Construction and characterization of zebrafish whole genome radiation hybrids.
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Animals↗
Biomedical subjects
K Schmitt
Publications and source records attributed to K Schmitt.
Short stature in Duchenne muscular dystrophy: a study of 34 patients.
In Duchenne muscular dystrophy (DMD), short stature is a feature of unknown cause. This cross-sectional study of 34 male patients (mean age 8.0 y, age range 1.2-13.7 y) was conducted to examine the relationship between auxological parameters, markers of growth and the extent of muscular weakness. Weight and length at birth (SDS +/- SD; 0.0 +/- 1.2; 0.2 +/- 1.5) and target height SDS (-0.2 +/- 0.7) were normal. Height (HT) SDS (-1.0 +/- 1.1) was lower than the normal population (p < 0.001) and did not correlate with age. Body mass index SDS (-0.1 +/- 1.6) was normal. Tests of insulin-like growth factor-I SDS (-0.6 +/- 1.2) and insulin-like growth factor binding protein-3 SDS (0.1 +/- 1.3) ruled out a severe derangement in the GH-IGF-axis. The carboxy-terminal propeptide of type I procollagen (PICP) SDS (0.6 +/- 1.5) was normal, but bone-specific alkaline phosphatase (BAP) SDS (-1.7 +/- 0.8) was low (p <0.001). HT SDS did not correlate with BAP SDS. The Vignos scale, a grading of muscular function (score: 0 = unaffected; 11 = confined to bed) (median (range): 3 (0-9)) correlated strongly with age (r = 0.77, p < 0.0001), but did not correlate with HT SDS, PICP SDS or BAP SDS. In conclusion, DMD patients are significantly shorter than the normal population, though the HT SDS does not change with age. Growth hormone deficiency does not seem to be the cause of short stature in DMD. Significantly low BAP levels are probably the result of the reduced muscle mass, which leads to a lower biomechanical load on the bone and thus a reduction in bone turnover. The short stature observed in our study is unlikely to be the result of muscular weakness.
Adolescent↗
Autoimmune thyroiditis and myelosuppression following treatment with interferon-alpha for hepatitis C.
CASE: We describe the case of a 48-year-old woman from Thailand diagnosed with chronic hepatitis C, who experienced a suppression of all blood cell counts accompanied by a newly developed clinically manifested autoimmune thyroid disorder after treatment with interferon alpha-2b (INF-alpha) 46 days after beginning of therapy a decrease of platelet, red and white blood cell counts became obvious. Concomitantly we observed an increase of FT4 and FT3 with a totally depressed TSH level 80 days after starting INF-alpha administration. Antibody assessment resulted in detection of high numbers of antithyroid-microsomal antibodies and antithyroglobulin antibodies. Thyroid hormone levels normalized under treatment with methimazole/propylthiouracil within 4.5 months. However, two months after cessation of antithyroid therapy increasing TSH levels and decreasing FT4 levels indicated a new tendency towards a hypothyroid state. CONCLUSION: We classify this case as an interferon-alpha-induced disorder of thyroid function accompanied by myelosuppression. A close monitoring for thyroid dysfunction, e.g. evaluation of TSH-levels before and after administration of INF-alpha is mandatory.
Autoimmune Diseases↗
[Detection and evaluation of adverse drug reactions].
Adverse drug reactions (ADRs) occur in about 5% of drug-treated patients. Hospital admissions are caused by ADRs in 5% of patients and roughly 2% of hospitalized patients will experience an ADR. The economic burden of ADRs can only be estimated. Type A reactions can be explained by the pharmacological action of the drugs, and are preventable in many cases. However, Type B reactions involving the immune system and/or idiosyncratic reactions occur rarely and most of them are not fully understood. Genotyping represents an elegant method to explain the presence of abnormal enzyme activities and allows prediction of adverse drug effects in individual cases. Typical time frames have been identified for the occurrence of hypersensitivity reactions, although definite causality assessment is often impeded due to the absence or unavailability of specific laboratory tests and the impossibility of rechallenge. Diagnosis of an ADR is often difficult due to comorbidity and polypharmacy, thus causality assessment is often divergent even between specialists. In Germany, ADRs are reported preferably to the manufacturer of the suspicious drug and then collected and evaluated at the Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM. However, total number and quality of reported ADRs could be improved.
Adverse Drug Reaction Reporting Systems↗
Characterization of whole genome radiation hybrid mapping resources for non-mammalian vertebrates.
Radiation hybrid panels are already available for genome mapping in human and mouse. In this study we have used two model organisms (chicken and zebrafish) to show that hybrid panels that contain a full complement of the donor genome can be generated by fusion to hamster cells. The quality of the resulting hybrids has been assessed using PCR and FISH. We confirmed the utility of our panels by establishing the percentage of donor DNA present in the hybrids. Our hybrid resources will allow inexpensive gene mapping and we expect that this technology can be transferred to many other species. Such successes are providing the basis for a new era of mapping tools, in the form of whole genome radiation hybrid panels, and are opening new possibilities for systematic genome analysis in the animal genetics community.
Animals↗
Genome-wide search for schizophrenia susceptibility loci: the NIMH Genetics Initiative and Millennium Consortium.
Schizophrenia has a complex pattern of inheritance, indicative of interactions among multiple genes and environmental factors. The detection and replication of specific susceptibility loci for such complex disorders are facilitated by the availability of large samples of affected sib pairs and their nuclear families, along with standardized assessment and systematic ascertainment procedures. The NIMH Genetics Initiative on Schizophrenia, a multisite collaborative study, was established as a national resource with a centralized clinical data base and cell repository. The Millennium Schizophrenia Consortium has completed a genome-wide scan to detect susceptibility loci for schizophrenia in 244 individuals from the nuclear families of 92 independent pairs of schizophrenic sibs ascertained by the NIMH Genetics Initiative. The 459 marker loci used in the scan were spaced at 10-cM intervals on average. Individuals of African descent were higher than those of European descent in their average heterozygosity (79% vs. 76%, P < .0001) and number of alleles per marker (9.2 vs. 8.4, P < .0001). Also, the allele frequencies of 73% of the marker loci differed significantly (P < .01) between individuals of European and African ancestry. However, regardless of ethnic background, this sample was largely comprised of schizophrenics with more than a decade of psychosis associated with pervasive social and occupational impairment.
Adolescent↗
NIMH Genetics Initiative Millenium Schizophrenia Consortium: linkage analysis of African-American pedigrees.
The NIMH Genetics Initiative is a multi-site collaborative study designed to create a national resource for genetic studies of complex neuropsychiatric disorders. Schizophrenia pedigrees have been collected at three sites: Washington University, Columbia University, and Harvard University. This article-one in a series that describes the results of a genome-wide scan with 459 short-tandem repeat (STR) markers for susceptibility loci in the NIMH Genetics Initiative schizophrenia sample-presents results for African-American pedigrees. The African-American sample comprises 30 nuclear families and 98 subjects. Seventy-nine of the family members were considered affected by virtue of having received a DSMIII-R diagnosis of schizophrenia (n = 71) or schizoaffective disorder, depressed (n = 8). The families contained a total of 42 independent sib pairs. While no region demonstrated evidence of significant linkage using the criteria suggested by Lander and Kruglyak, several regions, including chromosomes 6q16-6q24, 8pter-8q12, 9q32-9q34, and 15p13-15q12, showed evidence consistent with linkage (P = 0.01-0.05), providing independent support of findings reported in other studies. Moreover, the fact that different genetic loci were identified in this and in the European-American samples, lends credence to the notion that these genetic differences together with differences in environmental exposures may contribute to the reported differences in disease prevalence, severity, comorbidity, and course that has been observed in different racial groups in the United States and elsewhere.
Adolescent↗
Genome scan of European-American schizophrenia pedigrees: results of the NIMH Genetics Initiative and Millennium Consortium.
The Genetics Initiative of the National Institute of Mental Health (NIMH) was a multisite study that created a national repository of DNA from families informative for genetic linkage studies of schizophrenia, bipolar disorder, and Alzheimer's disease. The schizophrenia families were collected by three sites: Washington University, Harvard University, and Columbia University. This article, one in a series that describes the data collected for linkage analysis by the schizophrenia consortium, presents the results for the European-American sample. The European-American sample comprised 43 nuclear families and 146 subjects. Ninety-six of the family members were considered affected by virtue of having received a DSM-III-R diagnosis of schizophrenia (N = 82) or schizoaffective disorder, depressed (N = 14). The families contained a total of 50 independent sib-pairs. Using the significance threshold criteria suggested by Lander and Kruglyak [(1995): Nat Genet 241-247], no region showed statistically significant evidence for linkage; two markers on chromosome 10p showed statistical evidence suggestive of linkage using the criteria of Lander and Kruglyak [(1995): Nat Genet 241-247]: D10S1423 (nonparametric linkage (NPL) Z = 3.4, P = .0004) and its neighbor, D10S582 (NPL Z = 3.2, P = .0006).
Adolescent↗
Molecular analysis of 9p deletions associated with XY sex reversal: refining the localization of a sex-determining gene to the tip of the chromosome.
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Chromosome Mapping↗
Doxycycline and azithromycin for prevention of chlamydial persistence or recurrence one month after treatment in women. A use-effectiveness study in public health settings.
BACKGROUND: To treat chlamydial infection, the Centers for Disease Control and Prevention recommends either a single dose of azithromycin or a 7-day course of doxycycline. Cost is a concern with the single-dose regimen; compliance is a concern with the multidose regimen. GOAL: To compare the use-effectiveness of azithromycin and doxycycline for preventing persistence or recurrence of Chlamydia trachomatis infection in women and to evaluate associated risk behaviors. STUDY DESIGN: One hundred and ninety-six chlamydia-infected women and their sex partners were recruited into a randomized controlled trial of single-dose versus multidose regimens in seven public health clinics, with no incentives for enrollment, compliance, or follow-up. The outcome, measure was a positive test for C. trachomatis by polymerase chain reaction testing at 1 month after treatment. RESULTS: C. trachomatis positivity at 1 month was similar for women receiving single-dose (5.1%, 5/98) and multidose therapy (4.1%, 4/98). Reported compliance among 73 women taking multidose therapy was 94.5%. A twofold to threefold increased risk of chlamydial persistence or recurrence was observed among women who were < or = 24 and white or who reported: a recent new partner, multiple partners, or a partner who may have had multiple partners at the time of enrollment or that not all partners were treated during the 1-month follow-up period after initiation of treatment. CONCLUSIONS: The use-effectiveness of single-dose and multidose therapy was comparably high. Observed rates of persistence or recurrence were consistent with reported rates of pharmacological treatment failure. However, all women with C. trachomatis detected at 1 month had behavioral risk factors that may have contributed to reinfection.
Adolescent↗
Norplant selection and satisfaction among low-income women.
OBJECTIVES: This study examined correlates of Norplant selection and satisfaction among low-income women. METHODS: Interviews were completed in family planning clinics in 4 Florida counties with 1152 Norplant users and 1268 nonusers, with follow-up interviews with a subsample up to 1 year later. Logistic regression models estimated the associations of socio-demographic and medical characteristics with Norplant selection and method satisfaction. RESULTS: Odds ratios for Norplant selection were significantly greater among women who planned to have children in 5 or more years, those who were "offered" Norplant, those who lived in Palm Beach County, those who were using drugs, and those who were Medicaid clients. Women younger than 17 and those who learned about Norplant from a friend were twice as likely as others to select Norplant. Ninety-two percent of Norplant users were satisfied with the method; women with side effects and those who felt pressure to select a method were significantly less likely than others to be satisfied. CONCLUSIONS: Norplant provides an acceptable and satisfying method of birth control for many low-income women. Proper counseling about all methods of birth control and about Norplant's side effects remains critical to the appropriate delivery of this method.
Adolescent↗
The influence of growth hormone monotherapy and growth hormone in combination with oxandrolone or testosterone on thyroxid hormone parameters and thyroxine binding globulin in patients with Ullrich-Turner syndrome.
UNLABELLED: Administration of human growth hormone (GH) has yielded conflicting results concerning its role on thyroid function in patients with Ullrich-Turner syndrome. Therefore, we investigated the course of thyroid hormone parameters and thyroxin binding globulin in relation to GH therapy, IGF-I and additional oxandrolone-(Ox) or testosterone (T) treatment in 20 patients with Ullrich-Turner syndrome. During the 1st year the patients received only GH. There was no change in T4, fT4, and TSH levels, T3 increased significantly (P < 0.01) after 6 and 12 months, resulting in a higher T3/T4 ratio. TBG (P < 0.05) and IGF-I (P < 0.01) increased after 6 months and remained elevated at 12 months. A significant positive correlation was found between the change of T4 and TBG after 6 months (r = 0.47, P < 0.05) and after 12 months (r = 0.69, P < 0.005). Thirteen patients were further investigated after addition of an anabolic compound; 7 received Ox (0.0625 mg/kg/day po) and 6 low dose T (5 mg i.m. every 14 days). Chronological age was comparable in these groups (10.7 +/- 2.7 vs 10.7 +/- 3.6 years). After 6 months of combination therapy with Ox, T4, T3 and TSH decreased. As T4 and T3 showed a parallel decrease the T3/T4 ratio remained elevated. TBG declined after 6 and 12 months (P < 0.05), while IGF-I showed a further increment (P < 0.05). There was no correlation between the changes in T4 and IGF-I, TSH and TBG, respectively. In the T-treated group only IGF-I increased (P < 0.05) to the same extent as in the Ox-treated patients, whereas the thyroid parameters did not change. CONCLUSION: The observed changes in thyroid hormone and TBG levels in the Ox group were not mediated by GH or IGF-I. The Ox-induced TBG decrease might be linked to altered pancreatic functions regulating carbohydrate metabolism.
Adolescent↗
Short- and long-term (final height) data in children with normal variant short stature treated with growth hormone.
UNLABELLED: Seventeen children with normal variant short stature and a predicted height below -2 SDS were treated with growth hormone (GH) six times a week for a period of 5 years. Patients were randomly selected to receive three different doses of GH, group 1 (n = 6) 3 IU/m2 per day, group 2 (n = 6) 4.5 IU/m2 per day and group 3 (n=5) 3 IU/m2 per day in the 1st year and 4.5 IU/m2 per day thereafter. There was a significant increase in height after 1 and 2 years for all patients and for all subgroups. However, this increase was not dependent on GH dose. The decrease in height velocity during the 2nd year was not prevented by the increase of GH dose in group 3. The change of predicted height after 2 years was +0.75 SDS (according to Tanner Whitehouse). Fourteen children have been treated for 4 years and 8 children for 5 years without a further change in height prediction. Nine patients have reached final height which was 2.4 cm (+0.41 SDS) above pretreatment height prediction. Final height was nearly identical to predicted height after 1 year of therapy. CONCLUSION: An increment in height prediction was observed during the first 2 years of GH treatment and maintained thereafter. However, there was only a minor increase in final height over predicted height which does not justify the general use of GH in children with normal variant short stature.
Adolescent↗
[Effect of panretinal photocoagulation on the ocular pulse curve].
BACKGROUND: Most studies on the effects of panretinal photocoagulation (PRPC) on ocular circulation are concerned with retinal circulation. In the present study, we examined the ocular pulse curve after PRPC and determined pulsatile ocular blood flow (an indicator of choroidal circulation) and ocular perfusion pressure. PATIENTS AND METHOD: In 10 patients with diabetes mellitus (8 with type II and 2 with type I; mean age 64 yrs) and severe, hitherto untreated, bilateral proliferative diabetic retinopathy, an intensive unilateral PRPC with 1500 argon laser burns (spot size: 500 mu) was performed in 2 sessions (interval: 3 wks). Before and-in 3-wk intervals-up to 9 wks after onset of treatment, an ocular pulse curve was recorded using oculo-oscillo-dynamography, and the following variables were determined: ocular pulsation amplitude (OPA), pulsatile ocular blood flow (POBF), systolic ophthalmic artery pressure (SOAP), and systolic ocular perfusion pressure (SOPP). RESULTS: PRPC led to a reduction of OPA and POBF in relation to the untreated contralateral eyes. 3 wks after the 1st coagulation, the reduction averaged 20% (OPA) and 19.1% (POBF). The maximum reduction was found 9 wks after onset of treatment (6 wks after the 2nd coagulation) and amounted to 29.9% and 29.2%, respectively. The differences between photocoagulated and untreated eyes were highly significant on average (P < 0.01; ANOVA) as well as for the time course (P < 0.001). SOAP and SOPP were not changed significantly during PRPC. CONCLUSIONS: OPA and POBF are determined by the cardiac cycle-related intraocular volume changes depending predominantly on choroidal blood flow. Thus, the reduction of POBF after PRPC is indicative of a lowered pulsatile choroidal blood flow. The morphological substrate is probably the choriocapillaries closure after photocoagulation described in the literature.
Adolescent↗
CYP11B1 mutations causing non-classic adrenal hyperplasia due to 11 beta-hydroxylase deficiency.
Steroid 11 beta-hydroxylase deficiency is the second most common cause of congenital adrenal hyperplasia, the inherited inability to synthesize cortisol. Severely affected patients carry mutations in the CYB11B1 gene that destroy enzymatic activity. Such patients have signs of androgen excess and usually have hypertension. Mild or non-classic 11 beta-hydroxylase deficiency has been reported previously but not studied genetically. In this study we report analysis of the CYP11B1 genes of three patients thought to suffer from non-classic 11 beta-hydroxylase deficiency. Mutations were detected in the CYP11B1 genes of two patients. One was a compound heterozygote for missense mutations N133H and T319M, whereas the other carried a nonsense mutation (Y423X) on one allele and a missense mutation (P42S) on the other. All three missense mutations affected enzymatic activity when expressed in vitro. No mutations were detected in the coding regions or intron-exon boundaries of the CYP11B1 genes of the other putative non-classic patient. In addition, we were unable to detect CYP11B1 mutations in two hirsute women with mildly elevated levels of 11 beta-hydroxylase precursors who had previously been identified in a screening study of patients in a reproductive endocrinology clinic. We conclude that nonclassic 11 beta-hydroxylase deficiency is a rare disorder. It is not a significant cause of hyperandrogenism in women and relatively stringent criteria should be used to prevent its misdiagnosis.
Adrenal Glands↗
A first-generation whole genome-radiation hybrid map spanning the mouse genome.
We have assembled a first-generation anchor map of the mouse genome using a panel of 94 whole-genome-radiation hybrids (WG-RHs) and 271 sequence-tagged sites (STSs). This is the first genome-wide RH anchor map of a model organism. All of the STSs have been previously localized on the genetic map and are located 8.8 Mb apart on average. This mouse WG-RH panel, known as T31, has an average retention frequency of 27.6% and an estimated potential resolution of 145 kb, making it a powerful resource for efficient large-scale expressed sequence tag mapping. [All of the mapping data for the maps presented here have been deposited at the Research Genetics, Inc., web site and can be freely accessed and downloaded at http://www.resgen.com/.]
Animals↗
Short- and long-term (final height) growth responses to growth hormone (GH) therapy in patients with Turner syndrome: correlation of growth response to stimulated GH levels, spontaneous GH secretion, and karyotype.
In 41 girls with Turner syndrome, the growth hormone (GH) peak values during stimulation tests and parameters of spontaneous nocturnal GH secretion were studied and compared with respect to different karyotypes, short-term growth response to GH therapy, and final height. 22.0% of the girls tested had a subnormal (peak < 11 ng/ml) and 9.7% a pathological (< 7 ng/ml) GH response. The spontaneous GH secretion showed a good correlation with the data of the provocation tests, providing no further information regarding GH capacity. Short-term growth response to GH treatment could not be predicted by any of the investigated parameters. Although patients with isochromosomes had frequent subnormal GH tests, their growth response to GH treatment after 1 year was comparable to that of girls with XO karyotype and mosaicism. In 18 patients who had reached final height, the height gain during treatment (calculated as final height minus projected adult height) was not different among patients with normal, subnormal, or pathological GH tests. In contrast, final height minus projected adult height in 4 girls with isochromosomes was 15.7 +/- 5.1 versus 7.6 +/- 3.3 cm in 14 patients with other karyotypes (p < 0.01). These girls had a more pronounced bone age delay (3.3 +/- 0.3 vs. 1.8 +/- 1.2 years) at the start of therapy and thus a better growth potential. We conclude that short- and long-term growth responses to GH treatment in Turner syndrome could not be predicted by GH testing. Patients with isochromosomes might represent a subpopulation which is more frequently GH deficient and shows a marked bone age delay.
Adolescent↗
A gene map of the human genome.
The human genome is thought to harbor 50,000 to 100,000 genes, of which about half have been sampled to date in the form of expressed sequence tags. An international consortium was organized to develop and map gene-based sequence tagged site markers on a set of two radiation hybrid panels and a yeast artificial chromosome library. More than 16,000 human genes have been mapped relative to a framework map that contains about 1000 polymorphic genetic markers. The gene map unifies the existing genetic and physical maps with the nucleotide and protein sequence databases in a fashion that should speed the discovery of genes underlying inherited human disease. The integrated resource is available through a site on the World Wide Web at http://www.ncbi.nlm.nih.gov/SCIENCE96/.
Amino Acid Sequence↗