ringer’s lactate, knowing the NS was compatible with blood products to be used later and more useful in managing heat casualties. Farther from the hospitals, medics might use heat-starch, a hypertonic starch-based solution designed to draw interstitial fluid into the circulatory system and keep it there longer, thus providing more effective fluid volume replacement per liter of IV fluid administered. This is especially useful when medics must carry supplies over long distances in rucksacks. Water is heavy. Then there was QuikClot, a powder that undergoes an exothermic reaction in the presence of 11) ___, effectively cauterizing wounds it’s poured into. We also carried HemCon bandages, which are fabricated from chitosan and designed to stop bleeding by adhering to wounds. Both of these tools were expensive, in short supply and we were concerned about potential complications such as burns and foreign-body emboli in the bloodstream.While we carried these tools for hemorrhage that couldn’t be controlled through other means, I never used either of them.

 

While control of major bleeding was an obvious necessity, it was also imperative to provide definitive and reliable airways. In the civilian sector, we might have enough medical personnel to spare a rescuer who does nothing but attend to the airway, but in combat this is not always the case. The combat medic often has to give the patient their best chance of survival and move on to the next casualty. Just as in the civilian sector, there are a variety of tools to accomplish that task.

 

Traditionally, medical personnel did not carry weapons and wore a distinguishing red 12) ___, to denote their protection as non-combatants under the Geneva Convention. This practice continued into World War II. However, the enemies faced by professional armies in more recent conflicts are often insurgents who either do not recognize the Geneva Convention, or do not care, and readily engage all personnel, irrespective of non-combatant status. For this reason, most modern combat medics are armed combatants who do not wear distinguishing markings.Combat Medics in the United States Army and United States Navy Hospital Corpsman are virtually indistinguishable from regular combat troops, except for the extra medical equipment they carry. The colloquial form of address for a Hospital Corpsman is “Doc.“

 

ANSWERS: 1) deaths; 2) aid; 3) medical; 4) lives; 5) care; 6) brain; 7) tourniquet; 8) hemorrhage; 9) medic; 10) airway; 11) blood; 12) cross

Dominique Jean Larrey (1766 1842)

20140519-7

Dominique Jean Larrey was a French surgeon in Napoleon’s army and an important innovator in battlefield medicine.

 

Larrey was born in the little village of Beaudean, in the Pyrenees. Larrey was orphaned at the age of 13 and then raised by his uncle Alexis, who was chief surgeon in Toulouse. After serving a 6-year apprenticeship, Larrey went to Paris to study under the great Desault, who was chief surgeon at the Hotel-Dieu de Paris. However, his studies were cut short by war.

 

Larrey was surgeon-in-chief of the Napoleonic armies from Italy in 1797 to Waterloo in 1815. During this time, he initiated the modern method of army surgery, field hospitals and the system of army ambulance corps. After seeing the speed with which the carriages of the French flying artillery maneuvered across the battlefields, Larrey adapted them as Flying Ambulances for rapid transport of the wounded and manned them with trained crews of drivers, corpsmen and litter bearers. Larrey also increased the mobility and improved the organization of field hospitals, effectively creating a forerunner of the modern MASH units.

 

Larrey established a rule for the triage of war casualties, treating the wounded according to the seriousness of their injuries and urgency of need for medical care, regardless of their rank or nationality. Soldiers of enemy armies, as well as those of the French and their allies, were treated. Before Larrey’s initiative in the 1790s, wounded soldiers were either left amid the fighting until the combat ended or their comrades would carry them to the rear line. Larrey was made a Commandeur of the Legion d’Honneur on 12 May 1807, and was the a favorite of the Emperor, who commented, “If the army ever erects a monument to express its gratitude, it should do so in honor of Larrey.“ Larrey was ennobled as a Baron on the field of Wagram in 1809.

 

In 1811, Baron Larrey co-led the surgical team that performed a pre-anesthetic mastectomy on Frances Burney in Paris. Her detailed account of this operation gives insight into early 19th century doctor-patient relationships, and early surgical methods in the home of the patient.

 

At Waterloo in 1815, Larrey’s courage under fire was noticed by the Duke of Wellington who ordered his soldiers not to fire in his direction so as to “give the brave man time to gather up the wounded“ and saluted “the courage and devotion of an age that is no longer ours“?. Larrey was taken prisoner by the Prussians and condemned to death. However, he was recognized by one of the German surgeons, who pleaded for his life. Perhaps partly because Larrey had saved the life of General Gebhard Leberecht von Blucher, Furst von Wahlstatt, Prussian General Blucher’s son, when he was wounded and taken prisoner by the French, Larrey was pardoned, invited to Blucher’s dinner table as a guest and taken back to France under escort. Larrey devoted the remainder of his life to writing and to a civilian medical career; he died on July 25, 1842 in Lyon.

 

Often considered the first modern military surgeon, Larrey’s writings are still regarded as valuable sources of surgical and medical knowledge and have been translated into all modern languages.

 

20140519-8

An illustration showing a variety of wounds from the Feldbuch der Wundarznei (Field manual for the treatment of wounds) by Hans von Gersdorff, (1517). Editor’s note: We’ve come a long way from brutal warfare, or have we? Give me intelligent negotiations that persevere and loyal allies, any day.

 

20140519-9

Statue of Larrey at Val-de-Grace

 

His statue in bronze, as sculpted by David d’Angers in 1843, is standing in the courtyard outside the Val-de-Grace military hospital.

Next Page →