Renal osteodystrophy in older adults with end-stage renal disease.
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Aged↗
Biomedical subjects
C Roth
Publications and source records attributed to C Roth.
Response to different measles vaccine strains given by aerosol and subcutaneous routes to schoolchildren: a randomised trial.
BACKGROUND: More than one dose of measles vaccine is necessary for the sustained control of measles. The aerosol route is thought to be more immunogenic for booster doses than traditional subcutaneous injections, so we did a randomised comparative trial of aerosol and subcutaneous measles vaccines in South African schoolchildren. METHODS: 4327 schoolchildren (aged 5-14 years), assigned by block randomisation of classrooms, received standard titre doses of either Schwarz or Edmonston-Zagreb measles vaccines subcutaneously or by aerosol. Blood samples for antibody assay were collected before vaccination, at 1 month, and 1 year after vaccination. The main endpoints (antibody titres at 1 month and 1 year) were compared between groups. FINDINGS: 992 children had antibody titre data available for all timepoints. 14 (3.6%) of 385 children who received Edmonston-Zagreb vaccine by aerosol were seronegative 1 year after vaccination, compared with 28 (8.6%) of 326 children who received Edmonston-Zagreb subcutaneous vaccine and 39 (13.9%) of 281 children who received Schwarz subcutaneous vaccine. At 1 month, 326 (84.7%) children who received aerosol Edmonston-Zagreb vaccine had seroconverted, compared with 257 (78.8%) who received subcutaneous Edmonston-Zagreb vaccine and 176 (62.6%) who received subcutaneous Schwarz vaccine. At 1 month, only 116 (22.7%) of 511 children in the Schwarz aerosol group had seroconverted; this aerosol vaccine had no detectable potency after 2 min of nebulisation. There were no serious side-effects: about 5% of children in each group had a rash within 2 weeks of vaccination. INTERPRETATION: An aerosol vaccination method that uses currently available devices and a suitably stable vaccine is effective and acceptable. This form of delivery is adaptable to mass campaigns, avoids the risks associated with injections, and could help measles eradication.
Administration, Inhalation↗
Genomic structure and DNA binding properties of the human zinc finger transcriptional repressor AP-2rep (KLF12).
We recently cloned a novel murine transcriptional repressor, the Krüppel-like zinc finger protein AP-2rep (HGMW-approved symbol KLF12), that binds to a regulatory element in the AP-2alpha gene promoter. In the present study, we characterize the human AP-2rep homolog and describe expression patterns in human urogenital and lymphoma cell lines. The predicted human protein of 402 amino acids exhibits 95.8% identity and 98.5% similarity to the murine AP-2rep peptide. The genomic locus of human AP-2rep consists of seven exons and was assigned to chromosome 13q22 by fluorescence in situ hybridization to metaphase chromosomes. Human AP-2rep repressed both reporter expression from a transiently transfected AP-2alpha promoter and the endogenous AP-2alpha gene and inversely was negatively regulated by AP-2alpha. The consensus motif CAGTGGG was identified by an in vitro binding site selection assay. In summary, our data further point to an important role of AP-2rep as a transcriptional silencer and reveal reciprocal regulation of AP-2alpha and AP-2rep.
Amino Acid Sequence↗
Features of Antley-Bixler syndrome in an infant born to a mother with pregnancy luteoma.
UNLABELLED: We report a female newborn with characteristic signs of Antley-Bixler syndrome (ABS) such as midface hypoplasia, radiohumeral synostosis and multiple joint contractures. The newborn also presented ambiguous genitalia, stage Prader V, and congenital adrenal hyperplasia. The mother experienced midterm virilization due to a pregnancy luteoma. Her elevated androgen levels and virilization symptoms normalized post partum without treatment. The newborn had elevated serum testosterone and 17-OH-progesterone levels which remained elevated because of a 21-hydroxylase deficiency. The child's treatment in order of priority was: hydrocortisone substitution, craniofacial/skeletal anomaly management and surgical correction of the external genitalia. Mutations in the genes for fibroblast growth factor (FGF) 8 and receptors FGFR1, FGFR2, and FGFR3 were not detected. CONCLUSION: A newborn girl with manifestations of the Antley-Bixler syndrome showed severe virilization probably caused by the association of a mild 21-hydroxylase deficiency and maternal hyperandrogenism due to a pregnancy luteoma. Abnormalities of androgen metabolism may be responsible for virilization reported in other cases of the Antley-Bixler syndrome.
Adrenal Hyperplasia, Congenital↗
Congenital adrenal hyperplasia associated with maternal pregnancy luteoma and the Antley-Bixler syndrome.
The authors report on a child with indifferent external genitalia consisting of severe micropenis with penile urethra leading to the tip of the glans and bilateral cryptorchidism. Diagnostic workup findings showed a female karyotype, homozygous 21-hydroxylase deficiency, and excessive testosterone exposure prenatally as a consequence of maternal pregnancy luteoma, altogether causing this unusual phenotype. In addition, the girl suffered from skeletal anomalies consistent with the diagnosis of Antley-Bixler syndrome. Our case shows that, although the association of congenital adrenal hyperplasia with other syndromes is rare, and even if other possible reasons for in utero virilization are present, complete diagnostic workup including karyotyping and hormonal status should be done in all patients with ambiguous genitalia, especially in cases of an unusual phenotype. The authors report on the diagnostic procedures and discuss the surgical approach in this particular case, never described before in the literature.
Abnormalities, Multiple↗
Clonal acquisition of inhibitory Ly49 receptors on developing NK cells is successively restricted and regulated by stromal class I MHC.
We report an in vitro stroma-dependent system for the clonal growth and differentiation of natural killer (NK) cells from lymphoid-restricted bone marrow progenitors or bone marrow NK1.1+ cells. Strikingly, the potential to initiate expression of specific Ly49 receptors becomes increasingly restricted as NK cells develop. Moreover, when NK cells express a Ly49 receptor specific for stromal cell class I MHC, they are less likely to initiate expression of another Ly49 receptor in the clonal culture system. The results indicate multiple roles for stromal cells in NK cell development, in supporting clonal growth, in initiation of Ly49 receptor expression, and in formation of the NK cell receptor repertoire.
Animals↗
Effects of medial thalamotomy and pallido-thalamic tractotomy on sleep and waking EEG in pain and Parkinsonian patients.
OBJECTIVES: Investigation of sleep and sleep EEG before and after stereotactic neurosurgery. METHODS: All-night polysomnographic recordings were obtained in 3 neurogenic pain patients and 3 parkinsonian patients. One subject of each group was recorded in addition 3 months after surgery. Stereotactic operations were performed in the medial thalamus and on the pallido-thalamic tract to relieve neurogenic pain and parkinsonian symptoms, respectively. RESULTS: Sleep efficiency was little affected by the surgical intervention in neurogenic pain patients and a dramatic reduction in REM sleep occurred, which had recovered in the subject recorded after 3 months. After the surgery parkinsonian patients showed an increase in total sleep time and in sleep efficiency, and a decrease in REM sleep latency. Sleep efficiency remained elevated in the 3 months follow-up. Medial thalamotomy abolished spindle frequency activity (SFA) in the power and coherence spectra in non-REM sleep stage 2 systematically. Pallido-thalamic tractotomy attenuated SFA only to varying degrees. After 3 months SFA had reemerged. The alpha peak of the waking EEG was shifted to lower frequencies after surgery in 5 of 6 patients and had reverted to the original frequency 3 months later. CONCLUSIONS: Medial thalamotomy or pallido-thalamic tractotomy had acute and reversible effects on the EEG and long-term deleterious side effects of stereotactic surgery on sleep and sleep EEG are improbable. The results provide further evidence for the involvement of the human thalamus in the generation of sleep spindles.
Aged↗
Functional neuroanatomy of human sleep states after zolpidem and placebo: a H215O-PET study.
Changes in the functional organization of the brain during the course of sleep and waking are reflected by different patterns of regional cerebral blood flow (rCBF). To investigate the effect of the hypnotic zolpidem, a benzodiazepine receptor agonist, drug or placebo were administered to eight young, healthy men prior to bedtime. The subjects were sleep-deprived to promote sleep during the 4-h recording period in the positron emission tomography scanner. Intravenous injections of labelled water were administered during pre-drug wakefulness, and during Stage 2, Stage 4 and rapid eye movement (REM) sleep, each injection being followed by an emission scan. Statistical parametric mapping was used to investigate the effects of treatment and sleep states. During sleep (combined Stages 2 and 4, and REM sleep) relative rCBF was lower after zolpidem than after placebo in the basal ganglia and insula, and higher in the parietal cortex. A 'multiple study' analysis of REM sleep revealed that rCBF in the anterior cingulum was lower after zolpidem than after placebo, whereas rCBF in the occipital and parietal cortex, parahippocampal gyrus and cerebellum was higher. When the pooled data (drug and placebo) of Stages 2 and 4 were compared with wakefulness, rCBF was lower in prefrontal cortex and insula, and higher in the occipital and parietal cortex. The results indicate that some differences in rCBF from wakefulness to non-REM sleep are further augmented by zolpidem.
Adult↗
Zolpidem and sleep deprivation: different effect on EEG power spectra.
To study the role of GABA-ergic mechanisms in sleep regulation, the combined action of 40 h sleep deprivation and either 20 mg zolpidem or placebo on the sleep electroencephalogram (EEG) were investigated by quantitative EEG analysis in eight young men who participated in a positron emission tomography study. Compared with baseline, sleep deprivation increased low-frequency (1.25-7.0 Hz) EEG power in non-rapid eye movement (NREM) sleep in the placebo night. After administration of zolpidem, power in the 3.75-10.0 Hz range and 14. 25-16.0 Hz band was reduced. The largest decrease was observed in the theta band. Comparison with placebo revealed that zolpidem attenuated power in the entire 1.75-11.0 Hz range. The plasma concentration of zolpidem at 4.5 h after intake showed a positive correlation with the drug-induced difference in power from placebo in the 14.25-16.0 Hz band. Regional EEG analysis based on bipolar derivations along the antero-posterior axis disclosed, for NREM sleep, a drug-induced posterior shift of power in the frequency range of 7.75-9.75 Hz. Zolpidem did not affect rapid eye movemnt sleep spectra. We conclude that sleep deprivation and agonistic modulation of GABAA receptors have separate and additive effects on power spectra and that their effects are mediated by different neurophysiological mechanisms.
Adult↗
GnRH antagonist cetrorelix prevents sexual maturation of peripubertal male rats.
UNLABELLED: Gonadotropin releasing-hormone (GnRH) analogues contain amino acid substitutions of the native decapeptide. Depending on the substitutions, the analogues have GnRH agonistic or antagonistic properties. GnRH agonists are the established treatment in cases of central precocious puberty caused by premature activation of the hypothalamic GnRH pulse generator. Much less data exist on the use of GnRH antagonists to influence the onset of puberty. Using the GnRH antagonist cetrorelix we conducted a 5 day treatment of peripubertal male rats (cetrorelix group n=12, 100 microg/d intraperitoneally injected; placebo n=10, NaCl 0.9% intraperitoneally injected) from postnatal day 32 to 36 and decapitated on postnatal day 37 to investigate the effects on pubertal development, serum gonadotropin and testosterone levels as well as the GnRH release from explanted hypothalami. A control group of 5 male rats was added for hypothalamus superfusion experiments on day 25. We observed no progress of testicular development in the cetrorelix group. Cetrorelix injected rats had lower testicular weights (531+/-13 versus controls 819+/-25 mg, mean+/-SEM, p<0.0001). 12 h after the last injection testosterone levels were in the castrate range (serum testosterone, median controls: 1.7 ng/ml, median cetrorelix <0.30 ng/ml, p<0.001), and they showed lower serum LH and FSH compared to the same age placebo group. After decapitation the preoptic mediobasal hypothalamic area (POA/MBH) was dissected from 5 randomly selected rats from each treatment group and the release rates of GnRH were determined in superfusion experiments: The hypothalamic GnRH secretion was comparable in the CET and the same age placebo rats but significantly higher than in the 25 day old control group. CONCLUSION: The GnRH antagonist cetrorelix inhibits the pituitary-gonadal axis in peripubertal male rats and may be effective in treating central precocious puberty in males.
Animals↗
Salient value similarity, social trust, and risk/benefit perception
It was postulated that shared values determine social trust in institutions and persons related to a technology: One has trust in people holding similar salient values. Furthermore, it was hypothesized that social trust has a positive influence on perceived benefits and a negative impact on perceived risks. Results of a survey of University of Zurich students indicated that the proposed causal model explained perception of pesticides, nuclear power, and artificial sweetener very well. When social trust was controlled, the relation between risks and benefits perceived diminished. Results indicate that social trust is a key predictive factor of the perceived risks and benefits of a technology, and provide support for the salient values similarity theory of social trust.
Journal Article↗
Cranial irradiation of female rats causes dose-dependent and age-dependent activation or inhibition of pubertal development.
Cranial irradiation in prepubertal children with leukemia or brain tumors can lead to precocious or in high doses to late puberty. To unravel the underlying mechanisms, we developed a rat model with selective cranial Co60-irradiation technique. Infantile (12-16 d old) or juvenile (21-23 d old) female Sprague-Dawley rats received a single dose of 4, 5, 6, 9 or 2 x 9 Gy (at days 21 and 23). Each group consisted of 7-20 animals. High radiation doses (9 Gy and more) caused retardation of sexual development, whereas low radiation doses (5 or 6 Gy) led to accelerated onset of puberty in 20% of infantile irradiated rats animals as determined by vaginal opening. Interestingly, at peripubertal age (postnatal day 32-34), 5 or 6 Gy infantile irradiated rats had significantly higher serum LH levels stimulated by GnRH and estradiol levels (p < 0.05). 2 x 9 Gy irradiated rats had at the age of 3 mo a marked growth retardation and significantly lower GH levels than the controls (p < 0.05) whereas prolactin, FSH, TSH, T4, and corticosterone levels were comparable with controls. These studies demonstrate that the GnRH-pulse generator is very radiosensitive as precocious activation occurred after low dose irradiation (5 or 6 Gy) of infantile rats without any other endocrine disorder. High radiation doses (9 or 2 x 9 Gy) induced retardation of sexual maturation and later on growth hormone deficiency. Moreover this model of cranial irradiation seems to be suitable to study the molecular mechanisms of radiation induced pubertal changes.
Age Factors↗
Comparative analysis of different puberty inhibiting mechanisms of two GnRH agonists and the GnRH antagonist cetrorelix using a female rat model.
GnRH agonists are the established treatment of precocious puberty caused by premature stimulation of gonadotropin secretion. It has been reported that after an initial stimulation ("flare-up") they reduce LH secretion by desensitization of pituitary GnRH receptors. Little has been published about the use of GnRH antagonists such as cetrorelix to control the onset of puberty and whether they are potentially advantageous compared with GnRH agonists. We conducted two multigroup experiments (12 and 10 d, respectively) treating prepubertal/peripubertal female rats with either the GnRH agonist triptorelin or buserelin and compared them with rats treated with the GnRH antagonist cetrorelix and controls to assess the effects on pubertal progress and serum hormones. In the second experiment, the effects of buserelin and cetrorelix on gene expression of the GnRH receptor, LH-beta, FSH-beta, and the alpha subunit genes in the pituitary were also investigated. Cetrorelix, triptorelin, and buserelin retarded the onset of puberty as determined by delayed vaginal opening, lower ovarian weights, and lower serum estradiol levels. However, although LH and FSH levels were stimulated by both agonists, they were inhibited by cetrorelix. In the cetrorelix versus buserelin experiment, pituitary gene expression of the GnRH receptor and LH-beta subunit were significantly lower in cetrorelix treated rats compared with controls whereas buserelin had little effect. Expression of FSH-beta and alpha subunit were stimulated by buserelin but not by cetrorelix. Even though all three of these GnRH analogues inhibited gonadal development and delayed the onset of puberty, the GnRH agonists had stimulating and inhibiting effects on the pituitary-gonadal axis whereas cetrorelix exerted only inhibiting effects. We conclude from this female rat model that cetrorelix may offer advantages for a more controlled medical treatment of precocious puberty compared with GnRH agonist treatment.
Animals↗
AP-2beta represses D(1A) dopamine receptor gene transcription in neuro2a cells.
Expression of the D(1A) dopamine receptor in brain is restricted to specific neuronal populations. To investigate the mechanism of this selective expression, we localized a silencer upstream of the human D(1A) gene and identified its binding transcription factor in the D(1A)-negative neural cell line Neuro2a. Using deletion CAT analysis, we narrowed this silencer to the region between nucleotides -561 and -532 relative to the CAP site. This 30-bp region, designated D1AS1, contains a sequence homologous to the AP-2 binding site and binds to a factor that also interacts with the AP-2 consensus sequence. In gel supershift assays, this factor is recognized by anti-AP-2beta antibody. Co-transfection of Neuro2a cells with an AP-2beta expression vector repressed the basal CAT activity of D(1A) promoter-reporter plasmids in a D1AS1-dependent manner. RT-PCR analysis indicated that, among AP-2 family members, Neuro2a cells express only AP-2beta. Furthermore, co-transfection of these cells with decoy oligonucleotides corresponding to the D1AS1 sequence de-repressed the D(1A) gene promoter. Unlike in Neuro2a cells, AP-2beta could not repress the D(1A) promoter in the D(1A)-positive neural cell line, NS20Y. In addition, the expression of AP-2beta in different brain regions does not inversely correlate with that of D(1A) dopamine receptor. These observations taken together indicate that AP-2beta is a repressive transcription factor that acts on the D1AS1 silencer of the D(1A) dopamine receptor gene via some cell-specific mechanism(s) in Neuro2a.
Animals↗
Frequency and state specific hemispheric asymmetries in the human sleep EEG.
Regional differences in the sleep EEG along the antero-posterior axis have been recently described. To test for state related, hemispheric differences, sleep records from homologous fronto-central, centro-parietal and parieto-occipital derivations were obtained from 14 young right-handed males. Within the frequency range of sleep spindles (11-15 Hz) power in non-REM sleep dominated in the left hemisphere in all derivations. In the centro-parietal 4-8 Hz band a right-hemispheric predominance prevailed in non-REM sleep and a left-hemispheric predominance in REM sleep. Since the frequency bands exhibiting hemispheric asymmetries are those in which large antero-posterior power gradients had been observed, the left-right differences may arise from structural and functional asymmetries of brain regions involved in the generation of the sleep EEG.
Adult↗
Alpha activity in the human REM sleep EEG: topography and effect of REM sleep deprivation.
The topographical distribution of alpha activity (8.125-11.125 Hz) in the REM sleep EEG, its time course within and across REM sleep episodes, and the effects of selective REM sleep deprivation were investigated in 8 young males. Power spectra of bipolar derivations along the antero-posterior axis in the left (F3C3, C3P3, P301) and right (F4C4, C4P4, P402) hemisphere were calculated. Alpha activity increased along the antero-posterior axis in both hemispheres, and was dominant in the right hemisphere. It decreased within and across REM sleep episodes. Selective REM sleep deprivation resulted in a reduction of alpha activity in the REM sleep EEG. However, the topographical distribution and the time course were not affected. It is suggested that alpha activity in the REM sleep EEG is a marker of REM sleep homeostasis.
Brain↗
Hospital readmissions and quality of care.
BACKGROUND: Readmission rates are often proposed as markers for quality of care. However, a consistent link between readmissions and quality has not been established. OBJECTIVE: To test the relation of readmission to quality and the utility of readmissions as hospital quality measures. SUBJECTS: One thousand, seven hundred and fifty-eight Medicare patients hospitalized in four states between 1991 to 1992 with pneumonia or congestive heart failure (CHF). DESIGN: Case control. MEASURES: Related adverse readmissions (RARs), defined as readmissions that indicate potentially sub-optimal care during initial hospitalization, were identified from administrative data using readmission diagnoses and intervening time periods designated by physician panels. We used linear regression to estimate the association between implicit and explicit quality measures and readmission status (RARs, non-RAR readmissions, and nonreadmissions), adjusting for severity. We tested whether RARs were associated with inferior care and performed simulations to determine whether RARs discriminated between hospitals on the basis of quality. RESULTS: Compared with nonreadmitted pneumonia patients, patients with RARs had lower adjusted quality measured both by explicit (0.25 standardized units, P = 0.004) and implicit methods (0.17, P = 0.047). Adjusted differences for CHF patients were 0.17 (P = 0.048) and 0.20 (P = 0.017), respectively. In some analyses, patients with non-RAR readmissions also experienced lower quality. However, rates of inferior quality care did not differ significantly by readmission status, and simulations identified no meaningful relationship between RARs and hospital quality of care. CONCLUSIONS: RARs are statistically associated with lower quality of care. However, neither RARs nor other readmissions appear to be useful tools for identifying patients who experience inferior care or for comparing quality among hospitals.
Aged↗
Transcriptional regulation of the AP-2alpha promoter by BTEB-1 and AP-2rep, a novel wt-1/egr-related zinc finger repressor.
AP-2 transcription factors have been suggested to exert key regulatory functions in vertebrate embryonic development, in tumorigenicity of various cancer cell types, and in controlling cell cycle and apoptotic effector genes. In this study, we investigated transcriptional regulation of the AP-2alpha gene promoter mediated by an autoregulatory element (referred to as A32) with a core consensus AP-2 binding site at position -336 relative to the mRNA initiation site. AP-2 and multiple different nuclear proteins in HeLa and Neuro2A cell extracts form specific bandshifts with the A32 element. By screening a mouse brain cDNA expression library, we isolated two different cDNAs encoding the transcription factor BTEB-1 and a novel zinc finger protein, AP-2rep. AP-2rep reveals a modular structure with homology to transcription factors of the wt-1/egr-1-family. AP-2rep, BTEB-1, and AP-2 interact in a mutually exclusive manner with overlapping binding sites in the A32 element. Transfection studies revealed that BTEB-1 is a strong activator of AP-2alpha promoter activity, whereas cotransfected AP-2alpha resulted in moderate autoactivation of promoter activity. In contrast, AP-2rep confers strong transcriptional repression to the AP-2alpha gene, and we observed an excellent correlation between induction of AP-2rep mRNA expression and downregulation of AP-2alpha mRNA during development of the kidney. In summary, we have identified multiple transcription factors and cloned from an expression library a novel zinc finger silencing factor, AP-2rep, mediating positive and negative regulation of AP-2alpha expression through a set of overlapping cis-regulatory promoter elements.
Amino Acid Sequence↗