bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of meiotic recombination on the production of aneuploid gametes in humans
Authors: Lamb N.E. , Sherman S.L. , Hassold T.J.
Published: September 2005

Within the last decade, aberrant meiotic recombination has been confirmed as a molecular risk factor for chromosome nondisjunction in humans. Recombination tethers homologous chromosomes, linking and guiding them through proper segregation at meiosis I. In model organisms, mutations that disturb the recombination pathway increase the frequency of chromosome malsegregation and alterations in both the amount and placement of meiotic recombination are associated with nondisjunction. This association has been established for humans as well. Significant alterations in recombination have been found for all meiosis I-derived trisomies studied to date and a subset of so called “meiosis II” trisomy. Often exchange levels are reduced in a subset of cases where the nondisjoining chromosome fails to undergo recombination. For other trisomies, the placement of meiotic recombination has been altered. It appears that recombination too near the centromere or too far from the centromere imparts an increased risk for nondisjunction. Recent evidence from trisomy 21 also suggests an association may exist between recombination and maternal age, the most widely identified risk factor for aneuploidy. Among cases of maternal meiosis I-derived trisomy 21, increasing maternal age is associated with a decreasing frequency of recombination in the susceptible pericentromeric and telomeric regions. It is likely that multiple risk factors lead to nondisjunction, some age dependent and others age independent, some that act globally and others that are chromosome specific. Future studies are expected to shed new light on the timing and placement of recombination, providing additional clues to the link between altered recombination and chromosome nondisjunction.
The association of skewed X chromosome inactivation with aneuploidy in humans
Authors: Bretherick K. , Gair J. , Robinson W.P.
Published: September 2005

Recently, we reported that skewed X chromosome inactivation (XCI) was more common in women who had experienced a trisomic pregnancy as compared to control women. Rather than an overall shift in the distribution of skewing there appears to only be an excess of extreme (= 95%) skewing. Further analysis of our data reveals that the increase in skewed XCI is dependent on which chromosome is involved in the trisomy and how many trisomies the woman has experienced, although sample sizes in each group are small. In this review we discuss limitations of the commonly used assays of XCI, which use measurements of DNA methylation to infer skewing patterns, and review the data based on current knowledge of the causes of XCI skewing. Gonadal mosaicism, premature aging, loss of methylation at some CpGs, and X-linked mutations can all be considered as potential mechanisms explaining both increased risk of trisomy and skewed XCI. While further research is needed to evaluate the role of each of these, the association of trisomy with apparent skewed XCI in the mother offers new opportunities to clarify the risk factors for and causes of the high incidence of aneuploidy in human females.
Biological aging and the etiology of aneuploidy
Authors: Warburton D.
Published: September 2005

A prevalent hypothesis concerning the cause of the rise in aneuploid conceptions with maternal age is that the changes that accompany normal ovarian aging increase the rate of meiotic errors in the oocyte. Biological aging of the ovary is accompanied by a decline in both the total oocyte pool and the number of antral follicles maturing per cycle, as well as changes in the levels of circulating reproductive hormones. The biological aging hypothesis predicts that aneuploidy rates should be higher in women with a prematurely reduced oocyte pool, and that women with trisomic conceptions should show signs of earlier ovarian aging than women of the same chronological age without trisomic conceptions. Comprehensive studies of aneuploidy in groups of women with known causes of premature ovarian failure remain to be done, though anecdotal evidence does suggest increased rates of pregnancy loss and aneuploidy. Smoking, which is a well-documented cause of earlier ovarian aging, is not associated with an increase in aneuploid conceptions. Evidence from women with unilateral ovariectomies is inconsistent. Support for the biological aging hypothesis was provided by one study showing that menopause occurred about a year earlier in women with a trisomic spontaneous abortion compared to women with chromosomally normal conceptions. Associations between high FSH and pregnancies with Down syndrome and chromosomally abnormal spontaneous abortions have also been reported. However, the most direct test of the hypothesis, which compared antral follicle counts and hormonal levels in women with trisomic pregnancies and those with chromosomally normal pregnancies, failed to find a difference in the expected direction. A prospective study of FSH levels in women with subfertility also failed to find an association with the rate of pregnancy loss. The bulk of evidence thus suggests that, if the processes of biological aging are indeed related to aneuploidy, they probably involve factors other than those measured by oocyte or antral follicle pool size and reproductive hormone levels.
Risk factors for nondisjunction of trisomy 21
Authors: Sherman S.L. , Freeman S.B. , Allen E.G. , Lamb N.E.
Published: September 2005

The leading cause of Down syndrome (DS) is nondisjunction of chromosome 21 occurring during the formation of gametes. In this review, we discuss the progress made to identify risk factors associated with this type of chromosome error occurring in oogenesis and spermatogenesis. For errors occurring in oocytes, the primary risk factors are maternal age and altered recombination. We review the current progress made with respect to these factors and briefly outline the potential environmental and genetic influences that may play a role. Although the studies of paternal nondisjunction are limited due to the relatively small proportion of errors of this type, we review the potential influence of paternal age, recombination and other environmental and genetic factors on susceptibility. Although progress has been made to understand the mechanisms and risk factors that underlie nondisjunction, considerably more research needs to be conducted to dissect this multifactorial trait, one that has a considerable impact on our species.
Segregation of chromosomes in sperm of reciprocal translocation carriers: a review
Authors: Benet J. , Oliver-Bonet M. , Cifuentes P. , Templado C. , Navarro J.
Published: September 2005

Reciprocal translocations, the most frequent structural aberration in humans, are mainly transmitted by one of the parents. In order to analyze the chromosomal content of the spermatozoa from carriers of chromosomal reorganizations, two methods have been used, karyotyping of sperm chromosomes by the human-hamster system and fluorescence in situ hybridization (FISH) in decondensed sperm nuclei. In this work, we review 92 sperm chromosome segregation studies from 85 different reciprocal translocation carriers, including a triple translocation carrier. Using the human-hamster method, a total of 5,818 spermatozoa from 44 reciprocal translocation carriers have been analyzed, 43 of them carrying a single reciprocal translocation and one was a carrier of a double reciprocal translocation. A segregation analysis in a carrier of a t(2;22;11) has been also reported. Carrying out FISH in sperm nuclei, a total of 237,042 spermatozoa from 46 reciprocal translocation carriers have been analyzed. Six of these were also analyzed by the human-hamster system. Taking into account both methods, a total of 76 different reciprocal translocations have been studied. In 74 of these 76 translocations, the reorganization occurs between autosomes, and in the other two, the Y chromosome is involved. Although along general lines, there are similarities between the results obtained by the two methods of analysis, variations are observed when the distribution of the different types of segregations that produce imbalances is compared. As a general rule reciprocal translocation carriers produce more unbalanced sperm than normal or balanced sperm. The results reported also corroborate that the proportion of unbalanced forms depends on the characteristics of the reorganization and that it varies widely. Thus the importance of performing a detailed meiotic behavior analysis for each particular translocation in order to obtain enough information to give adequate genetic counseling is stressed. Aspects as to the possible overestimation of 3:1 segregations or the presence of interchromosomal effects still need to be elucidated.
Sperm studies in heterozygote inversion carriers: a review
Authors: Anton E. , Blanco J. , Egozcue J. , Vidal F.
Published: September 2005

The risk of producing unbalanced gametes in heterozygous inversion carriers mostly depends on the occurrence of recombination events within the inverted segment. Recombination determines the possibility of producing chromosomes with duplications/deficiencies (pericentric inversions) or with duplications/deficiencies which furthermore appear as dicentric and acentric fragments (paracentric inversions). In this work, a general description of the close relationship between the occurrence of crossovers in pericentric and paracentric inversions and the final segregation outcome is presented. After this introduction, a compilation of inversion segregation data and interchromosomal effect results from previously published sperm studies have been reviewed. Segregation results indicate a great heterogeneity in the percentage of unbalanced gametes, from 0 to 37.38%. The size of the inverted segments and their proportion in the chromosome are two parameters closely related with the incidence of recombination (P < 0.0001; using a quadratic model and Pearson’s correlation test). These results suggest that the production of a significant level of unbalanced gametes would require a minimum inversion size of 100 Mbp and the inversion of at least 50% of the chromosome. Interchromosomal effects are seldom observed in chromosomal inversions. Finally, implications of the meiotic behavior of the inversions in the progeny of the carriers and the incorporation of sperm FISH segregation analysis for reproductive genetic counseling are discussed.
Analysis of chromosome segregation during preimplantation genetic diagnosis in both male and female translocation heterozygotes
Authors: Munné S.
Published: September 2005

Individuals carrying translocations suffer from reduced fertility or spontaneous abortions and seek help in form of assisted reproductive technology (ART) and preimplantation genetic diagnosis (PGD). While most translocations are relatively easy to detect in metaphase cells, the majority of embryonic cells biopsied in the course of in vitro fertilization (IVF) procedures are in interphase. These nuclei are thus unsuitable for analysis by chromosome banding or painting using fluorescence in situ hybridization (FISH). Thus several methods have been devised to detect translocation imbalance through FISH in single cells for purpose of PGD, among them polar body chromosome painting, interphase FISH with combination of subtelomeric and centromeric probes, breakpoint spanning probes, and cell conversion. Results with PGD indicate a significant decrease in spontaneous abortions, from 81% before PGD to 13% after PGD. They also indicate very high rates of chromosome abnormalities in embryos from translocation carriers, 72% for Robertsonian translocations and 82% for reciprocal translocations. Sperm analysis was found to be a good predictor of IVF and PGD outcome, with samples with more than 60% abnormal forms indicating poor prognosis. Similarly, the predictability from first PGD cycle results for future cycles was 90%. In summary, PGD can help translocation carriers to achieve viable pregnancies, but the success of the process is conversely related to the baseline of unbalanced gametes.
Chromosome abnormalities in sperm of individuals with constitutional sex chromosomal abnormalities
Authors: Ferlin A. , Garolla A. , Foresta C.
Published: September 2005

The most common type of karyotype abnormality detected in infertile subjects is represented by Klinefelter’s syndrome, and the most frequent non-chromosomal alteration is represented by Y chromosome long arm microdeletions. Here we report our experience and a review of the literature on sperm sex chromosome aneuploidies in these two conditions. Non mosaic 47,XXY Klinefelter patients (12 subjects) show a significantly lower percentage of normal Y-bearing sperm and slightly higher percentage of normal X-bearing sperm. Consistent with the hypothesis that 47,XXY germ cells may undergo and complete meiosis, aneuploidy rate for XX- and XY-disomies is also increased with respect to controls, whereas the percentage of YY-disomies is normal. Aneuploidy rates in men with mosaic 47,XXY/46,XY (11 subjects) are lower than those observed in men with non-mosaic Klinefelter’s syndrome, and only the frequency of XY-disomic sperm is significantly higher with respect to controls. Although the great majority of children born by intracytoplasmic sperm injection from Klinefelter subjects are chromosomally normal, the risk of producing offspring with chromosome aneuploidies is significant. Men with Y chromosome microdeletions (14 subjects) showed a reduction of normal Y-bearing sperm, and an increase in nullisomic and XY-disomic sperm, suggesting an instability of the deleted Y chromosome causing its loss in germ cells, and meiotic alterations leading to XY non-disjunction. Intracytoplasmic injection of sperm from Y-deleted men will therefore transmit the deletion to male children, and therefore the spermatogenic impairment, but raises also concerns of generating 45,X and 47,XXY embryos.
Somatic chromosomal abnormalities in infertile men and women
Authors: Mau-Holzmann U.A.
Published: September 2005

Infertility – the inability to achieve conception or sustain a pregnancy through to live birth – is very common and affects about 15% of couples. While chromosomal or genetic abnormalities associated with azoospermia, severe oligozoospermia or primary ovarian failure were of no importance for reproduction prior to the era of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), advances in assisted reproductive techniques (ART) now enable many infertile couples to have children. These developments have raised the question of the genetic consequences of ICSI: concerns of the potential harm of the invasive procedure and concerns about the genetic risk. The infertile male and female definitely have an increased risk to carry a chromosomal abnormality. Detection of such an abnormality is of fundamental importance for the diagnosis of infertility, the following treatment, the evaluation of the risk for the future child and the appropriate management of the pregnancy to be obtained. Therefore, cytogenetic screening of both partners is mandatory prior to any type of ART. The present review is based on several surveys on male and female infertility and analyzes the types and frequencies of the different reported chromosome abnormalities according to the type of impairment of spermatogenesis and the type of treatment planned or performed. With regard to assisted reproductive techniques (especially ICSI) the main types of chromosomal abnormalities are discussed and their potential risks for ICSI. If available, reported cases of performed ICSI and its outcome are presented. The detection of an abnormal karyotype should lead to comprehensive genetic counselling, which should include all well-known information about the individual type of anomaly, its clinical relevance, its possible inheritance, the genetic risk of unbalanced offspring, and the possibilities of prenatal diagnosis. Only this proceeding allows at-risk couples to make an informed decision regarding whether or not to proceed with ART. These decisions can be made only when both partners have clearly understood the genetic risks and possible consequences when ART is used.
Male infertility in reciprocal translocation carriers: the sex body affair
Authors: Oliver-Bonet M. , Ko E. , Martin R.H.
Published: September 2005

Previous reports have linked chromosomal reorganization and spermatogenic failure. In this context, it has long been known that reciprocal translocation carriers are more likely to have anomalies in the meiotic process, including fertility failures. It has also been proposed that this fertility failure may be a consequence of an association between the translocated chromosomes and the sex body. In this work, we review different hypotheses explaining meiotic failure in these carriers, and propose a model that relates meiotic abnormalities with both sex body-translocation association and different checkpoints that are known to operate during meiosis.
Chromosome abnormalities in sperm from infertile men with normal somatic karyotypes: teratozoospermia
Authors: Machev N. , Gosset P. , Viville S.
Published: September 2005

Teratozoospermia is characterized by the presence of spermatozoa with abnormal morphology in sperm. This condition is frequently associated with infertility and intracytoplasmic sperm injection (ICSI) is frequently used as the treatment of choice. However, the use of ICSI has created consequential debate concerning the genetic risk for the offspring. Fluorescence in situ hybridization technique (FISH), allowing the specific identification of human chromosomes in sperm nuclei, has been used to study chromosome abnormalities in sperm from men with teratozoospermia and a normal karyotype. In this review, we present studies that have tried to determine if men with a normal blood karyotype but suffering from teratozoospermia present a higher aneuploidy frequency. The literature is limited to three forms of teratozoospermia. The first group consists of “polymorphic teratozoospermia”, where a majority of spermatozoa display more than one type of abnormality. In this case, only a slight increase in aneuploidy frequency is observed, which cannot be differentiated from the results observed in oligo-astheno-teratozoospermia (OAT). The second group, named “globozoospermia”, is characterized by round spermatic heads, absence of acrosome and disorganization of mid-piece and tail. In this case, some studies have shown a significant, but moderate, increase in the aneuploidy frequency for acrocentrics and sex chromosomes. The aneuploidy frequency remains low, also ICSI can be proposed to these patients, but few successes occur. The third group consists of “enlarged head teratozoospermia”, where almost all spermatozoa have an enlarged head, multiple tail and abnormal acrosome. In this case a very high level of missegregation is observed, leading to nearly 100% aneuploidy. In this particular group, ICSI must be refuted, and patients have to be redirected to other possibilities, like sperm donation.
Chromosome abnormalities in spermatozoa of patients with azoospermia and normal somatic karyotype
Authors: Burrello N. , Vicari E. , Calogero A.E.
Published: September 2005

Since epididymal and testicular spermatozoa of azoospermic patients are frequently used for intracytoplasmic sperm injection (ICSI), many studies have been carried out to evaluate their karyotype. This article will review all published data on this topic. In most of the studies, spermatozoa have been retrieved from the testis or the epididymis of patients with nonobstructive (NOA) or obstructive (OA) azoospermia, respectively. Sperm aneuploidy has been evaluated by fluorescence in situ hybridization using probes for sex chromosomes and an array of autosomes. A significantly higher sperm aneuploidy rate has been reported in patients with NOA and OA compared to ejaculated spermatozoa, mainly for sex chromosomes. The magnitude of the increase varies between studies, probably because of the heterogeneity of case selection as well as of the methodology employed. The majority of the studies reported that patients with NOA have a greater sperm aneuploidy rate compared to OA. The greater frequency of sperm aneuploidy in azoospermic patients increases the risk of transmitting a karyotype abnormality to the offspring generated by ICSI.
Immunofluorescent synaptonemal complex analysis in azoospermic men
Authors: Sun F. , Greene C. , Turek P.J. , Ko E. , Rademaker A. , Martin R.H.
Published: September 2005

The molecular cause of germ cell meiotic defects in azoospermic men is rarely known. During meiotic prophase I, a proteinaceous structure called the synaptonemal complex (SC) appears along the pairing axis of homologous chromosomes and meiotic recombination takes place. Newly-developed immunofluorescence techniques for SC proteins (SCP1 and SCP3) and for a DNA mismatch repair protein (MLH1) present in late recombination nodules allow simultaneous analysis of synapsis, and of meiotic recombination, during the first meiotic prophase in spermatocytes. This immunofluorescent SC analysis enables accurate meiotic prophase substaging and the identification of asynaptic pachytene spermatocytes. Spermatogenic defects were examined in azoospermic men using immunofluorescent SC and MLH1 analysis. Five males with obstructive azoospermia, 18 males with nonobstructive azoospermia and 11 control males with normal spermatogenesis were recruited for the study. In males with obstructive azoospermia, the fidelity of chromosome pairing (determined by the percentage of cells with gaps [discontinuities]/splits [unpaired chromosome regions] in the SCs, and nonexchange SCs [bivalents with 0 MLH1 foci]) was similar to those in normal males. The recombination frequencies (determined by the mean number of MLH1 foci per cell at the pachytene stage) were significantly reduced in obstructive azoospermia compared to that in controls. In men with nonobstructive azoospermia, a marked heterogeneity in spermatogenesis was found: 45% had a complete absence of meiotic cells; 5% had germ cells arrested at the zygotene stage of meiotic prophase; the rest had impaired fidelity of chromosome synapsis and significantly reduced recombination in pachytene. In addition, significantly more cells were in the leptotene and zygotene meiotic prophase stages in nonobstructive azoospermic patients, compared to controls. Defects in chromosome pairing and decreased recombination during meiotic prophase may have led to spermatogenesis arrest and contributed in part to this unexplained infertility.
Pesticides and the induction of aneuploidy in human sperm
Authors: Härkönen K.
Published: September 2005

Pesticides are some of the most frequently released toxic chemicals into the environment. Exposure to them has been associated with reproductive dysfunction, but the knowledge of the genotoxic risks of these substances is still limited. In vitro and in vivo, many pesticides are shown to induce aneuploidy. Analysis of sperm chromosomes by fluorescence in situ hybridization (FISH) with chromosome-specific probes has obtained increasing popularity in genetic toxicology. Sperm-FISH studies on men exposed to pesticides have yielded conflicting results: in men exposed to multiple pesticides during spraying no increased disomy frequencies in sperm were observed, although one study reported an increased rate of sex chromosome nullisomy. In contrast the two studies conducted in pesticide factories showed increased frequencies of sperm aneuploidy in exposed men compared to controls. The available data indicates that at least some of the commonly used pesticides are capable of inducing aneuploidy in human sperm when the exposure level is high enough.
Mechanisms and chemical induction of aneuploidy in rodent germ cells
Authors: Mailhes J.B. , Marchetti F.
Published: September 2005

The objective of this review is to suggest that the advances being made in our understanding of the molecular events surrounding chromosome segregation in non-mammalian and somatic cell models be considered when designing experiments for studying aneuploidy in mammalian germ cells. Accurate chromosome segregation requires the temporal control and unique interactions among a vast array of proteins and cellular organelles. Abnormal function and temporal disarray among these, and others to be identified, biochemical reactions and cellular organelles have the potential for predisposing cells to aneuploidy. Although numerous studies have demonstrated that certain chemicals (mainly those that alter microtubule function) can induce aneuploidy in mammalian germ cells, it seems relevant to point out that such data can be influenced by gender, meiotic stage, and time of cell-fixation post-treatment. Additionally, a consensus has not been reached regarding which of several germ cell aneuploidy assays most accurately reflects the human condition. More recent studies have shown that certain kinase, phosphatase, proteasome, and topoisomerase inhibitors can also induce aneuploidy in rodent germ cells. We suggest that molecular approaches be prudently incorporated into mammalian germ cell aneuploidy research in order to eventually understand the causes and mechanisms of human aneuploidy. Such an enormous undertaking would benefit from collaboration among scientists representing several disciplines.
Treatment of Obesity Hypoventilation Syndrome and Serum Leptin
Authors: Yee Brendon J. , Cheung Jane , Phipps Paul , Banerjee Dev , Piper Amanda J. , Grunstein Ronald R.
Published: September 2005

Background: Leptin is a protein produced by adipose tissue that circulates to the brain and interacts with receptors in the hypothalamus to inhibit eating. In obese humans, serum leptin is up to four times higher than in lean subjects, indicating that human obesity is associated with a central resistance to the weight-lowering effects of leptin. Although the leptin-deficient mouse (ob/ob) develops obesity hypoventilation syndrome (OHS), in humans with OHS, serum leptin is a better predictor of awake hypercapnia in obesity than the body mass index (BMI). This suggests that central leptin resistance may promote the development of OHS in humans. We speculated that the reversal of OHS by regular non-invasive ventilation (NIV) therapy decreases leptin levels. Objectives: The aim of this study was to investigate whether ventilatory treatment of OHS would alter circulating leptin concentrations. Method: We measured fasting serum leptin levels, BMI, spirometry and arterial blood gases in 14 obese hypercapnic subjects undergoing a diagnostic sleep study. Results: The average age of the subjects was (mean ± SE) 62 ± 13 years, BMI 40.9 ± 2.2 kg/m2, PaCO2 6.7 ± 0.2 kPa, PaO2 8.9 ± 0.4 kPa and total respiratory disturbance index 44 ± 35 events/hour. Subjects were clinically reviewed after a median of 2.3 years (range 1.6–3) with repeat investigations. Nine patients were regular NIV users and 5 were non-users. NIV users had a significant reduction in serum leptin levels (p = 0.001), without a change in BMI. In these patients, there was a trend towards an improved daytime hypercapnia and hypoxemia, while in the 5 non-users, no changes in serum leptin, BMI or arterial blood gases occurred. Conclusion: Regular NIV use reduces serum leptin in OHS. Leptin may be a modulator of respiratory drive in patients with OHS.
Production of Salivary Immunoglobulin A and Suppression of Dermatophagoides pteronyssinus-Induced Airway Inflammation by Local Nasal Immunotherapy
Authors: Liu Yi-Hsia , Tsai Jaw-Ji
Published: September 2005

Background: Local nasal immunotherapy (LNIT) is an effective immunotherapeutic modality, especially when targeting a single immunodominant peptide from an allergen. However, the working mechanisms of LNIT are poorly understood. We hypothesized that LNIT with a mixture of group 2 allergens of Dermatophagoides pteronyssinus (Der p 2) protein and fungal immunomodulatory peptide (FIP) would generate suppression of Der p-induced airway inflammation through immunoglobulin (Ig) A secretion in the airways. Method: Mice were sensitized with recombinant Der p 2 (rDer p 2) and Der p followed by LNIT with rDer p 2 in conjunction with FIP. After intratracheal challenge with rDer p 2 and Der p, the airway inflammation was determined by analyzing the cell subpopulation and cytokine concentration in the bronchoalveolar lavage fluid. The allergen-specific IgE, IgG2a and IgG in the sera and IgA in the saliva were measured by ELISA. Results: LNIT with rDer p 2 in conjunction with FIP could downregulate the lymphocyte infiltration in both rDer p 2- and Der p-induced airway inflammation. Both total and specific IgA in the saliva were increased after LNIT. Serum levels of IL-4, IL-10 and specific IgE were reduced and the specific IgG2a and IgG increased after LNIT. After LNIT, there was a reduction of airway hypersensitivity at 30 min after allergen challenge in the rDer p 2-and Der p-sensitized mice, with a significant decrease only in rDer p 2-sensitized mice. Conclusion: LNIT with rDer p 2 in conjunction with FIP was not only able to suppress rDer p 2-induced airway inflammation but also generate suppression of Der p-induced airway inflammation. The simultaneous reduction of IL-4 and IL-10 indicated that IL-10-producing cells were not activated by LNIT. The increment of IgA in the airway might play a role in the prevention of airway inflammation.
Matrix Metalloproteinase-12 and Cathepsin D Expression in Pulmonary Macrophages and Dendritic Cells of Cigarette Smoke-Exposed Mice
Authors: Bracke Ken , Cataldo Didier , Maes Tania , Gueders Maud , Noël Agnes , Foidart Jean-Michel , Brusselle Guy , Pauwels Romain A.
Published: September 2005

An imbalance between proteinases and their inhibitors is believed to play an essential role in the development of chronic obstructive pulmonary disease (COPD) and pulmonary emphysema. COPD is mainly caused by cigarette smoking, and is characterized by an increase in inflammatory cells in small airways and lung parenchyma. We examined the mRNA expression of several proteinases in lungs of mice exposed to cigarette smoke or control air. After 1, 3 and 6 months’ smoke exposure there was a significant increase of matrix metalloproteinase (MMP)-12 and Cathepsin D mRNA, compared to air-exposed mice. To determine the cellular origin of MMP-12 and Cathepsin D, we isolated dendritic cells (DCs) and macrophages from the lungs of mice. There was an increase in MMP-12 mRNA after smoke exposure in both macrophage and DC populations, whereas Cathepsin D was predominantly expressed in macrophages. Immunohistochemistry clearly revealed the expression of Cathepsin D protein in alveolar macrophages of cigarette smoke-exposed mice, in contrast to air-exposed littermates. Western blots on lung tissue demonstrated an increase of MMP-12 protein in cigarette smoke-exposed animals. These results indicate that cigarette smoke increases the expression of MMP-12 and Cathepsin D in the lungs of mice, and that not only macrophages but also DCs produce MMP-12.
Corpus Callosum in Neurodegenerative Diseases: Findings in Parkinson’s Disease
Authors: Wiltshire Katie , Foster Sheri , Kaye Jeffrey A. , Small Brent J. , Camicioli Richard
Published: September 2005

Corpus callosum area has been examined in neurodegenerative diseases as a marker for cortical pathology and for differential diagnosis; however, it has not been examined in Parkinson’s disease (PD). We compared callosal area in patients with PD and PD with dementia (PDD) to healthy controls and patients with Alzheimer’s disease (AD). We subsequently compared our results to a meta-analysis of studies examining callosal area in AD, frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). For the imaging study, midsagittal T1-weighted MRIs were analyzed and the callosal area was determined in patients with PD (n = 24), PDD (n = 25), AD (n = 16) and controls (n = 27). The meta-analysis combined results from all publications (Medline or PubMed) representing unique samples and measuring callosal area in AD, FTD, PSP, and CBD. We found that PD and PDD patients did not show statistically significant callosal atrophy compared to controls (effect size d, 95% CI, d = 0.13, –0.26 to 0.52, and d = 0.05, –0.44 to 0.33, respectively) or AD. The AD patients had a significant loss of callosal area compared to controls (d = –0.58, –1.01 to –0.15). Dementia severity was correlated with total callosal atrophy in AD (R = 0.66, p < 0.01) but not in PDD patients (R = 0.18, p > 0.1). The meta-analysis revealed significant combined effect sizes for callosal atrophy of: AD (d = –1.03, –1.13 to –0.93), FTD (d = –1.21, –1.56 to – 0.86), PSP (d = –1.09, –1.38 to –0.81), and CBD (d = –1.80, –2.18 to –1.43). We conclude that PD and PDD patients do not have callosal atrophy in contrast to other neurodegenerative diseases, including AD. Callosal atrophy was correlated with dementia severity in patients with AD but not PDD.
Two Cases of Endometrial Cancer Diagnosis Associated with Bone Metastasis
Authors: Loizzi Vera , Cormio Gennaro , Cuccovillo Annarita , Fattizzi Nicola , Selvaggi Luigi
Published: September 2005

Background: Endometrial adenocarcinoma is commonly seen in postmenopausal women and uterine bleeding is the first sign in 90% of the cases. Bone metastasis as the presenting feature is extremely rare. We report two endometrial cancer patients with metastasis to the tibia and cervical vertebra at the time of primary disease. Cases: Two patients were diagnosed with stage IVB endometrial cancer with involvement of the tibia and cervical column, respectively. The first case was treated with 8 cycles of platinum, doxorubicin, and cyclophosphamide, but she died 3 months after the completion of chemotherapy as a result of progressive disease. The second case received surgery followed by chemotherapy with cisplatin and doxorubicin, but she died 2 months later. Conclusions: These cases highlight the rare and unusual presentation of endometrial cancer. For this reason a review of the literature is also provided for all cases with evidence of bone metastasis at presentation of the disease, and as a recurrence.
Early Detection of Thinning of Retinal Nerve Fiber Layer in Glaucomatous Eyes by Optical Coherence Tomography 3000: Analysis of Retinal Nerve Fiber Layer Corresponding to the Preserved Hemivisual Field
Authors: Asaoka Ryo , Ishii Rumiko , Kyu Nobuo , Hotta Yoshihiro , Sato Miho
Published: September 2005

The retinal nerve fiber layer (RNFL) thickness was measured with the optical coherence tomography using version 3.0 software (OCT3000) in 153 eyes of 153 normal subjects. The mean of the average RNFL thickness over the entire 360° in the control group was 92.5 ± 12.9 µm which was significantly thinner than the normative data of 95.9 ± 11.4 µm included with the OCT3000 (p < 0.01). The RNFL thickness decreased with increasing age (p < 0.01, r = –0.395). The RNFL thickness was also measured in 53 eyes of 53 patients with glaucoma whose superior (13 eyes) or inferior (40 eyes) perimetric hemifields were normal. Only the RNFL thickness corresponding to the preserved perimetric hemifields were measured by OCT3000 and scanning laser ophthalmoscopy (SLO). The RNFL thickness in the superior and inferior 30° sectors, the maximum and average RNFL thickness in the superior (Smax and Savg), and inferior quadrants (Imax and Iavg) were analyzed.The Smax, Savg, Imax, Iavg, and the RNFL thickness in the superior (p< 0.05), superotemporal and inferotemporal sectors (p<0.01) in the glaucoma patients without a nerve fiber layer defect (SLO) were significantly thinner than in the control subjects in same age. OCT3000 measurements showed that the RNFL thickness in glaucomatous eyes with normal perimetric visual fields and SLO was significantly thinner than the RNFL thickness in normal eyes.
Association between Cognitive Performance and Cortical Glucose Metabolism in Patients with Mild Alzheimer’s Disease
Authors: Bokde A.L.W. , Teipel S.J. , Drzezga A. , Thissen J. , Bartenstein P. , Dong W. , Leinsinger G. , Born C. , Schwaiger M. , Moeller H.-J. , Hampel H.
Published: September 2005

Background: Neuronal and synaptic function in Alzheimer’s disease (AD) is measured in vivo by glucose metabolism using positron emission tomography (PET). Objective: We hypothesized that neuronal activation as measured by PET is a more sensitive index of neuronal dysfunction than activity during rest. We investigated if the correlations between dementia severity as measured with the Mini Mental State Examination (MMSE) and glucose metabolism are an artifact of brain atrophy. Method: Glucose metabolism was measured using [18F]fluorodeoxyglucose PET during rest and activation due to audiovisual stimulation in 13 mild to moderate AD patients (MMSE score ≧17). PET data were corrected for brain atrophy. Results: In the rest condition, glucose metabolism was correlated with the MMSE score primarily within the posterior cingulate and parietal lobes. For the activation condition, additional correlations were within the primary and association audiovisual areas. Most local maxima remained significant after correcting for brain atrophy. Conclusion: PET activity measured during audiovisual stimulation was more sensitive to functional alterations inglucose metabolism in AD patients compared to the resting PET. The association between glucose metabolism and MMSE score was not dependent on brain atrophy.
Does Insulin-Like Growth Factor 1 Contribute in Red Blood Cell Transfusions to the Pathogenesis of Retinopathy of Prematurity during Retinal Neovascularization?
Authors: Hübler Axel , Knote Kerstin , Kauf Eberhard , Barz Dagmar , Schlenvoigt Dorothea , Schramm Dirk
Published: September 2005

Background: Red blood cell (RBC) transfusions are associated with the development of retinopathy of prematurity (ROP). During the period of retinal neovascularization a rise of insulin-like growth factor 1 (IGF-1) may trigger rapid growth of new blood vessels. Objectives: To study endocrine factors in RBC transfusions that might be of importance for ROP. Methods: IGF-1, IGF-2 and their binding proteins 1–3 (IGFBP-1–3) were determined by radioimmunoassays in 7 very-low-birthweight (VLBW) infants with ROP ≧ stage 2 receiving a RBC transfusion, in 10 controls (VLBW infants with ROP ≤ stage 1, no transfusion), in supernatants of 7 RBCs and of 5 washed RBCs (WRBC). Results: IGF-1 (mean ± SD) in infants with ROP was 20.0 ± 4.2 µg/l, in controls 35.9 ± 15.2 µg/l (Mann-Whitney U test, p = 0.030). IGF-1 in RBC was 12.88 ± 5.03 µg/l and in WRBC 0.45 ± 0.74 µg/l (average of the three-course washing procedure). IGF-2 in infants with ROP was 485.67 ± 158.73 µg/l, in controls 389.9 ± 102.8 µg/l (not significant), in RBC 109.50 ± 117.89 µg/l, in WRBC 61.07 ± 30.0 µg/l. Except for IGFBP-3 other IGFBPs were barely or not detectable in RBC or WRBC. Conclusions: Considering lower IGF-1 concentrations in preterm infants than in adults (factor 20), the IGF-1 in RBC transfusions is equivalent to a single dose of 1 µg/kg IGF-1 (5–10% of the adult dose with proved metabolic responses). Endocrinological relationships between the donor’s load and the acceptor’s individual features are a new aspect of potential side effects of RBC transfusions. Further research is necessary to clarify the share of the described IGF administration on the development of ROP.
Intrapartum Magnesium Sulfate Exposure Attenuates Neutrophil Function in Preterm Neonates
Authors: Mehta Rajeev , Petrova Anna
Published: September 2005

Background: Prenatal exposure to magnesium sulfate, a drug that is frequently used for attempted tocolysis in preterm labor, could alter neutrophil functional activity in infants born preterm. Objectives: To determine the association between maternal tocolysis with magnesium sulfate and the cord blood neutrophil functional activity of preterm neonates. Methods: The chemotaxis, random motility, and chemiluminescence of neutrophils were compared in the cord blood of 10 preterm neonates born to mothers tocolysed with magnesium sulfate, 10 preterm infants whose mothers had not received any tocolysis, and 10 term infants. Data regarding the maternal and neonatal magnesium and calcium levels were collected and analyzed in association with the cord blood neutrophil functional activity of the preterm infants. Results: Neutrophil functional activity in the cord blood of the preterm neonates was significantly lower than in term neonates. However, the alteration of neutrophil chemotaxis, random motility and chemiluminescence was more noticeable in neonates with intrapartum exposure to magnesium sulfate as compared to preterm infants whose mothers received no tocolysis (30.9 ± 2.3 vs. 36.7 ± 2.7 µm, p < 0.01; 26.6 ± 1.9 vs. 33.1 ± 3.1 µm, p < 0.01; and 74.3 ± 6.5 vs. 89.9 ± 6.25 ×103 counts per min (cpm), p < 0.01, respectively). Furthermore, the reduction in neutrophil functional activity of preterm infants with intrapartum exposure to magnesium was directly correlated with the maternal serum magnesium levels (r = –0.90 to –0.85, p < 0.01). Conclusion: In infants born preterm, intrapartum exposure to magnesium sulfate is a risk factor contributing to the alteration in neutrophil motility and post-phagocytic bactericidal capacity.
Enterally but Not Parenterally Administered Phaseolus vulgaris Lectin Induces Growth and Precocious Maturation of the Gut in Suckling Rats
Authors: Linderoth Ann , Prykhod’ko Olena , Pierzynowski Stefan G. , Weström Björn R.
Published: September 2005

Background: The lectin, phytohemagglutinin (PHA) has been shown to induce growth and functional maturation of the gastrointestinal (GI) tract in suckling rats. Objectives: To investigate the effect of the administration route, and whether enteral exposure to PHA was necessary to induce functional maturation. Methods: Fourteen-day-old rats were daily administered PHA via orogastric feeding (0.05 mg PHA/g BW) or via subcutaneous injection (0.05 or 0.005 mg PHA/g BW) for 3 days, while the controls received saline orogastrically. At 17 days of age, organ weight, intestinal and pancreatic function, and plasma corticosterone levels were analyzed. Moreover, 14-days old pups receiving a single dose of PHA, enterally or parenterally, were sacrificed after 12 h and examined for organ PHA binding using immunohistochemistry. Results: Enteral PHA exposure resulted in PHA binding in the epithelial lining of the small intestine, increased gastrointestinal growth, reduced intestinal macromolecular absorption, altered the disaccharidase expression towards an adult-like pattern, and increased the pancreatic protein and trypsin contents. In contrast, parenteral PHA exposure (high dose) resulted in PHA-binding in extra-intestinal organs, increased liver and spleen weight, and decreased thymus weight. Moreover, the intestinal maltase activity increased moderately, and the transfer of BSA to blood plasma was partially reduced. Both PHA treatments led to elevated plasma corticosterone levels. Conclusion: These results demonstrated that enteral exposure to PHA was necessary to induce the precocious maturation of the GI tract and the pancreas, while parenteral administration affects the extra-intestinal organs. Furthermore, the enteral effects were probably not mediated via a corticosteroid dependent pathway.
Is Duplex Surveillance of Value After Leg Vein Bypass Grafting?
Authors: Davies A.H. , Hawdon A.J. , Sydes M.R. , Thompson S.G.
Published: September 2005

Background—

The purpose of this study was to assess the benefits of duplex compared with clinical vein graft surveillance in terms of amputation rates, quality of life, and healthcare costs in patients after femoropopliteal and femorocrural vein bypass grafts.

Methods and Results—

This was a multicenter, prospective, randomized, controlled trial. A total of 594 patients with a patent vein graft at 30 days after surgery were randomized to either a clinical or duplex follow-up program at 6 weeks, then 3, 6, 9, 12, and 18 months postoperatively. The clinical and duplex surveillance groups had similar amputation rates (7% for each group) and vascular mortality rates (3% versus 4%) over 18 months. More patients in the clinical group had vein graft stenosis at 18 months (19% versus 12%,
P
=0.04), but primary patency, primary assisted patency, and secondary patency rates, respectively, were similar in the clinical group (69%, 76%, and 80%) and the duplex group (67%, 76%, and 79%). There were no apparent differences in health-related quality of life, but the average health service costs incurred by the duplex surveillance program were greater by £495 (95% CI £183 to £807) per patient.

Conclusions—

Intensive surveillance with duplex scanning did not show any additional benefit in terms of limb salvage rates for patients undergoing vein bypass graft operations, but it did incur additional costs.
Dietary Recommendations for Children and Adolescents
Authors: Gidding Samuel S. , Dennison Barbara A. , Birch Leann L. , Daniels Stephen R. , Gilman Matthew W. , Lichtenstein Alice H. , Rattay Karyl Thomas , Steinberger Julia , Stettler Nicolas , Van Horn Linda
Published: September 2005

Since the American Heart Association last presented nutrition guidelines for children, significant changes have occurred in the prevalence of cardiovascular risk factors and nutrition behaviors in children. Overweight has increased, whereas saturated fat and cholesterol intake have decreased, at least as percentage of total caloric intake. Better understanding of children’s cardiovascular risk status and current diet is available from national survey data. New research on the efficacy of diet intervention in children has been published. Also, increasing attention has been paid to the importance of nutrition early in life, including the fetal milieu. This scientific statement summarizes current available information on cardiovascular nutrition in children and makes recommendations for both primordial and primary prevention of cardiovascular disease beginning at a young age.