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Biomedical subjects

Frank Weber

Publications and source records attributed to Frank Weber.

At least 37 records · Page 2Linked to original sources
PubMed2005

High frequency of loss of heterozygosity in imprinted, compared with nonimprinted, genomic regions in follicular thyroid carcinomas and atypical adenomas.

CONTEXT: Many mammalian genes that are imprinted regulate cell growth, differentiation, and apoptosis. Because imprinting silences one of the two alleles, resulting in functional haploinsufficiency, we hypothesized that loss of heterozygosity (LOH) at an imprinted locus may result in the deletion of the only functional copy of an imprinted tumor suppressor gene. OBJECTIVE: The goal of this study was to specifically address this hypothesis that in thyroid neoplasias loss of imprinted loci becomes enriched during oncogenesis. DESIGN: In total, thyroid tissue was obtained from 72 patients with thyroid neoplasias comprising 34 follicular thyroid carcinomas (FTCs) and 38 follicular adenomas. We performed PCR-based LOH analysis of DNA from paired normal-tumor samples using 18 markers mapped to imprinted regions (IR) and 13 markers in nonimprinted regions (NIR). RESULTS: Overall LOH frequencies for the IR markers were 26% for the adenomas and 38% for the carcinomas. In the NIR, the overall LOH frequency was 23 and 26% for adenomas and FTCs, respectively. The difference in LOH frequencies between IR and NIR was statistically significant only for the carcinomas (P = 0.001), although there was a similar trend for the atypical adenomas (ATY, P = 0.06). CONCLUSIONS: Our observations suggest that IRs are more prone to genomic instability in FTCs. The fact that the ATY trended toward differential IR/NIR LOH, similar to FTC, may suggest that loss of IR might be instrumental in the adenoma-carcinoma sequence in thyroid carcinogenesis and that ATY could be an important intermediate in this pathway.

Adenoma↗
PubMed2005

Genetic classification of benign and malignant thyroid follicular neoplasia based on a three-gene combination.

Thyroid carcinoma is a common endocrine cancer with a favorable prognosis if subjected to timely treatment. However, the clinical identification of follicular thyroid carcinoma (FTC) among patients with benign thyroid nodules is still a challenge. Preoperative fine needle aspiration-based cytology cannot always differentiate follicular carcinomas from benign follicular neoplasias. Because current methods fail to improve preoperative diagnosis of thyroid nodules, new molecular-based diagnoses should be explored. We conducted a microarray-based study to reveal the genetic profiles unique to FTC and follicular adenomas (FAs), to identify the most parsimonious number of genes that could accurately differentiate between benign and malignant follicular thyroid neoplasia. We confirmed our data by quantitative RT-PCR and immunohistochemistry in two independent validation sets with a total of 114 samples. We were able to identify three genes, cyclin D2 (CCND2), protein convertase 2 (PCSK2), and prostate differentiation factor (PLAB), that allow the accurate molecular classification of FTC and FA. Two independent validation sets revealed that the combination of these three genes could differentiate FTC from FA with a sensitivity of 100%, specificity of 94.7%, and accuracy of 96.7%. In addition, our model allowed the identification of follicular variants of papillary thyroid carcinoma with an accuracy of 85.7%. Three-gene profiling of thyroid nodules can accurately predict the diagnosis of FTC and FA with high sensitivity and specificity, thus identifying promising targets for further investigation to ultimately improve preoperative diagnosis.

Adenocarcinoma, Follicular↗
PubMed2005

Fatigue and regulation of the hypothalamo-pituitary-adrenal axis in multiple sclerosis.

BACKGROUND: Fatigue is a common and disabling symptom in patients with multiple sclerosis (MS). Underlying mechanisms postulated so far have involved localization of brain lesions and abnormalities of the neuroendocrine system and cytokine regulation. OBJECTIVE: To investigate the relationship between fatigue and the hypothalamo-pituitary-adrenal (HPA) axis in patients with MS. DESIGN: A prospective survey. SETTING: Outpatient and inpatient study at the Max Planck Institute of Psychiatry, Munich, Germany. PATIENTS: Thirty-one patients with clinically definite MS, a relapsing-remitting disease course, and without MS-specific treatment. INTERVENTIONS: Assessment of fatigue with 3 questionnaires: the Fatigue Severity Scale (FSS), the Modified Fatigue Impact Scale (MFIS), and the Visual Analog Scale. Assessment of HPA axis regulation with the combined dexamethasone-corticotropin releasing hormone (Dex-CRH) test. RESULTS: The FSS score was significantly correlated with the MFIS score. Patients with fatigue had significantly elevated adrenocorticotropin (ACTH) levels in the combined Dex-CRH test. CONCLUSIONS: In contrast to results for chronic fatigue syndrome, where a hyporeactivity of the HPA axis has been shown, MS patients with fatigue exhibited a higher activity of the HPA axis than those without fatigue, as evidenced by significantly increased ACTH concentrations. Proinflammatory cytokines, known to be elevated in patients with MS, may cause both HPA axis alterations and fatigue.

Adrenocorticotropic Hormone↗
PubMed2005

Pumpless extracorporeal lung assist (pECLA) in patients with acute respiratory distress syndrome and severe brain injury.

BACKGROUND: A retrospective analysis was performed to estimate the practicability of a pumpless extracorporeal lung assist system (pECLA) in trauma patients suffering from severe brain injury and the acute respiratory distress syndrome (ARDS). METHODS: Five patients with acute severe brain injury and ARDS, ventilated in a lung protective mode, were connected to pECLA to avoid the detrimental effects of hypercapnia on intracranial pressure (ICP) and cerebral outcome. With pECLA hypercapnia was eliminated in all patients while the minute volume of artificial ventilation could be reduced. Subsequently, ICP was reduced, systemic hemodynamics and cerebral perfusion pressure remained stable. One patient died due to multi-organ failure as a consequence of multi-trauma. The remaining patients survived showing a good neurologic function. CONCLUSIONS: pECLA is a promising alternative compared with conventional pump-driven systems for patients with ARDS and brain injury, since the pECLA system has minor restrictions, limitations and side effects.

Adolescent↗
PubMed2005

The correlation of the Narcotrend Index with endtidal sevoflurane concentrations and hemodynamic parameters in children.

BACKGROUND: The Narcotrend Index (NI) of anesthetic depth is potentially a pharmacodynamic measure of the effects of sevoflurane on the brain. METHODS: In this prospective observational study of 30 pediatric surgical patients (1-11 years), we investigated the correlation between nonsteady-state endtidal sevoflurane (eT(Sevo)), NI, mean arterial pressure (MAP), and heart rate (HR). The performance of the Narcotrend for differentiation between consciousness and unconsciousness was evaluated using prediction probability (P(K)). RESULTS: Spearman correlation analysis showed significant correlations (P < 0.01) between eT(Sevo) and NI (r = -0.85) and MAP (r = -0.43). P(K)-values for differentiation between consciousness and unconsciousness were 1.0 for NI and <0.85 for MAP and HR. During the surgical procedure, NI-values showed a constant rise with each 0.5% step of lowering eT(Sevo) (P < 0.03), whereas MAP remained unaltered and HR showed a constant decline (P < 0.03), except between 1.5 and 1%. CONCLUSIONS: In children, nonsteady-state eT(Sevo) concentrations are more closely related with NI than with MAP or HR. In this study, only NI reliably differentiated consciousness from unconsciousness.

Anesthesia, Inhalation↗
PubMed2005

The correlation of the Narcotrend Index and classical electroencephalographic parameters with endtidal desflurane concentrations and hemodynamic parameters in different age groups.

BACKGROUND: The Narcotrend Index (NI) for assessment of depth of anesthesia by analysis of the electroencephalogram (EEG), is potentially a pharmacodynamic measure of the effects of desflurane on the brain. METHODS: In this prospective study of 30 pediatric and adult patients (group 1: 3-6 years, n = 10; group 2: > 6 < 12 years; group 3: 12-40 years), undergoing ophthalmological surgery, we investigated the pharmacodynamic relationship between nonsteady state endtidal desflurane concentrations (eT(Des)), NI, classical EEG parameters (cEEG), heart rate (HR) and mean arterial pressure (MAP). The performance of the Narcotrend for differentiation between consciousness and unconsciousness was evaluated using prediction probability (P(K)). RESULTS: Spearman correlation analysis showed significant negative correlations (P < 0.001) between eT(Des) and NI (group 1: r = -0.93, group 2: r = -0.86, group 3: r = -0.66). Correlations between eT(Des) and MAP or HR were either only weak negative (r < -0.5) or not significant. Desflurane EC(50) (eT(Des) with half maximal effect on NI) was 7.18% for group 1, 7.34% for group 2, and 4.15% for group 3 (P < 0.001 Vs groups 1 and 2). Overall awake NI values (96.7 +/- 1.4) were significantly higher (P < 0.001) than at the moment of loss of consciousness (58.3 +/- 17.5), with no overlap (P(K) 1.0), whereas P(K) values for cEEG, MAP and HR were all <0.85. CONCLUSIONS: The pharmacodynamic relationship between eT(Des) and NI is age dependent with a significantly higher EC(50) in children than in adolescents and adults. The NI appears to be superior to cEEG, MAP and HR in differentiating consciousness from unconsciousness.

Adolescent↗
PubMed2005

Interventional closure with Amplatzer PFO occluder of patent foramen ovale in patients with paradoxical cerebral embolism.

Percutaneous transcatheter closure has been proposed as an alternative to surgical closure or long-term anticoagulation in patients with presumed paradoxical embolism and patent foramen ovale (PFO). We report our mid-term results of 55 consecutive symptomatic patients (mean age: 47 years, range: 20-79) who underwent percutaneous transcatheter closure of PFO after at least one event of cerebral ischemia; 16 (29%) patients had at least one transient ischemic attack and 39 (71%) patients at least one embolic stroke. Multiple embolic events had occurred in 6 (11%) patients. Percutaneous transcatheter closure was technically successful in all 55 patients (100%). For the majority of patients, an Amplatzer PFO occluder measuring 25 mm in diameter (n=49) or an Amplatzer PFO occluder measuring 35 mm in diameter (n=6) was used. Complete occlusion by color Doppler and transesophageal contrast echocardiography investigation was achieved in 96% at follow-up 3-6 months after implantation; only 2 patients had a trivial residual shunt at follow-up. Mean fluoroscopy time was 6.7 minutes (range: 1.7-47.1), and in-hospital follow-up was uneventful except for 1 patient who developed a cardiac tamponade requiring uneventful and successful needle pericardiocentesis. At a mean follow-up of 19 months (range: 3-32) no recurrent embolic neurological events was observed. Transcatheter closure of PFO with Amplatzer PFO occluder devices is a safe and effective therapy for patients with previous paradoxical embolism and aneurysmatic or nonaneurysmatic PFO. Percutaneous closure is associated with a high success rate, low incidence of hospital complications, and freedom of cerebral ischemia events.

Adult↗
PubMed2005

The impact of acoustic stimulation on the AEP monitor/2 derived composite auditory evoked potential index under awake and anesthetized conditions.

UNLABELLED: The AEP Monitor/2 features an auditory evoked potential (AEP) and electroencephalogram (EEG)-derived hybrid index of the patient's hypnotic state. The composite AEP index (AAI) is preferably calculated from the AEP, but in case of low signal quality it is based entirely on the spontaneous EEG. We investigated the impact of auditory input on the AAI in 16 patients with correctly positioned headphones for acoustic stimulation and headphones disconnected from the patient's ears under awake and anesthetized conditions. The AAI and the Narcotrend Index (NI), another EEG-based measure of hypnotic depth, were recorded simultaneously. AAI values under awake and anesthetized conditions were higher with correctly positioned headphones than with headphones disconnected from the patient's ears (P < 0.05) but remained within the range indicating the patient's actual hypnotic state as given by the manufacturer of the monitor. Under awake conditions with correctly positioned headphones we observed frequent fluctuations between AEP-derived and EEG-derived AAI, whereas with headphones disconnected from the patient's ears the AAI calculation was completely EEG based. Acoustic stimulation had no impact on the Narcotrend Index. Although relevant misinterpretations of the patient's hypnotic state as a consequence of a turnover from AEP-derived to EEG-derived AAI values should not occur, an improved harmonization of the two methods of indexing would be desirable. IMPLICATIONS: The AEP Monitor/2 generates an Index (AAITM) indicating the patient's hypnotic state by analyzing either auditory evoked potentials (AEP) or spontaneous electroencephalographic (EEG) activity. We demonstrate that, though significantly different under AEP-derived or EEG-derived conditions, AAI values remain within the range indicating the patient's actual hypnotic state as given by the manufacturer of the device.

Acoustic Stimulation↗
PubMed2005

Gene-expression profiling in differentiated thyroid cancer--a viable strategy for the practice of genomic medicine?

Thyroid neoplasias have been largely ignored as an active field of investigation due to the overall favorable prognosis of differentiated nonmedullary thyroid cancers. However, differentiated thyroid cancers have the highest estimated annual percentage increase in incidence amongst all cancer sites. Furthermore, no significant progress has been made to improve survival, especially for advanced disease. Compounding the problem, there remains a lack of highly accurate preoperative markers or molecular-based predictive models to differentiate benign from malignant follicular neoplasias, thus we continue to rely upon surgery for diagnostic purposes in this subset of patients. Therefore, new approaches are necessary to identify potential novel diagnostic, prognostic and therapeutic algorithms, which would not only allow accurate early diagnosis but also personalized patient management, with clinical management and surveillance tailored according to the genetic signature of the patient. The advent of modern genomic technologies, such as global gene-expression profiling, may begin to provide the data required for the evidence-based practice of genomic medicine as it relates to thyroid neoplasia. However, it is already clear that genomic technology alone is insufficient to fully achieve this vision.

Adenocarcinoma, Follicular↗
PubMed2004

Silencing of the maternally imprinted tumor suppressor ARHI contributes to follicular thyroid carcinogenesis.

The two most common subtypes of thyroid cancer, follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma, have been extensively studied, but our fundamental understanding of the molecular events in thyroid epithelial oncogenesis is still limited. Unreported data from our previous published global gene expression analysis revealed that the tumor suppressor gene aplysia ras homolog I (ARHI) is frequently underexpressed in FTCs. In this study, we elucidated the frequency and mechanism of ARHI silencing in benign and malignant thyroid neoplasia. We demonstrated that underexpression of ARHI occurs principally in FTCs (P = 0.0018), including its oncocytic variant (11 of 13), even at minimally invasive stage but not classic papillary thyroid carcinoma (two of seven) or follicular adenoma (FA) (three of 14). FTCs show strong allelic imbalance with reduction in copy number/loss of heterozygosity (LOH) in 69%, compared with less than 10% for FAs. In combination with our LOH data, bisulfite sequencing in a subset of samples revealed that FA displays a symmetric methylation pattern, likely representing one unmethylated allele and one presumptively imprinted allele, whereas FTC shows a virtually complete methylation pattern, representing LOH of the nonimprinted allele with only the hypermethylated allele remaining. Furthermore, we showed that pharmacologic inhibition of histone deacetylation but not demethylation could reactivate ARHI expression in the FTC133 FTC cell line. Therefore, our data suggest that silencing of the putative maternally imprinted tumor suppressor gene ARHI, primarily by large genomic deletion in conjunction with hypermethylation of the genomically imprinted allele, serves as a key early event in follicular thyroid carcinogenesis.

Adenocarcinoma, Follicular↗
PubMed2004

The effect of acetylsalicylic acid and captopril on uterine and ovarian blood flow during the estrous cycle in mares.

In previous studies, transrectal color Doppler sonography was used to demonstrate an increase in genital blood flow resistance in subfertile mares. The objectives of the present study were to determine the effects of an anticoagulant (acetylsalicylic acid) and a vasodilator (captopril) on uterine and ovarian perfusion and plasma progesterone concentrations in cycling mares. From Day 1 to 11 of an estrous cycle (Day 0=day of ovulation following prostaglandin-induced luteolysis), five Trotter mares were given 2500 mg lactose, 2500 mg ASA, or 50 mg captopril twice daily in their feed (one compound per cycle, in random order). Transrectal color Doppler sonography was used to examine both uterine arteries and the ovarian artery ipsilateral to the corpus luteum once daily, immediately prior to administration of the drug. Blood flow resistance was determined semiquantitatively using the pulsatility index (PI) and plasma progesterone concentrations were determined with an enzyme immunoassay. Compared to the placebo, both ASA and captopril decreased mean PI values of both uterine arteries of all mares. On average, ASA decreased the PI of the uterine arteries by 25%; this was more (P<0.05) than the average decrease (13%) caused by captopril. Both drugs decreased (P<0.05) blood flow resistance in the ovarian arteries, although there was no difference (P<0.05) in their efficacy. In addition, both ASA and captopril increased (P<0.0001) plasma progesterone concentrations (18 and 17%, respectively). In conclusion, either ASA or captopril improved uterine and ovarian perfusion; however the effects on fertility were not determined.

Animals↗
PubMed2004

Transrectal Doppler sonography of uterine and umbilical blood flow during pregnancy in mares.

Transrectal color Doppler sonography was used to investigate uterine and umbilical blood flow during pregnancy (duration, 46-48 weeks) in four mares. The resistance index (RI) and blood flow volume (VOL) of the uterine arteries ipsilateral and contralateral to the conceptus, and the presence of an early diastolic notch in the Doppler wave, were evaluated every 4 week throughout pregnancy. Fetal blood flow was calculated semiquantitatively every 2 week (from 20 to 40 weeks), using the RI of the umbilical arteries. During the entire period of investigation, there were no significant individual variations in uterine RI and VOL nor differences between the two uterine arteries. Mean RI decreased by more than half during pregnancy from 0.89 +/- 0.01 to 0.39 +/- 0.03, and mean VOL increased almost 400-fold from 69 +/- 37 to 27,467 +/- 8851 ml/min. There were relationships (P<0.0001) between week of pregnancy (x) and RI as well as VOL. These were described by the equations RI=0.938-0.150 ln(x) and VOL (ml/min)=7.621x(2.157). Log transformed total estrogen (TE) were related to RI (r=-0.879; P<0.05) as well as to VOL (r=0.888; P<0.05). The notch in the Doppler wave of the uterine artery disappeared between 18 and 26 weeks. There was a correlation (P<0.0001) between week of gestation (x) and RI values of the umbilical arteries; this was described by the equation RI=1.763-0.071x+0.001x2. Further studies are needed to determine whether transrectal color Doppler sonography could be used to identify mares at risk of abortion.

Animals↗
PubMed2004

Quantification of temporary and permanent subpopulations of bull sperm by an optimized SYBR-14/propidium iodide assay.

BACKGROUND: The quality of bull sperm is a key factor in the field of controlled reproduction. Viability-testing is an important aspect of sperm quality definition, especially after cryopreservation where multiple factors such as handling, freeze-thaw cycle, and preservation media, have an impact on the metabolic and functional state of sperm cells. METHODS: We investigated the commonly used SYBR-14/propidium iodide (PI) assay to obtain functional information about sperm-dye and dye-dye interactions. After optimizing filter settings, dye concentrations and incubation times we used these dyes for an interruption free flow cytometric kinetic analysis of a mixture of viable and dead bovine sperm. RESULTS: For the sensitivity of this method and the separation of the different cellular subpopulations fluorescence quenching of SYBR-14 by PI is mainly responsible. Together with a spectral overlap of the two emission spectra of about 5%, even for a wavelength greater than 700 nm, this quenching effect has to be taken into account for a quantitative understanding of the observed fluorescence intensity signals. The fraction of a temporary "intermediate" population to be observed between the viable and dead cells in an SYBR-14/PI-dot-plot diagram becomes greater after stress on the sperm cells caused by cryopreservation. The temporary fraction of "intermediate" cells is maximal at about 6 min after staining and disappears after about 15 min by shifting towards the dead sperm population. The estimation of this "intermediate" population may be a good indicator for handling and storage induced detrimental effects on bovine sperm cells. CONCLUSION: The SYBR-14/PI assay is a fast, reliable and sensitive method to assess the membrane integrity of bull sperm and to separate viable, dead, and "intermediate" sperm subpopulations.

Animals↗
PubMed2004

Autoantibody synthesis in primary progressive multiple sclerosis patients treated with interferon beta-1b.

We conducted an open-labeled clinical trial of interferon beta-1b (IFNB) treatment in 20 patients with primary progressive multiple sclerosis (PPMS) and longitudinally monitored autoantibodies against double-stranded DNA (dsDNA), thyroid peroxidase (TPO),myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), synapsin and S-100B. Before treatment, one patient had elevated TPO antibodies, four patients had elevated antibodies against S-100B, two patients against MOG or synapsin and one patient against MBP. In two patients we observed a continuous increase of dsDNA or TPO antibodies above the normal range. This rise paralleled IFNB treatment. In addition, 11 of 20 patients developed neutralizing antibodies against IFNB. There was no increase of autoantibodies directed against central nervous system antigens. Like patients with relapsing remitting or secondary progressive multiple sclerosis, PPMS patients may be at risk of an autoimmune response during IFNB treatment.

Adjuvants, Immunologic↗