The Science of Support: Darlene E. and James “Jim” B. McCord

Darlene E. and James “Jim” B. (1969 B.S., 1972 M.A., 1974 Ph.D.) McCord believe in the power of character and commitment. These qualities are what inspired the two to form the McCord Foundation, which has made a generous gift of $75,000 for the new P. Sue Beckwith, M.D., Boathouse. They’re also the guiding principles by which the couple lives.

“This contribution is about Iowa’s women rowers,” says Darlene McCord. “It’s about their commitment to rowing, to the team, to the University. We value this kind of dedication, and we wanted to make a gift in recognition of it.”

It’s no surprise that the McCords would want to recognize such perseverance and hard work. The same values helped them establish McCord Research, an Iowa-based corporation that researches and develops high-quality products for wound and skin care. Darlene McCord — a biochemist with a Ph.D. degree from the University of California at Berkeley who specializes in the chemistry of skin-product formulation — is the company’s senior researcher, and Jim McCord is the director of business development. Prior to this, Jim McCord was dean at East Los Angeles College and Los Angeles Southwest College.

Together, the McCords are members of The Presidents Club, which recognizes the UI’s highest-level contributors, and they have used their professional success to give back generously to others — including Iowa’s women rowers. “Whether you’re a scientist or an athlete, you must persevere to reach that goal line,” says Darlene McCord. “You have to reach for something deep inside of you and keep striving. We hope this gift will help these young women do that.”

Jim McCord admits that before meeting with Head Coach Mandi Kowal, neither he nor his wife knew much about the rowing team’s pressing need for a new facility. Now, they understand just what a difference their gift — which will name a dock at the new boathouse — will make for these UI athletes.

“We hope this will give the coach a way to attract and retain a new generation of women rowers,” says Jim McCord. “It’s amazing that Coach Kowal has done as well as she has, given the resources she’s had to work with in the past.”

Darlene McCord agrees: “It’s all about the coach and her players — and their amazing level of teamwork. We hope our foundation’s gift will tell these athletes: ‘We support you. We respect you. You represent the UI with dignity and pride — and that deserves recognition.’”

Thanks to the vision and generosity of contributors like the McCords, current and future generations of UI women rowers will be able to show their Iowa pride on the water — and in the boathouse.

Darlene McCord – Cell Death and Proliferation

Darlene McCord – There are two distinct mechanisms for cell death. Apoptosis is the result of “normal” or programmed cell death. Through this physiological process cells are routinely eliminated, giving balance to the proliferation of new cells. During apoptosis the outer membrane of the cell forms “bubbles” known as blebs. The content of the cells becomes incased in the blebs. The blebs separate from the cell and are digested by nearby cells or macrophages. This orderly process greatly reduces toxicity to surrounding cells.

Necrosis is the other form of cell death. This is not a programmed event and is known as “accidental” death. This pathological process occurs when cells are exposed to extreme stress, chemical insult, and resultant free radical damage. The early stages of necrosis involve a swelling of the cell called oncosis. During oncosis the cell and its organelles begin to swell due to an exchange in the cell’s potassium to sodium ratios. Necrosis, after the oncosis stage, is an explosive event where the cells contents stream directly into the surrounding cells environment causing damage and an immune response.

Darlene McCord – The Use of Olivamine – Lymphadema Case Study

DV is a 54 year old male weighing 455 pounds with a body mass index greater than 60. He presents with severe localized lymphedema and multiple scaly lesions to the abdominal pannus. He experienced severe skin manifestations including maceration, pain, edema, erythema, and a bacterial infection. He was placed on systemic antibiotics and the Olivamine containing skin care products. DV experienced a significant reduction in skin symptoms after only 8 days.The skin care regimen included cleansing lotion, zinc protectant paste, dimethicone/silicone barrier and the antifungal cream. Over time, the lesions resolved completely, but left him with a darkly discolored, though healthy, abdominal pannus. His chronic symptoms were controlled and his quality of life improved with ongoing use of the Olivamine containing skin care products.

Dr. Darlene McCord

Dr. Darlene McCord – new website

I would like to invite everyone to visit my new website www.darlene-mccord.com

Dr. Darlene McCord

Darlene McCord Antioxidants

The outermost layer of the skin, the stratum corneum, is metabolically active and requires antioxidants and specific nutrients to maintain its integrity and proper function. Topically applied antioxidants reduce free radicals in skin cells and substantially inhibit the biochemical cascades responsible for infected and inflamed skin. There is an expressed concern in the scientific community that oral antioxidants may reduce oxidizing free radicals created by radiotherapy. However, there is significant evidence that exogenous antioxidants produce beneficial effects in numerous cancer cell lines. Multiple animal and human studies have demonstrated an increased effectiveness of cancer therapeutic agents, as well as decreased adverse effects, when given concomitantly with topical antioxidant application.

One of the most effective antioxidants in the terms of free radical scavenging is 3,4-dihydroxyphenyl ethanol or hydroxytyrosol (HT). HT is a simple phenol found predominantly in the aqueous fraction of olive pulp. HT application has been found to prevent both radiation-induced protein damage and radiation-induced oxidative DNA damage. The protective effects provided by HT are relevant to the radiation-induced DNA damage manifested by single- and double-strand breaks in epidermal and dermal skin cells. Furthermore, several studies have shown that HT inhibits leukocyte and macrophage activation, as well as their subsequent infiltration into epidermal and dermal skin cells. HT’s modulation of immune function helps reduce the inflammatory processes associated with radiation dermatitis.

n-3 and n-6 Polyunsaturated Fatty Acids (PUFAs)

The stratum corneum is composed of epidermal cell remnants surrounded by a combination of biological lipids. The epidermal cells producing these remnants require certain amino acids to sustain stratum corneum formation, while the lipid barrier requires specific PUFAs to maintain stratum corneum integrity. A mixture of sphingolipids, cholesterol, and free fatty acids forms the intercellular membrane bilayers of the stratum corneum which regulate barrier function. PUFAs have also been shown to reduce or prevent numerous side effects associated with radiotherapy, including radiation dermatitis.

In particular, linolenic (n-3) and linoleic (n-6) PUFAs were found to protect against radiation dermatitis while potentiating radiation treatment via lipid peroxidation. The fatty acids’ effect on tumor growth depends on the balance between n-3 and n-6 PUFAs and antioxidants. The proper formulation of potent antioxidants, n-3 and n-6 PUFAs significantly enhances radiotherapy while preventing fatty acid-induced oxidative stress on epidermal and dermal skin cells. PUFAs play important roles as regulators of the complex inflammatory processes established shortly after radiation-induced skin injury. PUFAs exert their functions in the form of protective phospholipids anchored in epidermal cell membranes or as soluble lipoic mediators of the inflammatory response. Linolenic n-3 fatty acids specifically inhibit proinflammatory interleukin-1, interleukin-6 and tumor necrosis factor-alpha (TNFα) production. Modulating the balance of lipid inflammatory mediators is an extremely valuable treatment for inflammatory skin disorders such as radiation dermatitis. Both n-3 and n-6 PUFAs balance lipid mediators and improve the reconstitution of epithelial integrity following skin injury.

There exist numerous n-3 and n-6 PUFA sources, several of which significantly protect against radiation-induced tissue damage. Canola oil has been reported as being one of the most potent antimutagenic compounds available for topical administration. Canola oil induces intracellular oxidative stress and apoptosis in human cancer cells while inhibiting inflammatory leukocyte activity and subsequent skin irritation. Similarly, safflower oil protects against normal cell damage. Olive oil is another PUFA that has been shown to exhibit substantial anticancer and antioxidative effects. In addition, olive oil specifically prevents radiation-induced skin injury by protecting normal DNA and sustaining skin cell homeostasis. Altogether, the proper balance of certain PUFAs provides important protection against radiation dermatitis.

Dr. Darlene McCord

Darlene McCord – Pathogenesis

Pathogenesis
The macrovascular and microvascular complications of diabetes are closely related to hyperglycemia and oxidative stress, which is when cells fail to detoxify the reactive oxygen species (ROS) produced during metabolism. Four hypotheses have been proposed to explain how hyperglycemia causes complications: 1) increased polyol pathway flux, 2) increased intracellular formation of advanced glycation end-products (AGE), 3) activation of protein kinase C (PKC) isoforms, and 4) increased flux through the hexosamine pathway.

A unifying concept is that hyperglycemia-induced mitochondrial superoxide overproduction activates these 4 pathways. Excess superoxide partially inhibits the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) thereby diverting upstream metabolites from glycolysis to pathways of glucose over-utilization. Superoxide anion achieves this by causing DNA strand breaks that result in activation of poly ADP ribose polymerase (PARP) which in turn ribosylates and deactivates GAPDH. By preventing their metabolism, this process increases energy substrates resulting in increased flux of dihydroxyacetone phosphate (DHAP) to diacylglycerol (DAG), an activator of PKC, and of triose phosphates to methylglyoxol, which is the main intracellular AGE precursor. Increased flux of fructose-6-phosphate to UDP-N-acetylglucosamine in the hexosamine pathway increases modification of proteins by O-linked N-acetylglucosamine and increased glucose flux through the polyol pathway consumes the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) and depletes GSH (reduced glutathione, a natural potent anti-oxidant).

Several mechanisms have been postulated to explain why increasing the polyol pathway flux is detrimental. These are sorbitol-induced osmotic stress, decreased (Na++K+) ATPase activity, increased cytosolic NADH/NAD+ and decreased cytosolic NADPH.

Activation of the hexosamine pathway results in intracellular glycosylation and donation of N-acetyl glucosamine to serine and threonine residues of transcription factors such as Sp1 resulting in increased production of factors such as plasminogen activator inhibitor-1 (PAI-1) and transforming growth factor beta 1 (TGF-beta 1).5

Production of intracellular AGEs damages target cells by three mechanisms. Intracellular proteins modified by AGEs have altered function (like neurotropism, axonal transport, and gene expression). Secondly, extra-cellular matrix components modified by AGE precursors interact abnormally with other matrix components and with the receptors for matrix proteins (integrins) on cells. Thirdly, plasma proteins modified by AGE precursors bind to AGE receptors (RAGE) on endothelial cells, mesangial cells, and macrophages inducing receptor-mediated production of ROS as a second messenger to activate the nuclear factor kappa B (NF-kappa B), a transcription factor causing pathological changes in gene expression.

Hyperglycemia-induced activation of PKC has a number of pathogenic consequences by affecting expression of endothelial nitric oxide synthetase (eNOS), endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), TGF-beta 1, and PAI-1, and by activating NF-kappa B and NAD(P)H oxidases. Increased eNOS and decreased ET-1 decrease blood flow causing hypoxia. Increased VEGF causes increased vascular permeability and angiogenesis. Increased TGF-beta leads to increased collagen, fibronectin, extra-cellular matrix, and basement membrane resulting in capillary occlusion. Increased PAI-1 decreases fibrinolysis leading to vascular occlusion. Increased NF-kappa B causes an increase in pro-inflammatory gene expression. Increased NAD(P)H oxidase causes increased ROS (resulting in DNA damage, oxidation of polydesaturated fatty acids in lipids, and oxidation of amino acids in proteins). These pathogenic mechanisms can all be characterized as a result of ROS effects on genes and proteins.5

Nishikawa T, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000; 404: 787-90.

Du X, et al. Inhibition of GAPDH activity by poly (ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest 2000; 112: 1049-57.

Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001; 414: 813-20.

DIABETIC SKIN CARE by Darlene McCord

Educational Objectives:

At the conclusion of the talk (paper), the audience member (reader) will be able to:

1. Discuss the extent and seriousness of diabetes mellitus in the United States,

2. Understand the pathogenesis of diabetic neuropathy,

3. Relate the serious complications of diabetes mellitus,

4. Understand the 500 Dalton Rule and

5. Identify some of the ingredients in Olivamine® patent pending and what beneficial effects they have on the skin.

Background:

Epidemiology

Diabetes mellitus is characterized by high blood glucose (hyperglycemia) which can be due to: a) decreased production of insulin (called Type I diabetes mellitus) due to destruction of the pancreas on an autoimmune basis or b) decreased peripheral sensitivity to insulin (called type II which also has some decreased production of insulin by the pancreas) associated with obesity and lack of physical activity. Only about 5-10% of the total have type I disease, the rest have type II.

The most recent statistics available (2005) reveal 20.8 million people (7% of the population) with diabetes of which 14.6 million were actually diagnosed leaving 6.2 million unaware of the presence of this serious disease. Moreover, its prevalence has increased 40% in the last decade and is expected to increase by 165% between 2000 and 2005 (figure 1). It has been estimated that fully 1/3 of the population born in 2000 will develop diabetes. In addition to patient suffering and disability, the economic impact in direct and indirect costs is enormous, amounting to $132 billion in 2002 representing 1/10th of all health care costs.

There were 224,092 deaths attributable to diabetes in the USA in 2002 (probably an underestimation). The risk for death in patients with diabetes is twice that for people of the same age without diabetes, and this decreased longevity is due to cardiovascular disease. Diabetes increases the risk of heart disease and stroke 2-4 fold over that for people without diabetes. Its microvascular complications of retinopathy, nephropathy, and neuropathy make diabetes mellitus the leading cause of blindness, end-stage renal disease, and non-traumatic lower extremity amputations in the U.S.A.2 The frequency of the last complication is increasing (figure 2).

Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the United States, 2005. Atlanta, GA: Department of Health and Human Services, Centers for Disease Control and Prevention, 2005.

National Diabetes Fact Sheet, United States, 2005. Data from the Lewin Group, Inc. for the American Diabetes Association.

Darlene McCord – Vitamins and Vitamin Derivatives

In addition to antioxidant application, specific micronutrients, including vitamins and vitamin derivatives, have been deemed invaluable for nourishing skin and protecting against radiation dermatitis. Moreover, micronutrient deficiency actually mimics radiation damage by causing DNA single- and double-strand breaks and oxidative lesions in normal skin cells. Supplementing micronutrients via the topical application of vitamin precursors and vitamin derivatives protects against radiation-induced skin injury. Accordingly, retinyl palmitate, the precursor to retinoic acid and a biological form of vitamin A, has been shown to prevent radiation-induced DNA damage and erythema in normal skin cells. The topical application of retinyl palmitate counteracts vitamin A depletion caused by radiotherapy and promotes recovery. Retinyl palmitate also helps treat radiation-induced skin ulcerations by nourishing the migratory epithelial cells responsible for closing the wound. Overall, retinyl palmitate has been found to increase radiation’s effect on tumor cells in vivo, while decreasing symptoms associated with radiation dermatitis.

Ascorbyl palmitate is another important vitamin derivative that nourishes human skin and helps prevent radiation dermatitis. The micornutrient is a lipid-soluble derivative of ascorbic acid capable of penetrating the stratum corneum to target sites of cell-signaling pathways that are not accessible to water-soluble molecules. Ascorbyl palmitate has been found to maintain tissue integrity while protecting against erythema and desquamation via its potent moisturizing effect. Furthermore, ascorbyl palmitate is an effective free radical scavenger and guards well against radiation-induced DNA damage in epithelial cell lines. Ascorbyl palmitate may play a critical role in preventing radiation-induced tissue damage by providing proper cell nourishment and antioxidative protection.

Cholecalciferol (CF), or vitamin D₃, is hydroxylated in the kidney to produce 1,25-dihydroxyvitmain D, which is an active metabolite and hormone that sustains proper cell function by binding to vitamin D receptors. In particular, the derivative demonstrates strong immunoreactivity in skin and hair follicle vitamin D receptors, thereby protecting against radiation toxicity and preventing radiation dermatitis. The topical application of certain micronutrients and subsequent uptake by the stratum corneum, epidermis and dermis, has a synergistic effect with radiotherapy. Altogether, CF, ascorbyl palmitate and retinyl palmitate have been shown to increase tumor response during radiation treatment while protecting against radiation dermatitis.

Table III. Beneficial anticancer effects and protective skin care functions of topical vitamins and vitamin derivatives. Specified micronutrients may work synergistically with radiotherapy while preventing symptoms associated with radiation dermatitis.

Amino Acids

Symptoms associated with radiation dermatitis are a result of tissue breakdown involving a decline in both collagen and glycosaminoglycans, as well as from changes in their chemical structure and 3-dimensional organization. The transdermal delivery of certain amino acids has been shown to restore collagen synthesis and deposition, while thickening the epidermal skin layer. Selected amino acids have been shown to inhibit the genotoxicity of reactive oxygen species in dermal and epidermal skin cells during radiotherapy. In particular, N-acetyl-l- cysteine (NAC) exhibits significant protective effects on skin, including the extracellular inhibition of mutagenic agents from exogenous sources such as irradiation.

NAC modulates reactive metabolic pathways, protects normal DNA and nuclear enzymes, and prevents the formation of carcinogen-DNA adducts. The amino acid exerts its effects via its potent antioxidative properties, as well as its unique ability to sequester nitric oxide (NO) and reverse TNFα toxicity in human cells. NO production was found to be significantly increased in cancer patients, especially in individuals being treated for breast cancer. Breast cancer patients are known to exhibit increased levels of both nitrate and nitrite, which may be in response to the inflammation characteristic of breast tumor growth. Since radiotherapy further increases NO activity and induces inflammation, the topical application of amino acids such as NAC should be considered. NAC reacts directly with NO to reduce the increased NO generation while reversing harmful glutathione depletion.

Darlene McCord – Skin Care for Neonates

The Evidence-Based Clinical Practice Guideline for neonatal skin care, including a Neonatal Skin Condition Scale (NSCS), has been validated by the Association of Women’s Health, Obstetric and Neonatal Nurses (AWHONN) and the National Association of Neonatal Nurses (NANN). Within the Guidelines, the use of emollients is recommended for infants less than 32 weeks during the first 2-4 weeks. For infants younger than 30 weeks, gestational age emollient use is recommended to reduce excessive transepidermal water loss (e-TEWL).

Over a period spanning three decades, the handling of neonates has radically changed and the new guidelines highlight this growth and development. However, this area of skin care has lagged behind. One concern that remains is the issue of the toxic effects of ingredients found in water-based products like preservatives and fragrances. While it is possible that these may be toxic, this article will present evidence that the current skin care products that contain petrolatum and lanolin may be more toxic and potentially harmful. Further, using a product that is not preserved, yet occlusive, may in fact allow for microorganisms in colony forming units to multiply, thereby yielding systemic implications. The purpose of this article is to further illuminate these issues and to allow for greater understanding and discussion.

Skin is the largest organ of the body and provides protection between the body and its environment. In term babies, while there may be issues related to skin breakdown and infection, the stratum corneum is fully developed and protects the newborn. In contrast, the skin and skin barrier of a preterm neonate is not fully developed.

The skin of a premature neonate accounts for approximately thirteen (13) percent of its body weight. This compares to three (3) percent of body weight for adult skin. The body weight to skin ratio is four (4) times greater in the neonate when compared to an adult. As related specifically to skin care, these characteristics in neonate skin call into account:

· Fluid imbalances

· Percutaneous absorption of toxins

· Tissue injury

· Infection

The structure of adult skin is understood, while embryonic and neonate skin is not fully appreciated. Development of the skin within the uterus is complex and still under investigation. In utero, the skin undergoes two-dimensional growth to cover the surface area of the developing embryo and fetus. Premature neonate’s skin has not gone through full epidermal and dermal epidermal development.

In neonatal intensive care units (NICU) skin care product selection is carefully reviewed. With the risks outlined above, great care must be taken to ensure the wellbeing of the neonate within the first hours and days of life. Care of the skin is one of the most important areas of care for these at risk infants. Currently, NANN and AWHONN recommended a Aquaphor, a petrolatum-based product as neonate skin care emollient.

In earlier work done at Stanford University, it was concluded that emollient cream moisturizer therapy of premature neonates decreases dermatitis without changing the microbiological flora. An emollient is an agent that softens or soothes skin. This definition is important because just as the standard-of-care has changed in NICUs over the past three decades, the selection of emollients has changed in the pharmaceutical industry.

High-tech silicone excipients have displaced petrolatum as companies have sought ways to improve treatment compliance traced to poor aesthetics associated with petrolatum-based formulations. Silicones are not new to the pharmaceutical industry. They are used in transdermal delivery systems, catheters and specialized medical devices, including pacemakers.

In a test to determine aesthetic benefits of silicone formulas over petrolatum-based formulas, 18 untrained volunteers were impaneled. They were asked to evaluate whether two products present any differences on individual sensory properties. The evaluation was conducted on the panelist’s forearms. Each panelist was asked to evaluate wetness, spreadability, speed of absorbance (not biologically, just feel), gloss, film residue, greasiness, silkiness and slip after perceived absorbance

Figure I shows the silicone-containing formulation was perceived to be easier to spread and was clearly less tacky before and after absorption. A perceptible film was present on the skin for both formulations but the silicone-containing formulation was less greasy, silkier and more slippery (better lubrication) than petrolatum. The panelist’ perception of higher wetness for the silicone-containing formulation was attributed to its lower oiliness.

In a study conducted at a 48-bed NICU private hospital in Houston, Texas, to evaluate why the rate of systemic candidiasis (SC) per 1000 NICU patient-days increased from 5.1% in 1996 to17.4% in 1997 (a three-fold increase), it was determined that the increase in SC incidences was linked to the use of topical petrolatum ointment (TPO). In this well designed study, the investigators went on to hypothesize that TPO enhanced the adherence of C albicans to mucocutaneous surfaces. Also referenced in the study was a finding by Law S, et al, that unlike petrolatum, skin surface lipids inhibit adherence of candida albicans to stratum corneum.

By way of further examination, let’s more closely examine these two hypotheses. As observed in the Houston study, petrolatum enhanced adherence of C albicans to mucocutaneous surfaces. Petrolatum is known as an occlusive barrier. Occlusion is problematic because while it blocks TEWL, it also blocks cellular respiration necessary for barrier repair. Further, occlusion traps microorganisms under the petrolatum where they can breed in the moisture trapped therein. On the other hand, natural skin lipids, like omega 3-6 fatty acids, inhibit adherence of microorganisms to the stratum corneum.

Studies linking petrolatum to increased incidences of infections in preterm infants is ongoing and demonstrates mixed results. However, long term studies reflect a concern over the use of TPO protocols in NICUs. Petrolatum based ointments, like Aquaphor’s^Ò twenty five year old formula, are the emollients of choice in NICUs. When one considers the changes in the standards of care in NICUs over the past three decades, perhaps now is the time to focus on new technologies in emollients that achieve skin care objectives without the aesthetic, epidermal challenges renders skin vulnerable to chemicals & infection, prevents normal TEWL & gland secretions, inhibits barrier repair, suppresses barrier recovery and reduces the epidermal proliferative response and microbial risk disadvantages of petrolatum.

To demonstrate the effectiveness of high products using molecular height silicones against petrolatum, Nutrashield ^TM was tested in a wash-off study against Aquaphor^Ò and other leading skin barriers to determine each product’s ability to maintain skin protection after cleansing. As shown in Figure II, Nutrashield performed well against Aquaphor^Ò, and did so while providing a breathable barrier instead of the occlusive barrier associated with Aquaphor^Ò (a lanolin and petrolatum-based product). In clinical trials Nutrashield has proven effective in the treatment of skin breakdown in disordered and damaged skin, encountered in the wound care setting, as compared to previously available products.