Thursday, February 28, 2008

Routine microscopic exam: Any samples taken (blood, bone marrow, or cerebrospinal fluid) are examined under a microscope by a pathologist (doctor specializing in diagnosis of disease by laboratory tests) and are often also reviewed by the patient's hematologist/oncologist (doctor specializing in medical treatment of cancer and blood diseases).

Based on the bone marrow cells’ size, shape, and granules, doctors can classify them into specific types. A key element of this cell classification is whether the cells appear mature (resembling normal cells of circulating blood) or immature (lacking features of normal circulating blood cells). The most immature cells are called blasts.

The percentage of cells in the bone marrow that are blasts is particularly important. Having at least 20% blasts in the marrow is generally required for a diagnosis of acute myeloid leukemia. IAMLcan also be diagnosed if the blasts have a chromosome change that occurs only in a specific type of AML, even though the blast percentage doesn’t reach 20%. In order for a patient to be considered to be in remission after treatment, the blast percentage must be no higher than 5%.
Sometimes this examination does not provide a definite answer, and other lab tests are needed.

Cytochemistry: Cytochemistry studies involve placing cells from the sample on glass microscope slides, then exposing them to chemical stains (dyes) that are attracted to or react with only some types of leukemia cells. These stains cause color changes that can be seen only under a microscope. For example, one stain distinguishes AML from acute lymphocytic leukemia (ALL). The stain causes the granules of most AML cells to appear as black spots under the microscope, but it does not cause ALL cells to change colors.

Flow cytometry: This technique is often used to examine the cells from bone marrow and blood samples. It is very accurate in determining the exact type of leukemia.
Leukemia cells can be distinguished by the kinds of molecules on their surface. A sample of cells is treated with special antibodies which stick to the cells only if certain molecules are present on their surfaces. The cells are then passed in front of a laser beam. If the sample contains cells that now have antibodies attached to them, the laser will cause them to give off light, which is measured and analyzed by a computer. Groups of cells can be separated and counted by these methods.

Immunocytochemistry: During this test, as in flow cytometry, cells from the bone marrow aspiration or biopsy sample are treated with special antibodies that react only to certain molecules. But instead of using a laser and computer for analysis, the sample is treated so that certain types of cells change color. The color change can be seen only under a microscope. Like flow cytometry, it is helpful in distinguishing different types of leukemia from one another and from other diseases.

Cytogenetics: These tests involve looking at a cell’s chromosomes under a microscope. Normal human cells contain 46 chromosomes, pieces of DNA that control cell growth and metabolism.
In certain types of leukemia, 2 chromosomes may exchange some of their DNA, so that part of one chromosome becomes attached to part of a different chromosome. This change, called a translocation, can usually be seen under a microscope. Other changes in chromosomes, such as inversions, deletions, or additions, are also possible. Recognizing these changes helps to identify certain types of AML and is important in determining the outlook for the patient.

The testing usually takes about 3 weeks, because the leukemic cells must grow in laboratory dishes for a couple of weeks before their chromosomes are ready to be viewed under the microscope. The results of cytogenetic testing are written in a shorthand form that describes which chromosome changes are present.

A translocation, written as t(1;2), for example, means a part of chromosome 1 is now located on chromosome 2 and vice versa.

An inversion, written as inv(16), for example, means that part of the chromosome 16 is upside down and is now in reverse order but is still attached to the chromosome it originated from.

A deletion, written as del(7) or -7, for example, indicates part of chromosome 7 has been lost.
An addition, +8, for example, means that all or part of chromosome 8 has been duplicated, and too many copies of it are found within the cell.

Molecular genetic studies: Special tests of leukemia cell DNA can also find most translocations that are visible under a microscope in cytogenetic tests, as well as some translocations too small to be seen with usual cytogenetic testing under a microscope.
This sophisticated testing, called FISH (fluorescent in situ hybridization), is helpful in classifying leukemia because many subtypes of AML have distinctive translocations. Information about these translocations may be useful in predicting how the patient will respond to treatment.
These tests may also be used after treatment to find small numbers of leukemia cells that can be missed under a microscope.

Tuesday, February 26, 2008

Pill Swallowing Cup- Help Your Child Swallow Pills

Oralflo makes a wonderful pill swallowing cup. Visit their website to order: Oralflo Website

The Oralflo Pill Swallowing Cup
• Pills go down smoothly
• Eliminates crushing & splitting pills
• Designed for all ages
• Perfect solution for time-released & coated pills

Monday, February 25, 2008

Social Stories- help for Anxiety

When my youngest was having problems and fears about getting blood in his SCIG line, a friend told me about social stories. We used this technique with great succes (along with the worry book I mentioned before). We would explain to Joseph that if he got blood in his line, we would take care of it and explain what would happen. This eased his fears. You can use social stories for helping your children cope with the many medical procedures and tests, too.

Here are a few links:

Social Stories, their use and Start

Social Stories

UF Study ShedsLight on cystic fibrosis-related diabetes

The article below comes from the above link.

UF study sheds light on cystic fibrosis-related diabetes

Wednesday, July 5, 2006.
GAINESVILLE, Fla. — A growing number of cystic fibrosis patients are battling a second, often deadly complication: a unique form of diabetes that shares characteristics of the type 1 and type 2 versions that strike many Americans.
Many of these patients are teens who take enzymes to help digest their food and undergo daily physical therapy to loosen the thick, sticky mucus that clogs their lungs. But despite treatments that are helping thousands to live decades longer than ever before, when diabetes strikes, their life expectancy plummets — on average by two years for men and an astounding 16 for women.
Now a University of Florida study in animals suggests diabetes in cystic fibrosis patients is not caused by the destruction of insulin-producing cells in the pancreas — as is often the case in patients with the traditional form of type 1 diabetes — but by differences in how these cells function. The findings were published this month in the American Diabetes Association’s journal Diabetes.
Cystic fibrosis patients with diabetes produce some insulin on their own, but they require daily injections to boost their levels when eating so they can properly use sugar and other food nutrients for energy. At times they also become very resistant to the insulin they do make, similar to people with type 2 diabetes.
“For the longest time, the development of diabetes in cystic fibrosis has been thought to be chronic destruction of pancreas, so eventually you get loss of the insulin-producing beta cells,” said Dr. Michael Stalvey, an assistant professor of pediatrics at UF. “Our study provides some early evidence to suggest there is an inherent difference in beta cell function.”
Cystic fibrosis patients suffer recurrent episodes of infection and inflammation that slowly destroy the lungs. The pancreas is also affected, interfering with proper digestion. The disease stems from a faulty gene that blocks the normal passage of salt and water through the body’s cells. It is this gene deficiency that is proposed to cause insulin-producing cells to malfunction, Stalvey said.
About 30,000 Americans have cystic fibrosis, making it the nation’s most common lethal hereditary disorder. On average, they will not live past 35, though some are living through their 40s and even into their 60s. As each year passes, the likelihood they will develop diabetes increases. As many as 16 percent of all patients with cystic fibrosis also have diabetes, a number that is expected to rise as overall life expectancy for cystic fibrosis patients increases. Half will show signs of diabetes by age 30 and will suffer a rapid decline in overall health and lung function, muscle mass and body mass index.
“It’s becoming more and more frequent because of the increasing age of patients,” Stalvey said. “That’s part of the reason why new recommendations call for screening patients 14 years and older yearly with an oral glucose tolerance test. Each year we know their likelihood of developing diabetes gets higher and higher.
“These young people, teenagers or young adults in their early 20s, have been fighting all their lives to stay healthy and keep their nutrition up,” he added. “Now they’ve just been given something that potentially will overwhelm them. It’s a huge thing for them, given the consequences that diabetes means to their underlying condition.”
In the UF study, researchers developed the first animal model for the study of cystic fibrosis-related diabetes. They used mice that scientists from the University of North Carolina engineered to be missing the gene that makes the protein responsible for transporting salt and water across the cell membrane. People with cystic fibrosis have a mutated form of this protein.
UF scientists administered a low dose of a chemotherapy drug that weakened insulin-producing cells but did not destroy them. They then tested the animals’ ability to regulate their blood sugar while fasting and after receiving glucose, simulating the rise in blood sugar that occurs after eating food.
Animals with the protein deficiency were more sensitive to the effects of the chemotherapy drug and had more difficulty regulating blood sugar levels, both while fasting and after receiving glucose. Mice that were still able to produce the crucial protein that prevents cystic fibrosis were able to maintain normal blood sugar levels, even after the drug had damaged some of their insulin-producing cells.
“This goes beyond improving our understanding of patients with cystic fibrosis-related diabetes; it also will help us improve our understanding of other forms of diabetes and help us work on strategies for a future cure,” Stalvey said.
Stalvey’s collaborators included Dr. Desmond Schatz, Dr. Terence Flotte and Mark Atkinson. The study was supported in part by the Lawson Wilkins Pediatric Endocrinology Society, the Cystic Fibrosis Foundation and the National Institutes of Health.
“Twenty-five percent of adolescents and 40 percent of adults with cystic fibrosis have diabetes, and diabetes is associated with poorer survival in this population,” said Dr. Antoinette Moran, division head of pediatric endocrinology and director of the Pediatric Diabetes Program at the University of Minnesota Medical School. “The cause of cystic fibrosis-related diabetes is not completely understood, but it is clearly different from other forms of diabetes. The study by Stalvey and colleagues is important because it is the first to show that there are intrinsic abnormalities in the insulin-producing cells of the pancreas related to the genetic defect that causes cystic fibrosis.”

Elevated Liver Enzymes-What does it mean?

It is common for children with SDS to have elevated liver enzymes. Most outgrow it. I thought this was an interesting article from Mayo Clinic. Since J's liver enzyms are slightly elevated, I was looking a few things up. The following comes from this link:

Elevated liver enzymes: What does it mean?

What causes elevated liver enzymes?

Mayo Clinic gastroenterologist Michael Picco, M.D., and colleagues answer select questions from readers.

A laboratory report of elevated liver enzymes is common and doesn't indicate a specific disease. However, elevated liver enzymes may be due to liver disease even if you have no symptoms. To determine the underlying cause of elevated liver enzymes, your doctor may recommend further testing.
Common causes of elevated liver enzymes include:
*Side effect of medication, such as certain nonsteroidal anti-inflammatory drugs (NSAIDs), *cholesterol medications, antibiotics or anti-seizure medications
*Drinking alcohol
*Elevated triglycerides
*Infection, such as viral hepatitis and mononucleosis
*Autoimmune disorders of the liver and bile ducts, such as autoimmune hepatitis, primary *sclerosing cholangitis or primary biliary cirrhosis
*Metabolic liver disease, such as hemochromatosis or Wilson's disease
*Excessive use of certain herbal supplements, such as kava, comfrey, pennyroyal or skullcap
*Tumors of the liver, pancreas or bile ducts
Treatment of elevated liver enzymes depends on its cause. It is important to tell your doctor about any nutritional or herbal supplements you're taking.

Joseph's Bone Marrow Donor Drive

Our family hosted a Bone Marrow Donor Drive in March of 2007. Here is a video:

I also wrote an article on how to host a bone marrow donor drive. If you are interested, click on the link below:

How to Host a Bone Marrow Donor Drive

Camps for Kids with Special Health Care Needs

Here is an article about Special Camps around the country:

Camps for Children with Special Needs

Traveling to Cincinnati Children's Hospital

Here is an article with tips on traveling to Cincinnati Children's Hospital:

Traveling To Cincinnati Children's

Probiotics- Digestive Wellness

Info taken from "Digestive Wellness" by Elizabeth Lipski

*Vit C--I have learned a lot about Vit C--including Vit C flushes (if you want more info on Vit C flushes, just let me know) I first read about the use of IV vitamin C several years ago in Dr. Weil's books. In this book she says, "Vitamin C is necesssary for maintenance of the cytochrome P-450 detoxification pathways in the liver. It is used by physicians intravenously to help remove toxins from the body during chelation therapy." (Dr. Weil notes in his books that he suggests to his patients who have surgery to use/have IV Vit C during surgery-- it has shown to increase healing from the surgery) Elizabeth goes on to say"Vitamin C has been well researched for its ability to help detoxify bacterial toxins, drugs, environmental toxins, and heavy metals from our bodies. Its gentle and potent detoxification counteracts and neutralizes the harmful effects of manufactures poisons. High levels of Vitamin C help to detoxify the body, rebalance intestinal flora, and strengthen the immune system...Humans are one of the only animals that do not produce their own Vit C, so we must replenish our supply daily."

*Ulcers--Many of you already know this, but I thought I would send a quote from this book on ulcers. "Ulcers, long believed to be a disease of high stress and high stomach acidity, are now known to be caused by bacteria. Of people with ulcers, 79 to 90 percent have a bacteria called Helicobacter pylori. When it takes hold, the mucus layere of the stomach is digested, and the acid comes into direct contact with the unprotected lining of the stomach, causing it to burn and develop sores called ulcers. Though Zantac and Tagemet, the most commonly used medications for ulcers, are the best-selling drugs of all time, the latest recommendations from the National Institutes of Health put these medications in the background and focus on killing the Helicobacter bacteria."

*FRIENDLY BACTERIA--ther are several quotes I want to share on this, so bear with me.. all VERY interesting. "Antibiotics kill not only disease-causing bacteria, but healthy ones, as well. healthful bacteria, like Lactobacillus acidophilus, attach tightly to the intestinal lining so that no parasitesor disease-producing organisms can get a foothold. Antibiotics also disrupt the natural symbiosis of the gut and can cause gross imbalance of the natural flora, leading to chronic and systemic illnes." "We have 400 to 500 types of bacteria in our digestive systems, each of which has as many types of strains. This variety may seem overwhelming, but 20 types make up three-quarters of the total. The most common are bacteroides, bifidobacteria, eubacterium, fusobacteria, lactobacillus, peptococceae, rheumanococcus and streptococcus. Most of the bacteria are anaerobic, meaning that they do not need oxygen to thrive, some are aerobic, which do need oxygen for survival; and a thrid group produces lactic acid and can be either aerobic or anaerobic. Lactic acid producing bacteria help acidify the intestinal tract and protect it from overgrowth of harmful bacteria. A total of one hundred trillion bacteria live in our digestive system, in either symbiotic or antagonistic relationships. Their total weight is about 4 pounds-- the size of the liver." "Friendly flora help increase our resistance to food poisoning. In 1993, the US reported 20 to 40 million cases of food poisoning, although the FDA estimates the true total to be 80 million. Many cases go unreported because symptoms closely resemble the flu. Some food-borne infections lead to chronic illness, causing heart and valve problems, immune system disorders, joint disease, and possibly even cancer. Use of supplemental acidophilus and bifidus can prevent food poisoning by making the intestinal tract inhospitable to the invading microbes. It is a common misconception that friendly flora kill invading microbes. What they actually do is change the environment by "competitive exclusion"-- they secrete large amounts of acids (acetic, formic, and lactic acids) which make the area unsuitable for pathogens." "In addition to these nutritional and digestive benefits, probiotics enhance immune function. They manufacture antibiotics, like acidophilin produced by acidophilus, whcih are effective against many types of bacteria, including streptococcus adn staph. lactobacillus acidophilus and lactobacillus bulgaricus have been shown to be efective in laboratory testing against the following pathogens: Bacillus subitilis, Clostridium botulinum, Colstridium profingens, Eschericha coli, Proteus mirabilis, Salmonella enteridis, Salmonella typhimurium, Shigella dysenteriae, Shigella paradysenteriae, Staphylococcus aureus and Staphylococcus faecalis." (Is this COMPLETELY amazing or WHAT?? This is one of the reasons I give my kids supplements daily and increase the dose when they are on antibiotics--I take them, too. Again-- they now make enteric coated probiotic supplements so that more of the good stuff gets to the intestines -- remember the stomach kills a lot of what you ingest in yogurt, etc...) Canidida albicans, a fungus which causes infections in nails and eyes, thrush and "yeast infections" is controlled by acidophilus. This works in at least two ways. First acidophilus bacteria ferment glycogen into lactic acid which changes the pH of the intestinal tract. Since Candida and many other disease causing microbes thrive in alkaline environments, this action discourages many disease causing microbes. Second, specific strains of Lactobacillus produce hydrogen peroxide which kills Candida directly. Studies show that supplementation with a hydrogen peroxide-producing strain of acidophilus, DDS-1, reduced the incidence of antibiotic induced vaginal yeast infections threefold." "Friendly bacteria also help us in other ways. Studies have shown that lactobacillus bacteria can help normalize cholesterol levels. Probiotics can also rebuild and breakdown hormones like estrogen. Probiotics aid digestive function, improve peristalisis and help to normalize bowel transit time. Finally, bacterial balance is essential for healthy metabolism." "L. bulgaricus adn Streptococcus thermophilus are two other friendly inhabitants of our digestive tracts. Transient residents of the digtestive tract, these flora are not native to it. They "vacation" in us for up to twelve days, which gives them time to have a beneficial effect on the intestinal ecology. Their most obvious function is inhancing the production of Bifidobacteria. They have also been shown to have antitumor effects, and L. bulgaricus has antibiotic and antiherpes effects, as well. They are found in cultured dairy products or can be taken supplementally." "Saccharomyces boulardi is a friendly fungus which enhances levels of Secretory IgA. In France it is called "yeast against Yeast". Clinically, it has been found to be useful for clearing the skin and controlling diarrhea caused by antibiotics, Clostridium difficile, and travelling. Saccharomyces has also been used effectively in people with Chron's disease, significantly reducing the number of bowel movements."

Pediatric Vital Sign Reference Ranges

Pediatric Vital Sign Reference Ranges

This is a GREAT site-- gives BP, heart rate, etc reference ranges by ag for pediatric patients.

Sunday, February 24, 2008

Liver Enzymes as a Predictor for Incident Diabetes....

from this link:

Liver Enzymes as a Predictor for Incident Diabetes in a Japanese Population: The Hisayama Study

Objective: We studied the relationship between liver enzymes and the development of diabetes in a general Japanese population.
Research Methods and Procedures: A total of 1804 non-diabetic subjects 40 to 79 years of age were followed-up prospectively for a mean of 9.0 years.
Results: During the follow-up, 135 subjects developed diabetes. In both sexes, the age-adjusted cumulative incidence of diabetes increased significantly with elevating quartiles of serum -glutamyltransferase (GGT) and alanine aminotransferase (ALT) levels. This pattern was also observed in aspartate aminotransferase (AST) quartiles for men but not for women. In multivariate analyses after adjusting for comprehensive risk factors and other liver enzymes, the risk of developing diabetes was significantly higher in the highest GGT quartile than in the lowest quartile [odds ratio (OR), 2.54; 95% confidence interval (CI), 1.03 to 6.26 for men; OR, 5.73; 95% CI, 1.62 to 20.19 for women]. Similar results were observed in ALT quartiles (OR, 2.32; 95% CI, 0.91 to 5.92 for men; OR, 4.40; 95% CI, 1.38 to 14.06 for women) but not in AST quartiles in either sex. Significant positive associations of GGT and ALT with diabetes were seen within each stratified category of risk factors, namely fasting insulin, BMI, waist-to-hip ratio, high-sensitivity C-reactive protein, and alcohol consumption. In receiver operating characteristic analyses, the areas under the receiver operating characteristic curve of GGT and ALT were significantly larger than that of AST, fasting insulin, waist-to-hip ratio, or C-reactive protein.
Discussion: Our findings suggest that serum GGT and ALT concentrations are strong predictors of diabetes in the general population, independent of known risk factors.
Key Words: liver • longitudinal • C-reactive protein • diabetes • visceral obesity

TOPAbstractIntroductionResearch Methods and ProceduresResultsDiscussionReferences The liver, a major site of insulin clearance, plays an important role in maintaining normal glucose concentrations during fasting and postprandially (1) . Recently, several cohort studies have shown that serum -glutamyltransferase (GGT)1 (2) (3) (4) (5) (6) , alanine aminotransferase (ALT) (7) (8) (9) , and aspartate aminotransferase (AST) (10) levels are predictors of diabetes. In one of these reports, a study on Pima Indians (8) found that high serum ALT levels were a significant risk factor for diabetes, although no clear association between serum GGT and diabetes was seen. On the other hand, serum GGT levels, but not AST levels, have been identified as an independent predictor of incident diabetes in British men selected from lists of general practitioners (2) . Moreover, the Mexico City Diabetes Study found that serum AST is an independent risk factor for future diabetes in multivariable adjustment, whereas no association was observed between serum GGT or ALT and the development of diabetes (10) . These reports suggest that the liver is associated with the development of diabetes; however, to the best of our knowledge, there have been no studies to date to determine which of these three enzymes is the best marker for incident diabetes. Furthermore, it also remains unknown whether liver enzyme markers are stronger predictors of future diabetes than well-known risk factors for diabetes, such as adiposity, insulin resistance, and inflammation. The purpose of this study is to examine the effects of serum liver enzymes, i.e., GGT, ALT, and AST, on the development of diabetes in a prospective study of a defined Japanese population, taking into account comprehensive risk factors, including BMI, waist-to-hip ratio, fasting insulin, and high-sensitivity C-reactive protein (HS-CRP) levels.

Research Methods and Procedures
TOPAbstractIntroductionResearch Methods and ProceduresResultsDiscussionReferences Study Population and Follow-up SurveyA population-based prospective study of cardiovascular disease has been underway since 1961 in the town of Hisayama, a suburb in the Fukuoka metropolitan area on Kyushu Island in Japan. The age and occupational distributions of the town population were almost identical to those of Japan as a whole from 1961 to the present based on data from the national census. A screening survey for this study was performed in 1988. A detailed description of this survey has been published previously (11) (12) . Briefly, of all 3227 residents 40 to 79 years of age listed in the town registry, 2587 (80.2%) consented to take part in a comprehensive assessment, including an interview covering medical history (including diabetes, hypertension, and other chronic diseases) and current medical treatment with insulin and oral anti-diabetic agents. The baseline classification of subjects as either having or not having diabetes was based on the fasting criteria of the American Diabetes Association (13) : subjects with a fasting plasma glucose level of 7.0 mM or those who were taking anti-diabetic medications were defined as having diabetes. A total of 2274 subjects (963 men and 1311 women) were enrolled in the baseline examination after the exclusion of 1 subject for whom no blood sample was obtained, 75 subjects who had already taken breakfast before the examination, 233 subjects with diabetes, and 4 subjects who had died before starting our follow-up.
After the initial screening in 1988, fasting glucose levels were again measured between 1993 and 1998. Of the 2274 subjects, 1804 (719 men and 1085 women) underwent a follow-up examination (follow-up rate, 79.3%). We considered a subject to have developed diabetes when his/her fasting glucose level met the above-mentioned American Diabetes Association criteria or if the subject started taking anti-diabetic medication during the follow-up period. During this period, 135 subjects (71 men and 64 women) developed diabetes.
Clinical Evaluation and Laboratory MeasurementsBlood samples were collected after at least 12 hours of fasting for the determination of serum liver enzymes, plasma glucose, and other parameters. Serum GGT concentrations were measured using a modified version of the method of Orlowski and Meister (14) . Both serum ALT and AST concentrations were determined by a kinetic ultraviolet ray method based on the rate of reduced nicotinamide adenine dinucleotide oxidation. Plasma glucose levels were determined by a glucose-oxidase method, and serum insulin levels were measured by double-antibody, solid-phase radioimmunoassay. Hemoglobin A1c levels were measured by high-pressure liquid chromatography. Total cholesterol, high-density lipoprotein cholesterol (HDL-C) and triglycerides were determined enzymatically. HS-CRP concentrations were analyzed using a modified latex-enhanced HS-CRP assay (Behring Diagnostics, Westwood, MA). Serum hepatitis B surface antigen was detected by an immunoprecipitation method (Shino-test, Tokyo, Japan), and presence of hepatitis C virus antibody was assessed by both particle agglutination assay (Serodia-HCV; Fujirebio, Tokyo, Japan) and recombinant immunoblot assay (RIBA 2.0; Ortho Diagnostic Systems, Raritan, NJ).
Blood pressure was obtained three times using a mercury sphygmomanometer with the subject in a sitting position; the averages of the three values were used in this analysis. Hypertension was defined as a systolic blood pressure of 140 mm Hg and/or a diastolic blood pressure of 90 mm Hg and/or current treatment with anti-hypertensive agents. The height and weight of each subject were recorded with the subject wearing light clothes but no shoes, and BMI (kg/m2) was calculated. Abdominal girth at the umbilical level and hip circumference at 5 cm below the spina iliaca anterior superior were measured and used to calculate the waist-to-hip ratio.
On baseline examination, each participant completed a self-administered questionnaire covering medical history, anti-hypertensive treatment, alcohol intake, and smoking habits, and the questionnaire was checked by trained interviewers at the screening. Diabetes in first- or second-degree relatives was taken to indicate a family history of diabetes. Subjects engaging in sports at least three times per week during their leisure time were defined as the regular exercise group. Alcohol intake and smoking habits were used to classify subjects as having current habits or not.
Statistical AnalysisBecause the distributions of GGT, ALT, AST, fasting insulin, HS-CRP, and triglycerides were skewed, these variables were natural log-transformed for statistical analyses. To analyze liver enzyme levels as categorical variables, these levels were divided into four groups on the basis of quartiles by sex: GGT, men, 6 to 16, 17 to 22, 23 to 37, and 38 to 529 U/L; GGT, women, 6 to 10, 11 to 13, 14 to 17, and 18 to 261 U/L; ALT, men, 5 to 10, 11 to 13, 14 to 18, and 19 to 354 U/L; ALT, women, 5 to 8, 9 to 11, 12 to 14, and 15 to 153 U/L; AST, men, 8 to 17, 18 to 21, 22 to 27, and 28 to 424 U/L; AST, women, 7 to 16, 17 to 18, 19 to 22, and 23 to 273 U/L. The age-adjusted cumulative incidences of diabetes were calculated by the direct method using all subjects, and the results were compared by the Mantel-Haenszel 2 test using 10-year age-groupings. Age- and multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression analysis. The sensitivity of cut-off points was defined as their ability to correctly identify individuals who later developed diabetes, and their specificity was defined as their ability to correctly identify individuals who did not develop diabetes. To compare the prognostic abilities of risk factors including liver enzymes and to detect the presence or absence of future diabetes across a range of the values for each risk factor, we plotted receiver operating characteristic (ROC) curves and compared the areas under them (15) (16) . The diagnostic properties of specific cut-off levels of each risk factor were defined by maximizing the sensitivity and specificity to identify future diabetes. A value of p < 0.05 was considered statistically significant in all analyses. This study was conducted with the approval of the Ethics Committee of the Faculty of Medicine, Kyushu University, and written informed consent was obtained from all participants.
TOPAbstractIntroductionResearch Methods and ProceduresResultsDiscussionReferences The clinical characteristics of all subjects by sex are shown in Table 1 . The mean age was 58 years for both sexes. The mean values of GGT, ALT, AST, fasting plasma glucose, hemoglobin A1c, waist-to-hip ratio, triglycerides, HS-CRP, systolic and diastolic blood pressures, frequency of hypertension, alcohol intake, smoking habits, and regular exercise were higher in men than in women, whereas women had higher concentrations of fasting insulin, total cholesterol, and HDL-C. The frequency of family history of diabetes and mean BMI levels did not differ between the sexes.

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Table 1. Characteristics of subjects by sex
The age-adjusted cumulative incidence of diabetes was 9.6% for men and 5.9% for women, giving a statistically significant difference (p = 0.002). Figure 1 shows the age-adjusted cumulative incidence of diabetes according to quartiles of each liver enzyme level by sex. The cumulative incidence in the third and forth GGT quartiles was significantly higher compared with that of the first quartile in both sexes. A similar tendency was observed for ALT quartiles: there were significant differences between the first and fourth quartiles in both sexes. This pattern was also found in AST quartiles for men but not for women.

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Figure 1: The age-adjusted cumulative incidences of diabetes according to quartiles of serum liver enzymes. (A) GGT, -glutamyltransferase; (B) ALT, alanine aminotransferase; (C) AST, aspartate aminotransferase.
The age-adjusted OR for the development of diabetes increased significantly with elevating quartiles of each liver enzyme concentrations in both sexes (Table 2 , Model 1). In the multivariate analyses after adjustment for age, family history of diabetes, fasting insulin, BMI, waist-to-hip ratio, total cholesterol, HDL-C, triglycerides, HS-CRP, hypertension, current drinking, current smoking, and physical activity, the ORs of future diabetes increased significantly with elevating quartiles of serum GGT and ALT (Model 2). These trends were also observed in AST quartiles for men but not for women. As shown in Model 3 of Table 2 , after additional adjustment for the other liver enzymes, these relationships remained substantially unchanged in both GGT and ALT quartiles but not in AST in either sex.

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Table 2. Age- and multivariate-adjusted ORs and 95% CIs for the development of diabetes according to quartiles of each liver enzyme by sex during mean 9 years of follow-up
To examine the influence of insulin resistance-related factors, inflammation and alcohol intake on the development of diabetes, we estimated the age- and sex-adjusted ORs and 95% CIs of diabetes by increments of 1 log in each liver enzyme in men and women together in accordance with other risk factor levels (Table 3) . Analyses were performed dividing the subjects into three groups according to tertiles of fasting insulin, BMI, waist-to-hip ratio, and HS-CRP or to alcohol intake levels (0, 1 to 30, and 30 g/d). Significant positive associations of GGT and ALT with diabetes were observed in all stratified categories of each risk factor; however, we found no significant associations between AST and diabetes in the third tertile of BMI, in the third tertile of waist-to-hip ratio, or in the second level of alcohol intake.

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Table 3. Age- and sex-adjusted ORs and 95% CIs for the occurrence of diabetes by increments of 1 log in each liver enzyme according to risk factor levels during mean of 9 years of follow-up
To compare the ability of each risk factor to predict future diabetes over a mean of 9 years of follow-up, we plotted ROC curves and calculated optimal cut-off points, sensitivities, specificities, and the area under the ROC curves (Table 4) . Both maximum sensitivity and specificity exceeded 60% only for GGT and ALT, and the areas under the ROC curve of GGT and ALT were significantly larger than that of AST, fasting insulin, waist-to-hip ratio, or HS-CRP and were slightly but not significantly larger than that of BMI. The difference in the area under the ROC curve between GGT and ALT was not significant.

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Table 4. Optimal cut-off points of risk factors defined by maximizing sensitivity and specificity to predict future diabetes and their ROC curve areas
Viral hepatitis infection can increase liver enzyme levels without liver fat accumulation. Thus, hepatitis B and C virus markers were examined in 1583 of the 1804 subjects in 1998. We found 13 viral hepatitis subjects (3 subjects with hepatitis B virus and 10 with C virus; 10.7%) in 122 subjects of the group developing diabetes and 104 viral hepatitis subjects (25 subjects with hepatitis B virus and 79 with C virus; 7.1%) in 1461 subjects of the group that did not develop diabetes: the difference was not significant (2 = 2.1; p = 0.15).

TOPAbstractIntroductionResearch Methods and ProceduresResultsDiscussionReferences We have shown, in a prospective study of a general Japanese population, that elevated levels of GGT and ALT, but not AST, are independent predictors of diabetes for both sexes after adjustment for age, family history of diabetes, fasting insulin, BMI, waist-to-hip ratio, total cholesterol, HDL-C, triglycerides, HS-CRP, hypertension, current drinking, current smoking, physical activity, and the other liver enzymes. In our stratified analyses, associations of both GGT and ALT with the development of diabetes were observed in all layers of other risk factors, such as fasting insulin, BMI, waist-to-hip ratio, HS-CRP, and alcohol intake. ROC analyses showed that the predictive power of GGT and ALT was similar to that of BMI but stronger than that of AST, fasting insulin, waist-to-hip ratio, and HS-CRP. To the best of our knowledge, this study is the first report to indicate that liver enzymes are independent risk factors for developing diabetes in a general Japanese population in either sex, taking into account comprehensive risk factors for diabetes. Several prospective studies have found that high levels of hepatic enzymes, including GGT (2) (3) (4) (5) (6) , ALT (7) (8) (9) , and AST levels (10) , are associated with later development of diabetes. These findings, together with these results, strongly suggest that the liver plays an important role in the development of diabetes in relatively lean Asian populations who may have smaller fat content in the liver, as it does in Western populations.
A recent study using a fatless mouse model has shown that ectopic fat accumulation in the liver is associated with severe insulin resistance (17) . In normal weight and moderately overweight subjects, directly determined liver fat content has also been shown to correlate with several features of insulin resistance, independent of BMI and intra-abdominal or overall obesity (18) . These findings indicate that hepatic fat accumulation is a critical manifestation of insulin resistance. However, direct measurement of liver fat requires ultrasound, computed tomography, or proton spectroscopy, and such techniques are unlikely to be recommended in routine clinical practice. Some circulating variables, including serum ALT, GGT, and AST, provide insight into the extent of liver fat accumulation. Among these, ALT is found primarily in the liver, whereas AST and GGT are also found in other tissues and are, therefore, less specific markers of liver function. Therefore, ALT is the most specific marker of liver pathology and seems to be the best marker for liver fat accumulation: serum ALT is correlated with liver fat measured by proton spectroscopy and, after weight loss, the change in serum ALT correlates with that in liver fat (19) .
In our multivariate analysis, serum GGT and ALT were mutually independent in predicting incident diabetes. It is known that serum GGT is not only a marker of liver fat amount but also a marker of oxidative stress (20) (21) (22) . GGT presenting at the outer side of the cell membrane is thought to maintain cellular glutathione levels, which are the major intracellular defense against free radicals (23) . Increased oxidative stress impairs insulin secretion from the islets of Langerhans and insulin action in target tissues by damaging DNA, membranes, enzymes, etc. (24) . Decreased insulin secretion and insulin sensitivity are major features of the pathophysiology of type 2 diabetes (25) . This may be the reason why GGT and ALT has a highly predictive value for the development of diabetes. On the other hand, several epidemiologic studies examined which of these enzymes was the best marker for incident diabetes. Lee et al. (3) (4) reported the dose–response relationship between GGT levels and incidence of diabetes in both Korean male workers and young black and white Americans with ALT or AST levels within the reference interval. Furthermore, in their other study, GGT levels within normal range predicted incidence of chronic elevation of ALT (26) . These findings indicate the possibility that GGT is a more powerful predictor of incident diabetes than other liver enzymes. However, we showed in the ROC analysis that ALT and GGT but not AST have equally predictive value for the development of diabetes. These findings should be confirmed in other populations, having different BMI levels and lifestyles.
Some experimental studies have shown that selective deletion of the insulin receptor from muscle results in a slight increase in serum free fatty acid and triglycerides but not in glucose intolerance or diabetes (27) , whereas a similar maneuver in the liver leads to marked glucose tolerance (28) , suggesting that maintaining normal glucose concentrations is related to the liver rather than to peripheral tissue. Our stratified analysis showed that the associations of both GGT and ALT levels with the occurrence of diabetes were independent of markers of systemic insulin resistance, such as fasting insulin, BMI, waist-to-hip ratio, and HS-CRP. In our subjects, the areas under the ROC curve of GGT and ALT were also significantly larger than that of fasting insulin, waist-to-hip ratio, or HS-CRP. Insulin resistance in the liver through fat accumulation may offer a better explanation of the cause of diabetes than peripheral insulin resistance or systemic inflammation.
Alcohol intake causes fatty change of the liver. In alcoholic fatty liver, serum ALT tends to be depressed relative to serum AST, and serum GGT has the specificity to detect alcohol abuse (29) , whereas liver fat accumulation caused by overeating predominantly increases ALT but not AST or GGT (19) . However, these findings indicated that both GGT and ALT predict future diabetes, independent of current drinking habits. Additionally, in our stratified analyses, the associations of both GGT and ALT with diabetes were unrelated to alcohol intake levels. These observations suggest that elevated serum levels of GGT and ALT, irrespective of the causes of fatty liver, are associated with incident diabetes.
Viral hepatitis infection often increases liver enzyme levels without hepatic fat accumulation, and several clinical studies have shown that chronic hepatitis C virus infection is linked to type 2 diabetes (30) (31) . In our study, however, the distribution of hepatitis B and C virus positive markers did not differ between subjects who developed diabetes and those who did not, indicating that viral hepatitis infection did not affect our findings.
A limitation of our study is that a diagnosis of diabetes was not based on a 75-gram oral glucose tolerance test, but on a single reading of fasting glucose level, as has been the case in other epidemiologic studies (3) (4) (5) (9) . Thus, subjects with diabetes having normal fasting glucose levels were misdiagnosed in our study. In addition, some of the participants who were classified as having worsening fasting glucose status may not have been so categorized after repeated testing. These misclassifications may have weakened the associations found in this study, and the true associations may, in fact, be stronger than those shown in our data.
In conclusion, we have shown that elevated serum GGT and ALT levels, even in the normal range, are better predictors of diabetes than the known risk factors except for BMI in a general Japanese population. The association between these enzymes and diabetes was found to be independent of insulin resistance, inflammation markers, and alcohol consumption levels. These results support the hypothesis that the liver is more important than previously thought in the pathogenesis of type 2 diabetes.

Acknowledgments This study was supported, in part, by a Grant-in-Aid for Scientific Research C (13670370), a Special Coordination Fund for Promoting Science, and a Fund for Technology and Innovative Development Project in Life Sciences from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Footnotes The costs of publication of this article were defrayed, in part, by the payment of page charges. This article must, therefore, be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Nonstandard abbreviations: GGT, -glutamyltransferase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; HS-CRP, high-sensitivity C-reactive protein; HDL-C, high-density lipoprotein cholesterol; OR, odds ratio; CI, confidence interval; ROC, receiver operating characteristic.

TOPAbstractIntroductionResearch Methods and ProceduresResultsDiscussionReferences

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Lee, DH, Ha, MH, Kim, JH, et al (2003) Gamma-glutamyltransferase and diabetes—a 4 year follow-up study Diabetologia 46,359-364 [Medline]
Lee, DH, Jacobs, DR, Jr, Gross, M, et al (2003) Gamma-glutamyltransferase is a predictor of incident diabetes and hypertension: the Coronary Artery Risk Development in Young Adults (CARDIA) Study Clin Chem. 49,1358-1366 [Abstract/Free Full Text]
Nakanishi, N, Suzuki, K, Tatara, K. (2004) Serum gamma-glutamyltransferase and risk of metabolic syndrome and type 2 diabetes in middle-aged Japanese men Diabetes Care 27,1427-1432 [Abstract/Free Full Text]
Lee, DH, Silventoinen, K, Jacobs, DR, Jr, Jousilahti, P, Tuomileto, J. (2004) Gamma-glutamyltransferase, obesity, and the risk of type 2 diabetes: observational cohort study among 20,158 middle-aged men and women J Clin Endocrinol Metab. 89,5410-5414 [Abstract/Free Full Text]
Ohlson, LO, Larsson, B, Björntorp, P, et al (1988) Risk factors for type 2 (non-insulin-dependent) diabetes mellitus. Thirteen and one-half years of follow-up of the participants in a study of Swedish men born in 1913 Diabetologia 31,798-805 [Medline]
Vozarova, B, Stefan, N, Lindsay, RS, et al (2002) High alanine aminotransferase is associated with decreased hepatic insulin sensitivity and predicts the development of type 2 diabetes Diabetes 51,1889-1895 [Abstract/Free Full Text]
Sattar, N, Scherbakova, O, Ford, I, et al (2004) Elevated alanine aminotransferase predicts new-onset type 2 diabetes independently of classical risk factors, metabolic syndrome, and C-reactive protein in the west of Scotland coronary prevention study Diabetes 53,2855-2860 [Abstract/Free Full Text]
Nannipieri, M, Gonzales, C, Baldi, S, et al (2005) Liver enzymes, the metabolic syndrome, and incident diabetes: the Mexico City diabetes study Diabetes Care 28,1757-1762 [Abstract/Free Full Text]
Ohmura, T, Ueda, K, Kiyohara, Y, et al (1993) Prevalence of type 2 (non-insulin-dependent) diabetes mellitus and impaired glucose tolerance in the Japanese general population: the Hisayama Study Diabetologia 36,1198-1203 [Medline]
Doi, Y, Kiyohara, Y, Kubo, M, et al (2005) Elevated C-reactive protein is a predictor of the development of diabetes in a general Japanese population: the Hisayama Study Diabetes Care 28,2497-2500 [Abstract/Free Full Text]
The Expert Committee on the Diagnosis and Classification (1997) Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Diabetes Care 20,1183-1197 [Medline]
Orlowski, M, Meister, A. (1963) Gamma-glutamyl-P-nitroanilide: a new convenient substrate for determination and study of L- And D-gamma-glutamyltranspeptidase activities Biochim Biophys Acta. 73,679-681 [Medline]
Hanley, JA, McNeil, BJ. (1982) The meaning and use of the area under a receiver operating characteristic (ROC) curve Radiology 143,29-36 [Abstract]
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Kim, JK, Gavrilova, O, Chen, Y, Reitman, ML, Shulman, GI. (2000) Mechanism of insulin resistance in A-ZIP/F-1 fatless mice J Biol Chem. 275,8456-8460 [Abstract/Free Full Text]
Seppala-Lindroos, A, Vehkavaara, S, Hakkinen, AM, et al (2002) Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men J Clin Endocrinol Metab. 87,3023-3028 [Abstract/Free Full Text]
Tiikkainen, M, Bergholm, R, Vehkavaara, S, et al (2003) Effects of identical weight loss on body composition and features of insulin resistance in obese women with high and low liver fat content Diabetes 52,701-707 [Abstract/Free Full Text]
Kugelman, A, Choy, HA, Liu, R, Shi, MM, Gozal, E, Forman, HJ. (1994) Gamma-glutamyl transpeptidase is increased by oxidative stress in rat alveolar L2 epithelial cells Am J Respir Cell Mol Biol. 11,586-592 [Abstract]
Takahashi, Y, Oakes, SM, Williams, MC, Takahashi, S, Miura, T, Joyce-Brady, M. (1997) Nitrogen dioxide exposure activates gamma-glutamyl transferase gene expression in rat lung Toxicol Appl Pharmacol. 143,388-396 [Medline]
Karp, DR, Shimooku, K, Lipsky, PE. (2001) Expression of gamma-glutamyl transpeptidase protects ramos B cells from oxidation-induced cell death J Biol Chem. 276,3798-3804 [Abstract/Free Full Text]
Lieberman, MW, Barrios, R, Carter, BZ, et al (1995) Gamma-glutamyl transpeptidase. What does the organization and expression of a multipromoter gene tell us about its functions? Am J Pathol. 147,1175-1185 [Abstract]
Evans, JL, Goldfine, ID, Maddux, BA, Grodsky, GM. (2003) Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction? Diabetes 52,1-8 [Abstract/Free Full Text]
Kahn, CR. (1994) Banting Lecture. Insulin action, diabetogenes, and the cause of type II diabetes Diabetes 43,1066-1084 [Medline]
Lee, DH, Lim, JS, Yang, JH, Ha, MH, Jacobs, DR, Jr (2005) Serum gamma-glutamyltransferase within its normal range predicts a chronic elevation of alanine aminotransferase: a four year follow-up study Free Radic Res. 39,589-593 [Medline]
Bruning, JC, Michael, MD, Winnay, JN, et al (1998) A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance Mol Cell. 2,559-569 [Medline]
Michael, MD, Kulkarni, RN, Postic, C, et al (2000) Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction Mol Cell. 6,87-97 [Medline]
Morgan, M. (1999) Alcoholic liver disease: natural history, diagnosis, clinical features, evaluation, management, prognosis, and prevention Bircher, J Benhamou, J McIntyre, N Rizzetto, M Rodes, J eds. Oxford Textbook of Clinical Hepatology 2nd ed. ,1185-1238 Oxford University Press Oxford.
Wilson, C. (2004) Hepatitis C infection and type 2 diabetes in American-Indian women Diabetes Care 27,2116-2119 [Abstract/Free Full Text]
Antonelli, A, Ferri, C, Fallahi, P, et al (2005) Hepatitis C virus infection: evidence for an association with type 2 diabetes Diabetes Care 28,2548-2550 [Free Full Text]Received for publication September 13, 2006. Accepted for publication January 7, 2007.

For information on Shwachman-Diamond Syndrome check out Shwachman-Diamond America

Using a Straw to Help your Child take Enzymes

This link includes pictures! If you have a child who is unable to swallow enzyme pills, you may want to try the flexible straw method.

Saturday, February 23, 2008

SCN-HAX1 article

Link to full text of this article can be found here:

Severe developmental delay and epilepsy in a Japanese patient with severe congenital neutropenia due to HAX1 deficiency.
Matsubara K, Imai K, Okada S, Miki M, Ishikawa N, Tsumura M, Kato T, Ohara O, Nonoyama S, Kobayashi M.
Department of Pediatrics, Nishi-Kobe Medical Center, Japan.
HAX1 deficiency has recently been identified as a cause of severe congenital neutropenia (SCN), but little is known about the phenotype. We described an SCN patient with a homozygous 256C-to-T transition causing an R86X mutation in the HAX1 gene. Notably, the patient has been complicated by epilepsy and severe delay of motor, cognitive, and intellectual development; each developmental quotient was 21-26 at 7 years old. Growth failure and dental development delay were also noted. Neurodevelopmental delay in this patient expands the clinical phenotype of HAX1 deficiency and suggests an important role of HAX1 on neural development as well as myelopoiesis.

Longaberger Fundraiser for SDA

I am doing a fundraiser for SDA. All you need to do is to go to and place an order. All proceeds go to SDA. I love this year’s Easter basket!

Also, don’t forget that we have the “Find a Cure” Bumper Stickers available for $2 each plus S&H if I need to mail them. Click on teh "fundraisers" link to the right to see a picture of the bumper sticker.

Please feel free to pass this along to anyone you feel might be interested in helping SDA.

SDS Diabetes article

We often talk about diabetes on the SDS Support list There are several of us with children who either have diabetes or insulin resistance (like my two boys). There is a known link between CF and Diabetes, here is a link for CF Diabetes info. There is also an article on SDS and Diabetes titled: A case of Shwachman-Diamond syndrome presenting with diabetes from early infancy.

If you would like more information on the article above, please feel free to contact me.

Don't forget that Shwachman-Diamond America has links to over 50 full-text medical articles on Shwachman-Diamond Syndrome. Visit the SDA website and click on th "Mdical Articles" link.

Article: MRI Findings of the Pancreas in patients with SDS and mutations in the SBDS gene

Magnetic resonance imaging findings of the pancreas in patients with Shwachman-Diamond syndrome and mutations in the SBDS gene.
Medical Imaging Center, Helsinki University Hospital, Helsinki, Finland.
Pancreatic MRI was evaluated in 14 patients with a clinical diagnosis of Shwachman-Diamond syndrome, and the findings were correlated with Shwachman-Bodian-Diamond gene (SBDS) genotype. The findings suggest that patients with mutations in the SBDS gene have a characteristic magnetic resonance imaging pattern of fat-replaced pancreas and that SBDS mutations are unlikely in patients without this pattern.

This article contains charts on how each of the 14 patients pancreatic function was assessed. It lists all 14 patients and how each one’s pancreatic function was assessed and then lists the criteria for their SDS diagnosis. It also lists their neutrophil count (range) and height Z-score. In another chart, it lists how long they were on enzymes--- i.e. lists the age at which the person became pancreatic sufficient. One child was 4 years old when she came off of enzymes (i.e. she was on enzymes until age 4) and another one was 5 years old. Two came off of enzymes at 11 years and one at 22 years, one at 29 years, 3 never took enzymes and the rest are on on-going enzyme replacement.

There were 14 patients. 10 males and 4 females. 13 of them were diagnosed at a median age of 18 months….but one was referred to them at age 13 for suspected SDS. One of the patients was diagnosed with type I diabetes at age 15. With all of our diabetes talk recently, I thought that was an interesting note. The article says hat all patients with SBDS mutations showed fatty pancreas on MRI—the patients without the SBDS mutations and proven PI had NORMAL pancreatic MRIs.

Friday, February 22, 2008

p53 tumor suppressor protein

Genes and Disease Cancers

The p53 tumor suppressor protein

The p53 gene like the Rb gene, is a tumor suppressor gene, i.e., its activity stops the formation of tumors. If a person inherits only one functional copy of the p53 gene from their parents, they are predisposed to cancer and usually develop several independent tumors in a variety of tissues in early adulthood. This condition is rare, and is known as Li-Fraumeni syndrome. However, mutations in p53 are found in most tumor types, and so contribute to the complex network of molecular events leading to tumor formation.

The p53 gene has been mapped to chromosome 17. In the cell, p53 protein binds DNA, which in turn stimulates another gene to produce a protein called p21 that interacts with a cell division-stimulating protein (cdk2). When p21 is complexed with cdk2 the cell cannot pass through to the next stage of cell division. Mutant p53 can no longer bind DNA in an effective way, and as a consequence the p21 protein is not made available to act as the 'stop signal' for cell division. Thus cells divide uncontrollably, and form tumors.

Help with unraveling the molecular mechanisms of cancerous growth has come from the use of mice as models for human cancer, in which powerful 'gene knockout' techniques can be used. The amount of information that exists on all aspects of p53 normal function and mutant expression in human cancers is now vast, reflecting its key role in the pathogenesis of human cancers. It is clear that p53 is just one component of a network of events that culminate in tumor formation.

Transplant Centers with Experience in SDS

Ø Cincinnati Children’s Hospital
Contact: Richard Harris MD, , (513) 636-3570

Ø Schneider Children’s Hospital, North Shore of Long Island, NY Contact: Jeff Lipton, MD,, (718) 470-3460

Ø University of Iowa
Contact: Fred Goldman, MD,, (319) 356-7360

CF Related Diabetes

Here is another link where you can find information on CF related diabetes, which may be helpful for those of us dealing with SDS related diabetes and insulin resistance.

CF Diabetes Info


Fluorescence in situ Hybridization (FISH): FISH is a molecular cytogenetic technique that can detect chromosomal abnormalities that cannot be appreciated by standard chromosomal analysis (e.g. microdeletion syndromes) or when mitotic cells are not available for chromosomal analysis (e.g. X/Y FISH for cross-sex transplants). Briefly, metaphase chromosomes or interphase nuclei are denatured on the slide, as is the fluorescently labeled DNA probe. The probe and the chromosomes/nuclei are then hybridized, slides are washed, counterstained and analyzed by fluorescent microscopy. There are a number of different types of FISH probes including unique sequence probes (e.g. microdeletion syndromes), whole chromosome painting probes, repetitive probes (e.g. centromeric alpha satellite probes, subtelomeric probes), gene fusion probes (e.g. BCR/ABL in t(9;22) in CML and ALL) and break apart probes (e.g. MLL in 11q23 rearrangements in ALL and AML).

HER2 Amplification by FISH in Breast Cancer: The HER2 oncogene is overexpressed in 25-30% of human breast cancer. In 90-95% of these cases, the overexpression is a direct result of gene amplification. This amplification correlates with a poor clinical prognosis, and therefore, amplification status has become increasingly important in therapeutic decisions for patients with breast cancer. Specifically, women with breast cancer are eligible for treatment with the monoclonal antibody trastuzumab (Herceptin, Genentech), which targets the HER2 gene product, if they show amplification and/or overexpression of HER2.

Screening for Recurrent Bladder Cancer Using FISH: Transitional cell carcinoma (TCC) constitutes 90% of human bladder cancer, 75% of which are considered “superficial”, i.e., carcinoma in situ, non-invasive papillary TCC or minimally invasion TCC. Recurrence of superficial TCC or progression to muscle invasive TCC occurs in 50-80% and 15-25% of cases, respectively. Patients with TCC are monitored with cystoscopy and/or urine cytology for recurrent disease, both of which are relatively insensitive methods of testing. Numerous studies have correlated various chromosomal aneuploidies with TCC. Fluorescence in situ hybridization (FISH) using a variety of probes has been utilized for detection of aneuploidies on cells from voided urine. The UroVysion Bladder Cancer Screening Kit (Abbott, Vysis) provides a FISH probe mixture that includes centromeric probes for chromosomes #3, #7 and #17 and a unique sequence probe for the p16 gene (located at 9p21). Specifically, concurrent extra copies of two or more chromosomes and/or loss of 9p21 is consistent with a diagnosis of recurrent TCC.

from this link:

Thursday, February 21, 2008

SBDS Gene, DNA Rpair and Telomere Elongation Study

SBDS Gene, DNA Rpair and Telomere Eogation Sudy
Dr. Neal Young and Dr. Rodrigo Calado from the NIH are looking into SBDS gene function, specifically DNA repair and telomere elogation. This study only requirres a small sample of blood to be collected and sent to the NIH.
To participate, contact Dr. Rodrigo Calado or 301-496-5093

UTMB SDS Bone Marrow Study

UTMB SDS Bone Marrow Study
Dr. Elghetany is studying the bone marrow of SDS patients to identify markers/signs of early myelodysplastic syndrome and leukemia. For more information or to obtain the forms needed to participate, please contact Dr. Elghetany at 409-747-2468 or email

NIH bone marrow failure study

Division of Cancer Epidemiolgy and Genetics New study Etiologic Investigation of Cancer Susceptibility in Inherited Bone Marrow Failure Syndromes (IBMFS)
The NCI IBMFS Cohort consists of affected individuals and their immediate families in North America who have an inherited bone marrow failure syndrome (IBMFS), either one that has been specifically identified and defined, or bone marrow failure which appears to be inherited but has not yet been clearly identified as having a genetic basis. A cohort is a group of carefully defined and thoroughly evaluated study participants which is followed over time to analyze the medical events which occur in each person.
The most common of the IBMFS are:
• Amegakaryocytic Thrombocytopenia
• Diamond-Blackfan Anemia
• Dyskeratosis Congenita
• Fanconi's Anemia
• Pearson's Syndrome
• Severe Congenital Neutropenia
• Shwachman-Diamond Syndrome
• Thrombocytopenia Absent Radii
• Other Bone Marrow Failure Syndromes
There will be two subgroups of study participants in the NCI IBMFS Cohort: those who are seen and evaluated at the NIH Clinical Center (called the CC IBMFS Cohort), and those who participate by providing information but who are not seen by the NCI team at the NIH (called the Field IBMFS Cohort). email: Lisa LeathwoodFor more information about this study click this link:

SBDS Protein Expression in Peripheral Blood Leukocytes

Many families have participated in this study through CCHMC (Cincinnati Children's Hospital). For contact information, please visit the Shwachman-Diamond America website. From inforamtion given out at CCHMC:

Why is this research being done?

Shwachman-Diamond Syndrome (SDS) is a rare condition which is usually diagnosed in infancy or early childhood. It can affect a wide range of organs but most commonly the digestion and the blood system are involved. Bone abnormalities and poor growth are also often seen in SDS patients. The main hematologic (blood) problem is reduced prduction of some types of white blood cells by teh bone marrow. The pancreas is normally responsible for digesting food, but in SDS it doesn;t make enough digestive enzymes (e.g. trypsin and amylase). However, we have found that people with SDS may have quite different symptoms in teh various organs. In some people, for example, the pancreatic problem is severe and patients need to take extra digestive enzymes with meals. In others, digestive function may improve enough to allow the enzymes to be discontinued. Similarly, some people have more difficulties with their blood problem than others. Some of our research is directed at trying to explain why these differences occur from one individual to another.

Researchers at th Hospital for Sick Children have recently identified the altered gene (SBDS) gene that causes Shwachman-Diamond Syndrome. To date, a number of genetic mutations (mistakes in the SBDS gene) have been found in people who have this syndrome. In addition to the 3 common mutations which account for 75% of all mutations found, there are a ariety of less common mutations.

Healthy people with the normal SBDS gene make SBDS protein in their cells, whereas patients with mutations of teh SBDS gene do not produce this protein or only make very little. This special protein can be measured in blood samples. The amount of the SBDS protein detected in teh blood may vary depending on the tpe of SBDS mutation that is inherited. We think it is important to measure the amount of SBDS protein because it may help us to understand why SDS affects people differently. In addition, we think that measuring the SBDS protein in the blood may be helpful to make a diagnosis of SDS (or rule out the diagnosis), because it is not always possible to screen for all the SBDS mutations.

To do this, we need to test the SBDS protein in a defined group of people, who have common or rare SBDS mutations as well as people who have medical problems that may or may not be due to SBDS mutations. The later group includes children or adults who have a problem in the bone marrow or pancreas and/or skeleton that is suggestive of SDS but no identified mutations in the SDS gene. We will compare the results from people who are healthy as well as people who are known to be carriers such as parents of known SDS patients.

We are collaborating with Drs. Peter Durie and Johanna Rommens at the Hospital for Sick Cildren in Toronto and Dr. Akiko Shimamura at the University of Washington, as well as Drs. Elena Nicolis and MarcoCipolli in Verona, Italy, who will be measuring the corresponding SBDS mRNA in your blood sample. mRNA transmits the information from the gene (DNA) in order to make the protein. Since the SBDS mRNA controls the manufacture of SBDS protein, pople with SBDS mutations may also have very little SBDS mRNA. we will compare the SBDS mutations may alos have very little SBDS mRNA. We will compare the SBDS mRNA content with the SBDS protein level in each patient from our defined groups.

SDS Dentist-Dental Article

Dr. Glogauer and his team have done dental studies in SDS children. He is with teh University of Toronto. He has been helpful to my family in the past. They recently published an article on the Dental features of SDS titled: Prevalence of Oral Diseases in Shwachman-Diamond Syndrome

For more information, please contact me through the profile or Shwachman-Diamond America

Wednesday, February 20, 2008

Centers with a Bone Marrow Failure Clinic or GI clinic with experience in SDS

Ø Cincinnati Children’s Hospital
Contact: Richard Harris, MD, , (513) 636- 3570

Ø Hospital for Sick Children, Toronto
Contact Peter Durie, MD,, (416) 813-6185

Ø Children’s Hospital-Seattle, University of Washington, Seattle, WA Contact: Akiko Shimamura, MD,, (206) 685-5282

Ø Schneider Children’s Hospital, North Shore of Long Island, NY Contact: Jeff Lipton, MD,, (718) 470-3460

Ø National Institutes of Health (NIH), Division of Cancer Epidemiology and Genetics (Bone Marrow Failure Program)
Contact: Blanche Alter, MD,, (301) 402-9731

Saturday, February 16, 2008

Bone Marrow Biopsy Day

Bone Marrow Biopsy Day

A book for children who are facing a bone marrow biopsy. The idea for this book came from a scrapbook Pattie made for her two sons with Shwachman-Diamond Syndrome who have had over fifteen bone marrow biopsies each. Her youngest son, Joseph, always wanted to know what happened to him once he fell asleep in the OR. Once the first book was made for her children, a Child Life Specialist suggested that the book could help other families dealing with similar issues. A few changes later and this book was a reality. This edition includes a section for parents on helping children cope with medical procedures and other helpful topics for families dealing with chronic illness

We Take Enzymes

We Take Enzymes
We Take Enzymes was first written when Pattie’s sons were in pre-school and wondering why they had to take enzymes. In the first construction paper draft, Sean and Joseph helped with the text and drew the pictures in crayon. This book was read every day and helped them to understand the need for enzymes. This book educates young readers on the importance of taking enzymes and how these enzymes aid digestion. Told from Sean and Joseph’s perspective, this book will engage young readers with Shwachman-Diamond Syndrome and Cystic Fibrosis. The book also focuses on the role good nutrition and exercise play in growing and keeping one healthy. This book may be an encouragement to young readers who have special needs because it shows children with special needs leading full, exciting and rewarding lives.

Friday, February 15, 2008

Families Coping with Bone Marrow Failure Diseases

The Aplastic Anemia & MDS International Foundation, Inc has several great resources for families that have children with bone marrow diseases, such as Shwachman-Diamond Syndrome. Below is a summary of one booklet we found helpful for our own families. To order a free copy of this book, please visit the AA& MDS Foundation website.

Families Coping with Bone Marrow Failure Diseases: Aplastic Anemia, Myelodysplastic Syndromes and PNH -- This booklet goes into Reactions to illness, how to deal with reactions from others, changes to expect within the family, learning to cope…… also has sections on coping with hospital life and a section on helping children cope.

Thursday, February 14, 2008

Teachers and School Nurses Guide to Bone Marrow Failure Disease

The Aplastic Anemia & MDS International Foundation, Inc has several great resources for families that have children with bone marrow diseases, such as Shwachman-Diamond Syndrome. Below is a summary of one booklet we found helpful for our own families. To order a free copy of this book, please visit the AA& MDS Foundation website.

Teachers & School Nurses Guide to Bone Marrow Failure Disease – This booklet is an excellent resource for school staff. It discusses bone marrow failure, what symptoms to look for in a child that has bone marrow disease and includes a section on supporting a child’s emotional needs along with the classmates. Divided in sections for nurses and teachers, this is an excellent resource for any school that has a child with bone marrow failure attending.

Talking to a Child with Bone Marrow Disease

The Aplastic Anemia & MDS International Foundation, Inc has several great resources for families that have children with bone marrow diseases, such as Shwachman-Diamond Syndrome. Below is a summary of one booklet SDA found helpful for our own families. To order a free copy of this book, please visit the AA& MDS Foundation website.

Talking to a Child with Bone Marrow Disease – This is an excellent book created to be read aloud to a child of any age. It was written to encourage children with bone marrow diseases to ask questions and express their feelings. The illustrations are wonderful and the writing is excellent. It not only addresses having a bone marrow disease, but brings up topics that can help children learn positive coping skills in dealing with their disease. Topics include: What can I do when I am feeling bad?, What if I don’t want to talk? , Why do I get sick?, Why do I have to go to the hospital and Why do I need Medicine. It also touches on such topics as: Why is my family upset? And What do I tell my friends? There is a thoughtful section for children to fill out questions (fill in the blank) such as, I’m sad about____________, I need to speak up when __________________ and I love _______________ . The back part of the book includes a blank journal where the child can write about his or her experiences with bone marrow disease.

ANA and the anti-neutrophil antibody tests

The tests sometimes get confused because people who have autoimmune diseases such as Lupus (SLE) often times HAVE autoimmune induced neutropenia and thus have anti-neutrophil antibodies as well. One of the complications of SLE is neutropenia and leukopenia. BUT…not all people with SLE have neutropenia or leukopenia…… The anti-neutrophil test tests for specific neutrophil anitbodies while the ANA tests for or is used as a marker for SLE, RA, SJogren’s, etc and the effectiveness of treatment.

My understanding from the diagnostics books I have is that the ANA test tests for specific types of ANA that include antibodies to deoxyribonucleic acid, nucleoprotein, histones, nuclear ribonucleoprotein and other nuclear constituents. In the chart (Springhouse Diagnostics) they list 14 diseases where one would have a positive ANA test and autoimmune neutropenia is not listed. I’m not a doctor, so it could be a test they use to r/o AIN…. I’m just giving info from the book and it is not listed.

The anti-neutrophil antibody tests for antibodies against the antigens in the cytoplasm of the neutrophil.

The anti-neutrophil antibody test can be called the anti-neutrophil cytoplasmic antibody (ANCA) or some labs simply call it the Anti-neutrophil antibody w/o using an acronym here is what one lab says about the anti-neutrophil antibody test. It can get confusing because of the SLE (Lupus) connection of the two tests--

Again—I am not a doctor—just going on what I have read. My diagnostics testing books list them separately—and I could be interpreting that in the wrong way—so take what I write here with a grain of salt. Below is a bit of info on both tests from the internet—these are from ARUP’S laboratory test directory. ARUP’S lists them as two separate tests.

0055506: Anti-Neutrophil Antibody

See Frequently Asked Questions for this test.

Reference Interval:

Interpretive Data:
Anti-neutrophil antibody has been implicated in causing the neutropenia of various autoimmune disorders, including Felty syndrome, systemic lupus erythematosus (SLE), and drug-induced neutropenia. Isoimmune destruction may be caused by antibodies to neutrophil-specific antigens and HLA antigens in febrile transfusion reactions and isoimmune neonatal neutropenia. Circulating antibodies in patient's serum are measured by flow cytometry after incubation with normal neutrophils. Values greater than 2 standard deviations of the control population are interpreted as "weakly positive" and greater than 3 standard deviations as "positive." The ANA is the Antinuclear antibody test.

0050080: Anti-Nuclear Antibodies (ANA), IgG Screen with Reflex to IFA Titer

See Frequently Asked Questions for this test.


Reference Interval:
None detected /*EXISTREFRANGE>
Interpretive Data:
ANA samples are screened using an ELISA assay. All samples that screen positive or equivocal are titered using HEp-2 cells, and the titer and pattern will be reported. Anti-nuclear antibodies are seen in a variety of systemic rheumatic diseases. In general, a titer greater than or equal to 1:160 is considered a significant positive. Titers less than or equal to 1:80 are usually of no or questionable significance. Low titer ANAs are common with advancing age. /*EXISTINTERPDATA>
When cell culture substrates (HEp-2 cells) are used, the ANA incidence is 99% in systemic lupus erythematosus (SLE), 85% in Sjögren syndrome, 88% in scleroderma, 55% in rheumatoid arthritis, and 40% in juvenile rheumatoid arthritis. ARUP uses anti-human IgG conjugate since many (20-77%) normal individuals have low levels (1:10 to 1:80) of ANA-IgM. Conversion of ANAs from IgM to IgG generally precedes the onset of autoimmune disease states. If the physician feels that the patient may have an autoimmune disease that is the result of an atypical ANA, please contact the ARUP Immunology Lab to discuss alternative testing.

Alex Turnquist Memorial Research Grants

Alex Turnquist Memorial Research Grants

Shwachman-Diamond America awards Alex Turnquist Memorial Research grants up to $10,000. Grant proposals are accepted throughout the year. We do not have a grant request form.

SDA requires that the grant proposal be in writing and include the following:
1. Name of Applicant, Principal investigator, project title and summary of proposed investigation (include specific aims, significance and background, any preliminary studies…)

2. A detailed description of your hypothesis/hypotheses and proposed methodologies

3. Relevance of the research to Shwachman-Diamond Syndrome

4. Biographical information on the principal investigator and co-principal investigator, if relevant

5. A detailed budget sheet (grants are available up to $10,000)
Statement of facilities available

6. A starting date for the project

General Conditions for the Awarding of Alex Turnquist Memorial Research Grants:
1. The board wishes to receive periodic progress reports. They need not be lengthy. These reports will help Shwachman-Diamond America give updates to our donors, allow evaluation of progress by our medical advisor and assist SDA in future fundraising efforts.

2. Any publications distributed as a result of your research should give proper reference to Shwachman-Diamond America.

You can submit a grant proposal by emailing the Word or PDF file to: or via regular mail:

Shwachman-Diamond America
931-B South Main St. #332
Kernersville, NC 27284