Comparison of 3 Methods for Computing Loading Rate during Running.

Tibial stress fractures are among the most common and potentially serious overuse injuries in runners. The fractures are thought to be related in part, to excessive loading variables, such as vertical average loading rate (VALR) and vertical instantaneous loading rate (VILR). Although there are several methods for calculating loading rate in running, little is known about the differences between the results produced by these methods. The purpose of this study was to compare 3 previously published methods of calculating VALR and VILR during running. 9 male participants ran on a treadmill at 2.5, 3.0, and 3.5 m/s. VALR and VILR were calculated from vertical ground reaction force using 3 methods that differed by the period over which the loading rates were calculated; foot strike to first peak (method A), from 20 to 80% of the time to first peak (method B), and over the first 50 ms after foot strike (method C). There were significant differences among methods with regard to VALR, but not VILR. Therefore, the results of the present study suggest that VILR is preferable to VALR for consistent evaluation among methods, which make it more acceptable to make study comparisons.

The role of oxidative damage in poor scalp health: ramifications to causality and associated hair growth.

The oxidative stress element of unhealthy scalp leads to compromised pre-emergent hair formation and poorly formed hair as it grows. Only cosmetic solutions can minimize the impact of unhealthy hair and to achieve healthy looking and feeling hair, the scalp health must be normalized first. The objectives of this research were to both investigate whether oxidative stress was a relevant aetiological element in scalp dandruff and seborrhoeic dermatitis and whether scalp condition affects the quality of hair that grows from it. Further, this research was designed to determine whether an effective anti-dandruff shampoo would repair and protect the scalp and pre-emergent hair from oxidative stress. This study demonstrated that oxidative stress is an aetiological element relevant to the dandruff condition and that a potentiated ZPT shampoo effectively improves scalp condition, including a reduction in oxidative stress. The compromised hair condition associated with dandruff is concomitantly improved when the scalp condition is improved. It appears that there is a direct link between hair quality and scalp health.

Therapeutic efficacy of anti-dandruff shampoos: a randomized clinical trial comparing products based on potentiated zinc pyrithione and zinc pyrithione/climbazole.

OBJECTIVES: Dandruff is a chronic, relapsing scalp condition that negatively impacts the quality of life of sufferers. Regular use of anti-fungal shampoos represents a proven therapeutic strategy to improve the most common symptoms of flakes and itch. Two recent approaches for enhancing the efficacy of anti-fungal shampoos are maximizing bio-availability of the active material or the addition of a second active material. Our aim is to compare the therapeutic efficacy of these two approaches - maximization of bio-availability of the zinc pyrithione (ZPT) active material or the combination of ZPT with a secondary active material. METHODS: The anti-fungal potency of shampoos representing each of these approaches was evaluated in vitro using a standard microbiology method. Spatial delivery of ZPT particles in the follicular infundibulum was assessed in vivo using a novel confocal microscopy methodology. Clinical efficacy was assessed in a randomized, double-blind trial involving 620 male and female subjects using scalp flaking and epidermal histamine level as endpoints. RESULTS: The shampoo formula with maximized ZPT bio-availability known as the Potentiated ZPT formula exhibited greater anti-fungal potency than the Dual Active shampoo containing both ZPT and climbazole. The Potentiated ZPT formula also delivered more ZPT to the lower infundibulum than the Dual Active shampoo. A 4-week treatment with the Potentiated ZPT formula resulted in superior clinical efficacy compared with the Dual Active product at all 4 weekly time points for both flaking and epidermal histamine endpoints. CONCLUSION: These results highlight the critical role that the shampoo vehicle plays in realizing full potency of active materials. By optimizing the delivery vehicle, the enhanced anti-fungal potency and the maximized spatial delivery of active materials result in greater symptomatic improvement than a product with two active materials. The therapeutic efficacy of a product based on a complex delivery vehicle such as a shampoo must be considered from a full-product perspective rather than just the active system as the non-active components of the composition will often play a significant role in the overall product pharmacology and resultant efficacy.

Changes in blood circulation of the contralateral Achilles tendon during and after acupuncture and heating.

The purpose of this study was to investigate the effects of acupuncture and heating (application of hot pack) treatments on blood circulation in the contralateral Achilles tendon. During the treatments (10 min for acupuncture, 20 min for heating) and recovery period (40 min), the blood volume (THb) and oxygen saturation (StO2) of the treated and the non-treated tendons were measured using red laser lights. During both treatments, THb and StO2 of the treated tendon increased significantly from the resting level. The increased THb and StO2 of the treated tendon were maintained until the end of the recovery period after removal of the acupuncture needle, although these values decreased after removal of the hot pack. Although THb of the non-treated sides did not change during both acupuncture and heating treatments, it increased gradually after removal of the acupuncture needle or the hot pack. For both treatments, the amount of increase in THb of the non-treated tendon was significantly correlated to that of the treated tendon during the last phase of recovery period. These results obtained from the healthy subjects imply that blood circulation in the injured tendon in a plaster cast may be improved by applying acupuncture or heating treatments to the contralateral healthy limb.

Enhancement of heme and globin synthesis in cultured human marrow by certain 5 -H steroid metabolites.

These studies demonstrate that certain sex steroid metabolites are capable of significantly stimulating the synthesis of both heme and globin in cultured human bone marrow cells. These compounds, which are maximally effective at a concentration of 3 x 10(-8)M, are steroids of the C(19) and C(21) neutral type; share a common 5beta-H (A:B cis) configuration; and are derived from the in vivo biotransformation of testosterone or progesterone, or their intermediates, in man. Since these steroid metabolites have been shown to be capable in other systems of inducing the synthesis of delta-aminolevulinic acid synthetase, the limiting enzyme in the heme biosynthetic pathway, it is hypothesized that their action on human erythroid precursor cells is directed similarly at this enzymatic step leading thereby to increased heme production with consequent stimulation of globin synthesis. This steroid action is independent of erythropoietin, and since these compounds are effective at extremely low concentrations, it is suggested that they may play a physiologic role in the regulation of human erythropoiesis.

Natural killer-mediated lysis of normal and malignant target cells, and its regulation by monocytes.

After depletion of monocytes, natural killer (NK) cells were partially purified from peripheral blood by Percoll density gradient sedimentation. The NK cells were then cultured for 1 d and assayed for their cytotoxicity against various types of normal and malignant target cells. All types of target cells tested were found to be susceptible to NK cells. The susceptible targets were autologous T and B lymphocytes, mitogen-induced T and B blasts, monocytes, large granular lymphocytes, autologous or allogeneic lymphoma and leukemia cells isolated from patients, and cultured cell lines, including those resistant to interferon-activated lymphocytes. Such a broad spectrum of cytotoxicity was demonstrated in 1 d of culture, and freshly prepared NK cells were not cytotoxic, or, if anything, were less cytotoxic. Monocytes and their supernatants, added throughout the course of culture, markedly inhibited the development of their cytotoxicity. These results may suggest that, although NK cells having ability to lyse autologous normal and malignant target cells are present in vivo, their lytic activity is regulated by coexisting monocytes.

Fertilization of squirrel monkey and hamster ova in the rabbit oviduct (xenogenous fertilization).

Homologous sperm and ova of either squirrel monkeys or hamsters were placed in the oviducts of pseudopregnant rabbits. Xenogenous fertilization rates of 36 and 60 percent were obtained for squirrel monkey and hamster gametes, respectively.

Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice.

Impaired immune responses occur frequently in cancer patients or in tumor-bearing mice, but the mechanisms of the tumor-induced immune defects remain poorly understood. In an in vivo murine colon carcinoma model (MCA-38), animals bearing a tumor longer than 26 days develop CD8+ T cells with impaired cytotoxic function, decreased expression of the tumor necrosis factor-alpha and granzyme B genes, and decreased ability to mediate an antitumor response in vivo. T lymphocytes from tumor-bearing mice expressed T cell antigen receptors that contained low amounts of CD3 gamma and completely lacked CD3 zeta, which was replaced by the Fc epsilon gamma-chain. Expression of the tyrosine kinases p56lck and p59fyn was also reduced. These changes could be the basis of immune defects in tumor-bearing hosts.

Effect of selective vaccination on a decrease in the rate of hepatitis B virus-positive Japanese first-time blood donors.

The government of Japan started a selective vaccination programme to prevent mother-to-infant infection by hepatitis B virus (HBV) since January 1986. The effect of the programme on first-time blood donors has not been examined in detail. Data of first-time blood donors aged 16-25 years from 1996 to 2007 were extracted from the Japanese Red Cross (JRC) donors' database. Principal component analysis (PCA) was used to visualize the birth-year-dependent group of rate of HBV-positive donors. According to the birth of year, donors were divided into four groups by PCA. After the start of the programme, donors born in 1986-1989 comprised a single group. Before the start of the programme, three groups (1980, 1981-1984 and 1985) were identified. Although a significant time-dependent decrease in the rate of HBV-positive donors was observed before the start of the programme, a significant difference in the rate of HBV-positive donors was observed around the start of the programme by regression analysis for 16-19-year-old first-time blood donors. The selective vaccination programme has been effective to prevent the vertical transmission of HBV from the analysis of first-time blood donors. On the other hand, vaccination of blood donors should be considered to reduce the risk of post-transfusion HBV infection, because the horizontal transmission increases in HBV-positive blood donors.

A new method of concentrating hepatitis B virus (HBV) DNA and HBV surface antigen: an application of the method to the detection of occult HBV infection.

BACKGROUND: The risk of post-transfusion hepatitis B virus (HBV) infection has been reduced after the implementation of HBV nucleic acid amplification technology (NAT). However, the problem of HBV DNA-positive and HBV surface antigen (HBsAg)-negative occult HBV infections remains to be solved. This is in part due to the HBV DNA load being too low to detect these occult HBV infections using mini-pool NAT. In Japan, the assay for the antibody against the HBV core antigen (anti-HBc) has not completely excluded occult HBV infection. To solve this problem, we have developed a new method of concentrating HBV DNA and HBsAg simultaneously to increase the sensitivity of detection tests. METHODS: Virus concentration is achieved by the enhancement of the agglutination of viruses using poly-L-lysine in the presence of a bivalent metal. Poly-L-lysine-coated magnetic beads are used to shorten the time of each step of the concentration procedure. Seventy-seven anti-HBc-positive and HBsAg-negative donations were examined. HBsAg and anti-HBc were tested by enzyme immunoassay (EIA) (AxSYM; Abbott) and haemagglutination inhibition test (Japanese Red Cross), respectively. RESULTS: HBV surface antigen and HBV DNA levels were concentrated up to four- to sevenfold. Using this method, 35 of the 77 anti-HBc-positive and HBsAg-negative donors were HBV DNA-positive by individual NAT and a further five donors became HBV DNA-positive by HBV concentration. Twenty-seven of 40 occult HBV infections became HBsAg-positive by HBsAg concentration. CONCLUSION: Our new method of concentrating HBV and HBsAg increased the sensitivities of EIA and HBV NAT, and enabled us to detect 27 of 40 occult HBV infections by HBsAg EIA.

Telomeric DNA in normal and leukemic blood cells.

We studied telomeric DNA in leukemic cells as well as in normal T cells, B cells, monocytes, polymorphonuclear leukocytes, and bone marrow hematopoietic progenitor cells. No marked differences were observed in the sizes of the telomeric repeats in the various populations of normal blood cells obtained from donors in their twenties to sixties, and the telomere length ranged between 8.5 and 9.0 kb. The leukemic cells of 12 patients with acute leukemia (seven with myeloid and five with lymphoid leukemia) showed a variable reduction in the length of telomeric DNA, ranging from 2.7 to 6.4 kb. The average telomere length was 4.8 and 4.7 kb in myeloid and lymphoid leukemia, respectively, while the telomere length in peripheral blood mononuclear cells obtained from the same patients during complete remission was 8.5 and 7.9 kb, respectively. When the same Southern blots were hybridized with Alu or alphoid sequences, no marked changes in the sizes of the repetitive DNA sequences were observed, indicating that the DNA abnormality in the leukemic cells was specific to the telomere region. Investigation of telomeric DNA changes may be helpful in determining the biological properties of leukemic cells.

Reinforcing effects of morphine are reduced in tissue plasminogen activator-knockout mice.

Tissue plasminogen activator (tPA) plays a key role in neuroplasticity. We have recently demonstrated that the tPA-plasmin system is involved in the rewarding effects of drugs of abuse by regulating the release of dopamine in the nucleus accumbens. In the present study, we investigated whether tPA is involved in the reinforcing properties of morphine in a paradigm of drug self-administration. Eight-week-old tPA knockout and wild-type control mice were subjected to a single 24-h session of morphine self-administration under a fixed ratio (FR) 2 or a progressive ratio (PR) schedule of reinforcement after eight daily 30-min sessions of nose-poke training. tPA knockout mice responded significantly more often for morphine self-administration in a dose-dependent manner as compared with wild-type control mice. Under the PR schedule of morphine reinforcement, however, tPA knockout mice showed a lower breaking point than wild-type control mice. There was no significant difference in food-reinforced operant behavior, breaking points to food pellets, and saline self-administration between the two genotypes. The increased responding in tPA knockout mice under the FR2 schedule was significantly attenuated by the dopamine D1 receptor antagonist SCH23390 (0.3 mg/kg), whereas SCH23390, at a dose range of 0.03-2.0 mg/kg, demonstrated biphasic effects on morphine self-administration in wild-type control mice. Our findings suggest that the reinforcing effects of morphine are reduced in tPA knockout mice. Modulation of the tPA system in the brain may be a potential target against drugs of abuse.

17beta-estradiol attenuates hippocampal neuronal loss and cognitive dysfunction induced by chronic restraint stress in ovariectomized rats.

Several lines of evidence suggest that hormonal changes after menopause may play an important role in the incidence of cognitive dysfunction, and also in the development of Alzheimer's disease. In this study, we investigated the effect of estrogen on cognitive function in rats under different stress environment. Female rats were divided into four groups: two groups were ovariectomized (OVX) and two were sham-operated. One group each of OVX and sham rats was kept in a normal environment, and the other groups were assigned to a daily restraint stress (6 h/day) for 21 days from 2 months after the operation. Following the stress period, subjects were tested for performance in novel object recognition test and then used for morphological and neurochemical analyses. The OVX plus stress (OVX/stress) group showed a significant impairment of recognition of novel objects, compared with the other groups. The OVX/stress group also showed a marked decrease in the number of pyramidal cells of the CA3 region and levels of brain-derived neurotrophic factor mRNA in the hippocampus. We further examined the effect of estrogen against cognitive dysfunction and hippocampal changes of OVX/stress rats. Vehicle or 17beta-estradiol (E2) at 20 microg/day was s.c. administered to OVX/stress rats from 2 days before the stress period to the end of behavioral analysis through an implantable osmotic pump. Chronic E2 treatment decreased stress response and improved the cognitive and morphological impairments relative to vehicle group. These data have important implications for cognition enhancing effect of estrogen treatment in postmenopausal women.

Ginkgo biloba extract EGb 761 attenuates hippocampal neuronal loss and cognitive dysfunction resulting from chronic restraint stress in ovariectomized rats.

We have recently found that a combination of ovariectomy (OVX) and chronic restraint stress causes cognitive dysfunction and reduces hippocampal CA3 neurons in female rats and that estrogen replacement suppresses the OVX/stress-induced behavioral and morphological changes. In this study, we examined the effect of Ginkgo biloba extract (EGb 761), a popular herbal supplement, on the cognitive dysfunction and neuromorphological change in OVX/stress-subjected rats. Female Fisher 344 rats were randomly divided into three groups: vehicle-treated OVX, EGb 761 (50 mg/kg) -treated OVX and vehicle-treated sham-operated control groups. Two months after ovariectomy, all animals received restraint stress for 21 days (6 h/day), and were then subjected to a novel object recognition test followed by morphological examination by Nissl staining. EGb 761 was orally administered once daily until the behavioral analysis was done. Treatment with EGb 761 improved memory impairment and neuronal loss of hippocampus in the OVX/stress-subjected group in the same ways as 17beta-estradiol. On the other hand, EGb 761 did not affect the loss of bone mineral density and increase in body weight after OVX, although 17beta-estradiol attenuated them. These results have important implications for neuroprotective and cognition enhancing effects of EGb 761 in postmenopausal women and suggest that the effects are mediated by a different mechanism from estrogen.

Efficacy of a single evening dose of syrup containing paracetamol, dextromethorphan hydrobromide, doxylamine succinate and ephedrine sulfate in subjects with multiple common cold symptoms.

OBJECTIVE: The aim of this study was to evaluate the efficacy of a single night-time dose of a syrup containing paracetamol, dextromethorphan hydrobromide, doxylamine succinate and ephedrine sulfate in subjects with multiple cold symptoms. MATERIALS: A syrup containing 15 mg dextromethorphan hydrobromide, 7.5 mg doxylamine succinate, 600 mg paracetamol and 8 mg ephedrine sulfate (Wick MediNait produced by WICK Pharma, Germany, a subsidiary of Procter & Gamble GmbH; test syrup) or placebo (placebo syrup) for oral administration. METHODS: This was a randomized, double-blind, placebo-controlled, multi-center, parallel design study. At enrollment, eligible subjects had to have at least moderate nasal congestion and a runny nose, at least mild cough and at least mild pain with one or more of the following: sore throat, sore chest, headache or body pain/aches. Subjects were randomized into either Group T (test syrup) or Group P (placebo syrup). On the evening of enrollment, subjects rated baseline symptoms, ingested the assigned study product and completed symptom-relief assessments at 3 hours post-dosing. Within one hour of awakening the following morning, subjects completed night-time symptom relief and sleep satisfaction assessments. All symptoms were recorded using an Interactive Voice Response system. Treatment comparisons were made after adjusting for the severity of baseline symptom using analysis of covariance. RESULTS: Of 485 subjects who took the study product, 432 (224 in Group T; 208 in Group P) were evaluable for analysis. For the primary endpoint (composite of nasal congestion/runny nose/cough/pain relief scores 3 hours post-dosing), subjects in Group T had clinically and statistically significantly greater relief than Group P (p = 0.0002). Each individual symptom score also showed statistically significant improvement at this time point (p < or = 0.017). The next morning, Group T continued to show clinically and statistically significant benefits over Group P on the composite score and each of the individual symptoms (p < or = 0.003). Evidence of benefit with the test syrup was also seen in the higher score for overall night-time relief (p < 0.0001) and greater satisfaction on sleep (p = 0.002) compared to placebo syrup. Improvement in individual symptoms after 3 hours was obtained in 16-42% more subjects in Group T than in Group P, whereas the percentage of subjects in Group T having Good or Very Good relief the morning after dosing increased by 25-68% compared to subjects in Group P. 14 subjects (5 in Group T; 9 in Group P) reported AEs but none of these occurred with an incidence greater than 1%. There were no serious AEs. CONCLUSIONS: The results confirm the multisymptom benefit of a single dose of the test syrup containing paracetamol, dextromethorphan hydrobromide, doxylamine succinate and ephedrine sulfate and support its role as an effective and convenient therapy for symptoms of nasal congestion, runny nose, cough and pain/body aches associated with the common cold and for increasing sleep quality disturbed by the common cold.

Detection of novel germ-line p53 mutations in diverse-cancer-prone families identified by selecting patients with childhood adrenocortical carcinoma.

BACKGROUND: Germ-line p53 mutations appear to be inherited among the members of families diagnosed with Li-Fraumeni syndrome (LFS). The mutations detected in those families to date have been clustered in exon 7 of the p53 gene and, typically, have been single-base substitutions resulting in amino acid changes. PURPOSE: Our aim was to define the spectrum of p53 mutations associated with LFS. METHODS: From seven cancer-prone families identified by selecting members with childhood adrenocortical carcinoma as probands, we chose two families, each of which had two members from whom specimens could be obtained for genetic analysis. To detect germ-line p53 gene mutations in these individuals, we performed polymerase chain reaction (PCR)-single-strand conformation polymorphism analysis with Taq polymerase and oligonucleotide primers specific for p53 gene sequences. Genomic DNA extracted from fresh tissue samples and paraffin-embedded tumor samples was amplified, denatured, and electrophoresed on neutral polyacrylamide gels. PCR amplification was also carried out using total RNA from adrenocortical carcinoma samples of the proband in family 1. PCR products were purified, subcloned, and sequenced. RESULTS: We detected novel germ-line p53 mutations in affected members of both cancer-prone families. In the proband of family 1, a single-base deletion was detected at the first nucleotide of codon 307 in exon 8 of the p53 gene, resulting in a premature stop codon in exon 10. In family 2, we detected an A to C transversion at the second nucleotide of codon 286 in exon 8, both in DNA isolated from the adrenocortical tumor of the proband and in DNA isolated from the astrocytoma of the proband's father. This single-base substitution resulted in an amino acid substitution of alanine for glutamic acid. Both of these mutations are located outside the highly conserved region of the p53 gene where mutations in patients with LFS have been reported previously. CONCLUSION: Our results indicate that a wide range of germ-line p53 mutations is inherited in members of diverse-cancer-prone families.

Infrequent loss of chromosomal heterozygosity in human stomach cancer.

By molecular genetic approach using polymorphic DNA markers which detect allelic deletion at specific chromosomal loci, we analyzed 30 human stomach cancers for possible loss of chromosomal heterozygosity. We analyzed 25 loci on 18 different chromosomes covering regions frequently deleted in several types of cancers. Loss of chromosomal heterozygosity was observed only in five of 30 cases examined, and it was infrequently detected at 10 loci on seven different chromosomes including chromosome 1 in two of 12 cases, chromosome 12 in one of four cases and chromosome 13 in three of 27 cases. It was also observed at loci on chromosomes 11, 14, 16, and 19 with very low frequency (less than 10%), but not on other chromosomes: chromosomes 3, 5, 6, 9, 10, 15, 17, 18, 20, and 22. Thus, in human stomach cancer, loss of heterozygosity occurs infrequently even at chromosomal loci often deleted in other types of cancers.

Frequent allelic losses on chromosomes 2q, 18q, and 22q in advanced non-small cell lung carcinoma.

Although it is widely accepted that tumor suppressor genes play an important role in the genesis and progression of human cancer, little is known about genetic events that accumulate during multistage lung carcinogenesis. Thus, to determine a subset of tumor suppressor genes that are involved in the genesis and progression of non-small cell lung carcinoma (NSCLC), 22 brain metastases and 23 stage I primary lung tumors were examined for allelic losses at 40 loci on 10 chromosomes including the loci of 5 tumor suppressor genes, APC, WT1, RB, p53, and DCC. The incidence of allelic losses on chromosomes 3p, 13q, and 17p was high (> 60%) in both primary tumors and brain metastases. In brain metastases, a high incidence of allelic losses (> 60%) was also observed at loci on chromosomes 2q, 18q, and 22q, and the incidence of allelic losses on these chromosomes in brain metastases was significantly higher than that in primary tumors (P < 0.05). In two cases of brain metastases with corresponding primary lung tumors, sequential accumulation of allelic losses during progression of primary lung tumors was observed on several chromosomes including chromosomes 2q and 18q. These results indicate that, besides loss of heterozygosity for chromosomes 3p, 13q, and 17p, loss of heterozygosity for chromosomes 2q, 18q, and 22q also occurs frequently in advanced NSCLCS. Thus, it is possible that loss of heterozygosity on chromosomes 2q, 18q, and 22q occurs late in the progression of NSCLC and/or causes phenotypic alterations of NSCLC cells into more aggressive ones.

Maintenance of normal imprinting of H19 and IGF2 genes in neuroblastoma.

H19 and insulin-like growth factor II (IGF2) are among a few genes which have been confirmed to be imprinted in normal human embryonal tissues. This results in monoallelic expression of maternal H19 and paternal IGF2. Loss of imprinting of these genes producing biallelic expression has been observed in Wilm's tumor and embryonal rhabdomyosarcoma, suggesting that an epigenetic change of DNA, in addition to a genetic change in oncogene(s) and/or tumor suppressor gene(s), may be involved in the development of these childhood cancers. Neuroblastoma, which is an embryonal tumor originating from neural crest-derived cells, occasionally occurs in individuals with the Beckwith-Wiedemann syndrome; Wilm's tumor and embryonal rhabdomyosarcoma occur even more frequently in the Beckwith-Wiedemann syndrome; and paternal uniparental disomy of H19 and IGF2 loci (chromosome 11p15) is present in the Beckwith-Wiedemann syndrome. Furthermore, neuroblastoma cell lines express IGF2, and autocrine/paracrine effects of IGF2 have been demonstrated in these cells. Thus, we examined for imprinting of both H19 and IGF2 in primary untreated neuroblastomas using the RsaI and ApaI polymorphisms within these genes, respectively. Seven of 15 tumors were informative for H19 and for IGF2, and all of these cases showed monoallelic expression of both of these genes. These results indicate that loss of imprinting of H19 and IGF2 does not occur in neuroblastomas.

Allelic loss in the progression of myelodysplastic syndrome.

To elucidate the genetic events that may play an important role in the progression of myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML), we performed allelotype analysis of 24 individuals using matched MDS and AML samples from the same patients. Because the evolution can take years to occur, we used DNAs extracted from archival samples. These samples were analyzed with 79 microsatellite markers, which mapped to each of the autosomal arms except the short arms of the acrocentric chromosomes. Loss of heterozygosity on at least one locus was observed in 18 of the 24 cases (75%) as the disease progressed. Frequent allelic loss in >20% of the informative cases was observed on chromosome arms 6q (31%), 7p (23%), 10p (31%), 11q (27%), 14q (25%), and 20q (23%). Although cytogenetic information was available for many of our cases with allelic loss on 6q, 7p, 10p, 11q, 14q, and 20q, no deletions were observed on these arms. Fractional allelic loss, calculated for each sample as the total number of chromosomal arms lost per total number of arms with information, showed a median value of 0.06 and a mean of 0.15 (range, 0-0.59). No microsatellite instability at more than one marker was found in any of the samples. These results suggest that tumor suppressor genes exist on 6q, 7p, 10p, 11q, 14q, and 20q that have an important role in the evolution of MDS to AML when they are mutated.