Biomedical subjects

C Gross

Publications and source records attributed to C Gross.

At least 19 recordsLinked to original sources

PubMed2007

A novel conditional knockout strategy applied to serotonin receptors.

Here we demonstrate the feasibility of a doubly regulatable transgenic mouse design that allows for gene manipulation by both Cre-recombinase and the tetracycline inducible system. Using a knock-in strategy to insert both elements of the tetracycline inducible system and a neomycin (neo) cassette flanked by loxP sequences (floxed) into the wild-type locus, we generated mice that express the 5-HT(1B) receptor in a conditional manner. In the presence of a floxed neo-cassette, receptor expression was silenced. Removal of this cassette by Cre-mediated recombination led to 5-HT(1B) receptor expression, which was highly regulatable when doxycycline, a derivative of tetracycline, was administered to the mice. This system allowed for a determination of an in vivo time course of receptor half-life and recovery. Physiological studies also demonstrated that rescued 5-HT(1B) receptors were functional, and that this functionality was reversible upon treatment with doxycycline. Crossing mice where the 5-HT(1B), or the 5-HT(1A), receptors were silenced by the neo-cassette, with mice expressing either Cre-recombinase or the tetracycline transactivator (tTA) under the control of tissue-specific promoters, led to tissue-specific re-expression of these receptors. Our studies thus demonstrate the potential of this strategy for achieving both a classic knockout, as well as subsequent tissue-specific and/or inducible knockouts.

Animals↗

PubMed2006

High-performance liquid chromatography method for rapid assessment of viral particle number in crude adenoviral lysates of mixed serotype.

Accurate adenovirus (Ad) quantification requires labor- and time-intensive viral stock purification. While crude viral lysates can be titered by plaque assay, this cell-based assay is neither rapid nor accurate. Consequently, a method for quantification of crude, unpurified viral culture lysates is needed. Given growing interest in alternative Ad serotypes (different from well-studied and characterized serotype Ad5) for basic research and for therapeutic applications, such a method should also apply to alternative serotypes. Using a Q Sepharose XL (QSXL) column-based method, we describe a robust quantification method resulting in efficient retention of viral particles of all serotypes, while non-viral components of crude infected cultures remain largely in the flow-through. The high-performance liquid chromatography-QSXL method allows rapid, accurate adenoviral quantification in crude lysates as well as identification of the various serotypes present in mixed-serotype crude lysates. We also report on conditions that efficiently strip and regenerate the column, extending its functional life.

Adenoviridae↗

PubMed2006

Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome.

BACKGROUND: Andermann syndrome (OMIM 218000) is an autosomal recessive motor-sensory neuropathy associated with developmental and neurodegenerative defects. The cerebral MRI reveals a variable degree of agenesis of the corpus callosum. Recently, truncating mutations of the KCC3 gene (also known as SLC12A6) have been associated with Andermann syndrome. METHODS: The authors assessed clinically and genetically three isolated cases from Germany and Turkey with symptoms consistent with Andermann syndrome. RESULTS: The authors detected four novel mutations within the KCC3 gene in their patients: two different truncating mutations in the first patient, a homozygous truncating mutation in the second, and a homozygous missense mutation in the third patient. In contrast to the classic phenotype of the Andermann syndrome linked to truncating KCC3 mutations the phenotype and the course of the disease linked to the missense mutation appeared to be different (i.e., showing additional features like diffuse and widespread white matter abnormalities). CONCLUSIONS: Not only truncating but also missense mutations of the KCC3 gene are associated with Andermann syndrome. Different types of KCC3 mutations may determine different clinical phenotypes.

Agenesis of Corpus Callosum↗

PubMed2006

Further clinical and genetic characterization of SPG11: hereditary spastic paraplegia with thin corpus callosum.

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders leading to progressive spasticity of the lower limbs. Clinically, HSPs are divided into "pure" and "complicated" forms. In pure HSP, the spasticity of the lower limbs is the sole symptom, whereas in complicated forms additional neurological and non-neurological features are observed. Genetically, HSPs are divided into autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) forms. Up to date, 30 different HSPs are linked to different chromosomal loci and 11 genes could be defined for AR-HSP, AD-HSP and XL-HSP. SPG11, an AR-HSP (synonym: HSP11), is a complicated HSP associated with a slowly progressive spastic paraparesis, mental impairment and the development of a thin corpus callosum (TCC) during the course of the disease. SPG11 has been previously linked to chromosomal region 15q13 - 15. First, we applied rigid diagnostic criteria to systematically examine 20 Turkish families with autosomal recessive HSP for characteristic features of SPG11. We detected four large Turkish families with AR-HSP and TCC consistent with SPG11. Subsequent genetic linkage analysis of those 4 families refines the SPG11 locus further down to a small region of 2.93 cM with a maximum lod score of 11.84 at marker D15S659 and will guide further candidate gene analysis.

Adolescent↗

PubMed2006

Side-effects of subthalamic stimulation in Parkinson's disease: clinical evolution and predictive factors.

Chronic bilateral high-frequency stimulation of the subthalamic nucleus (STN) is an alternative treatment for disabling forms of Parkinson's disease when on-off fluctuations and levodopa-induced dyskinesias compromise patients' quality of life. The aim of this study was to assess the evolution of side-effects during the first year of follow-up and search for clinical predictive factors accounting for their occurrence. We compared the frequency of side-effects at 3 and 12 months after surgery in a cohort of 44 patients. The off-medication scores of Unified Parkinson's Disease Rating Scale (UPDRS) II, III, axial symptoms, disease duration and age at surgery were retained for correlation analysis. Dysarthria/hypophonia, weight gain and postural instability were the most frequent chronic side-effects. Whereas dysarthria/hypophonia remained stable over time, weight gain and postural instability increased during the first year post-op. High axial and UPDRS II scores at surgery were predictive of dysarthria/hypophonia. Age and axial score at surgery were positively correlated with postural instability. Despite the occurrence of side-effects, the benefit/side-effects ratio of STN stimulation was largely positive during the first year of follow-up. Age, intensity of axial symptoms and UDPRS II off-medication score before surgery are predictive factors of dysarthria/hypophonia and postural instability after surgery.

Aged↗

PubMed2006

Identifying interactions between genes and early environment in the mouse.

Interactions between genetic and early environmental factors are recognized to play a critical role in modulating susceptibility to disease, particularly mental illness. In order to better understand such mechanisms at the molecular level, we have developed a screening paradigm in mice that allows us to test the ability of targeted mutations in candidate genes to modify susceptibility to the long-term effects of different maternal environment. Offspring of genetically identical F1 hybrid dams produced by reciprocal breeding of C57BL/6 and BALB/c parents show alterations in anxiety-related behavior as a consequence of their different maternal environment. Introduction of targeted mutations into these offspring via the father allows for the identification of candidate genes that alter these maternal effects. Our strategy offers several advantages over other methods to study maternal effects, including the use of genetically identical parents, the ability to identify both prenatal and postnatal effects, the straightforward introduction of mutations and its adaptability to high-throughput screening. In order to test the utility of this paradigm to screen candidate genes, we tested for gene-environment interactions involving loss-of-function mutations in the serotonin 1A receptor gene. Our studies demonstrate that early gene-environment interactions can be successfully tested in the mouse. When combined with conditional gene targeting and other molecular genetic techniques available in the mouse, this approach has the potential to identify the molecular mechanisms underlying early gene-environment effects.

Animals↗

PubMed2006

The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric disorders.

The role of the D(3) receptor has remained largely elusive before the development of selective research tools, such as selective radioligands, antibodies, various highly specific pharmacological agents and knock-out mice. The data collected so far with these tools have removed some of the uncertainties regarding the functions mediated by the D(3) receptor. The D(3) receptor is an autoreceptor that controls the phasic, but not tonic activity of dopamine neurons. The D(3) receptor, via regulation of its expression by the brain-derived neurotrophic factor (BDNF), mediates sensitization to dopamine indirect agonists. This process seems responsible for side-effects of levodopa (dyskinesia) in the treatment of Parkinson's disease (PD), as well as for some aspects of conditioning to drugs of abuse. The D(3) receptor mediates behavioral abnormalities elicited by glutamate/NMDA receptor blockade, which suggests D(3) receptor-selective antagonists as novel antipsychotic drugs. These data allow us to propose novel treatment options in PD, schizophrenia and drug addiction, which are awaiting evaluation in clinical trials.

Animals↗

PubMed2006

[Use of hyaluronic acid cleaving enzymes for absorption acceleration. Results of an in vitro study with xylazine and ketamine].

The so-called "Hellabrunner Mischung", (combination of xylazine and ketamine with hyaluronidase) is frequently used for the immobilisation of wildlife animals. The enzyme hyaluronidase shall improve the distribution of the intramuscularly or subcutaneously administered compounds in the tissue and enhance their absorption. These enhancing effects of two hyaluronate lyases of bacterial origin (Streptococcus agalactiae and Streptococcus equisimilis) and a testicular hyaluronidase were compared in an in vitro test. Using the isolated perfused bovine udder, 2 ml of a solution were administered subcutaneously containing 125 mg/ml xylazine and 100 mg/ml ketamine and one of the above mentioned enzymes (150 I.U.). All three enzymes enhanced the absorption rate of xylazine and ketamine determined by measurement of the concentration in the perfusate. The bacterial hyaluronate lyases were significantly more efficient, especially during the clinically important first minutes after administration.

Adrenergic alpha-Agonists↗

PubMed2005

Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is the most common behavioral disorder in childhood with substantial heritability. Pharmacological and molecular genetic studies as well as characterization of animal models have implicated serotonergic dysfunction in the pathophysiology of ADHD. Here, we investigated the effect of polymorphic variants in the gene of the tryptophan hydroxylase-2 (TPH2), the rate-limiting enzyme of serotonin (5-HT) synthesis in the brain, in children and adolescents with ADHD. We analyzed three single nucleotide polymorphisms (SNPs) in and downstream of the transcriptional control region of the TPH2 gene in 103 families with 225 affected children. Allelic association in families with more than one affected child was assessed using the pedigree disequilibrium test. Preferential transmissions were detected for the two SNPs in TPH2's regulatory region (rs4570625, P=0.049; rs11178997, P=0.034), but not for the third SNP in intron 2 (rs4565946, P=0.3517). Haplotype analysis revealed a strong trend of association between the regulatory region SNPs (rs4570625, rs11178997) and ADHD (P=0.064). Our results link potentially functional TPH2 variations to the pathophysiology of ADHD, and further support the relevance of 5-HT in disorders related to altered motor activity and cognitive processes.

Adolescent↗

PubMed2005

Progression of macrovascular diseases is reduced in type 1 diabetic patients after more than 5 years successful combined pancreas-kidney transplantation in comparison to kidney transplantation alone.

Recent reports have demonstrated an improved cardiovascular outcome after simultaneous pancreas-kidney transplantation (SPKT) compared with kidney transplantation alone (KTA) in type 1 diabetic patients with end-stage renal disease. The purpose of this study was to determine the impact of SKPT and KTA on the progression of cerebrovascular disease (CVD), coronary heart disease (CHD) and peripheral vascular disease (PVD) 5 and 10 years after transplantation. Only patients with graft survival more than 5 years, were included in this study. In summary, 12 type 1 diabetic patients with SPKT and 10 diabetic subjects with KTA were evaluated. The immunosuppressive therapy was similar in both patient groups. The mean observation period was 124 (72-184) months in the SPKT group and 122 (64-216) months in the group with KTA. To investigate the vascular risk profile we examined mean HbA1c, blood pressure and lipid levels in both patient groups during the first 5 years (period I) and the second 5 years (period II) after transplantation (measurements at least at 3-month intervals). Additionally, we evaluated the prevalence of moderate (stage I-II) and severe (stage III-IV) macrovascular diseases prior as well as 5 and 10 years after transplantation. During period I the mean HbA1c-value was 5.7+/-0.4% in the group with SPKT versus 7.4+/-0.8% in the KTA group, and in period II 5.8+/-0.4% in the SPKT group versus 7.6+/-0.9% (P<0.001) in the patients with KTA. The cholesterol levels were approximately the same in both groups, the triglycerides were lower in the patients with SPKT than in the subjects with KTA with 1.3+/-0.4 vs. 2.2+/-0.9 mmol/l in period I, and 1.4+/-0.5 vs. 2.3+/-0.6 mmol/l in period II (P<0.05). The BP-values were similar in both groups. Five years after transplantation the prevalence of vascular diseases was not significantly different between both groups. During the following 5 years the prevalence of macrovascular diseases increased more in the KTA than in the SKPT group. After a mean observation period of 10 years the SKPT group showed a lower prevalence of vascular diseases (stage I-IV) with 41% CVD, 50% CHD and 50% PAV in comparison to the KTA group with a prevalence of 80% CVD, 90% CHD and 80% PAV), the difference was not statistically significant because of the small patient groups. The frequency of the vascular complications myocardial infarction (16% vs. 50%), stroke (16% vs. 40%) and amputations (16% vs. 30%) was in summary significant lower in the patients with SPKT than in the patients with KTA (P<0.05). In conclusion, while for the first 5 years after transplantation the progression of macroangiopathy in patients with SPKT and KTA was not significantly different, after a mean 10-year observation period the progression of macrovascular diseases was significantly lower in recipients with a functioning SPKT compared to patients with a KTA; this can be explained by a better vascular risk profile after SPKT. The 10-year patient survival was 83% in the SPKT group and 70% in patients with KTA.

Adult↗

PubMed2004

Nanoparticle composition of a ferrofluid and its effects on the magnetic properties.

Experiments were carried out on a water-based ferrofluid (gamma-Fe2O3 with carboxydextran shell) using photon correlation spectroscopy (PCS), atomic force microscopy, and magnetic nanoparticle relaxation measurements. The experiments were designed with the aim to relate the Néel signals that are in theory generated by large single core particles with nanoscopic properties, that is, particle size, particle size distribution, shell properties, and aggregation. For this purpose, the ferrofluid was fractionated by magnetic fractionation and size exclusion chromatography. Nanoparticles adsorbed onto positively charged substrates form a two-dimensional monolayer. Their mean core diameters are in the range of 6 to about 20 nm, and particles above 10 nm are mostly aggregates. The hydrodynamic particle diameters are between 13 and 80 nm. The core diameter of the smallest fraction is confirmed by X-ray reflectometry; the surface coverage is controlled by bulk diffusion. Comparison with the hydrodynamic radius yields a shell thickness of 3.8 nm. Considering the shell thickness to be constant for all particles, it was possible to calculate the apparent particle diameter in the original ferrofluid from the PCS signals of all fractions. As expected, the small cores yielded no Néel relaxation signals in freeze-dried samples; however, the fractions containing mostly aggregates yielded Néel relaxation signals.

Journal Article↗

PubMed2004

Agenesis of the corpus callosum, abnormal genitalia and intractable epilepsy due to a novel familial mutation in the Aristaless-related homeobox gene.

Mutations in the Aristaless-related homeobox (ARX) gene are associated with a broad spectrum of disorders including X-linked lissencephaly with abnormal genitalia (XLAG) and absent corpus callosum. Here, we describe a family with two male infants suffering from agenesis of the corpus callosum (ACC), intractable epilepsy, and abnormal genitalia. The phenotype of both affected patients differed in severity of the cerebral malformation with one showing no obvious evidence for lissencephaly. Both infants lacked any psychomotor development and died at the age of 17 weeks and 18 months, respectively. Genetic analysis of the ARX gene revealed a novel frameshift mutation in exon 4 (nt1419_1420insAC) leading to a shortened protein lacking the aristaless domain. In summary, analysis of the ARX gene should not only be considered in male patients with typical features of XLAG but also in those presenting with early onset epilepsy, ACC, and abnormal genitalia without obvious neuroradiological features of lissencephaly.

Abnormalities, Multiple↗

PubMed2004

X-linked lissencephaly with abnormal genitalia associated with renal phosphate wasting.

X-linked lissencephaly with abnormal genitalia (XLAG) is a rare disorder caused by mutations in the aristaless-related homeobox (ARX) gene. We report on the clinical data of a boy with a 1-bp deletion (790 delC) resulting in a frame shift in the ARX gene and prolonged survival until age 18 months. Similar to other patients, the boy showed postnatal microcephaly, hypothalamic dysfunction, intractable neonatal seizures, and chronic diarrhoea. In addition, he suffered from exocrine pancreatic insufficiency and renal phosphate wasting became apparent from age 5 months, both of which have not been described previously in XLAG. This allows us to speculate that the phenotype of XLAG is more complex than hitherto known and may include renal phosphate wasting which might not have been observed in other patients due to early death.

Abnormalities, Multiple↗

PubMed2004

Different cardiorespiratory responses to hemorrhage and hyperoxia in normotensive (WKY) and spontaneously hypertensive (SHR) rats.

OBJECTIVE: To compare the cardiorespiratory responses underlying the beneficial effects of hyperoxia during blood loss between normotensive (WKY) and hypertensive (SHR) rats. METHODS: Experiments were carried out in anesthetized animals with both carotid bifurcations either innervated or denervated. The effects of breathing 60% O2 in N2 were studied either in combination with non-hypotensive hemorrhage or during hemorrhagic hypotension. RESULTS: In normoxia arterial pressure fell more in SHR than in WKY for a given blood loss. During hyperoxia, nerve-intact rats showed initial suppression of ventilation, but bifurcation-denervated rats a powerful enhancement. In all groups, hyperoxia increased the overall tone of venous capacitance vessels. CONCLUSIONS: The greater blood loss in SHR than in WKY when bleeding down to a given arterial pressure results from a stronger constriction of venous capacitance vessels. Hyperoxia improves the ability of the cardiorespiratory system to resist the effects of hemorrhage by increasing the overall venous tone, thus supporting cardiac filling, and in some cases also by increasing alveolar ventilation, probably secondary to improved cerebral oxygenation. The beneficial effects of hyperoxia were: (i) not prevented by carotid denervation, and thus were presumably direct tissue effects of oxygen, (ii) strikingly weaker in SHR than in normotensive (WKY) rats.

Animals↗

PubMed2004

Clinical spectrum of muscle-eye-brain disease: from the typical presentation to severe autistic features.

Muscle-eye-brain disease (MEB) is an autosomal recessive congenital muscular dystrophy with ocular abnormalities and type II lissencephaly. MEB is caused by mutations in the protein O-linked mannose beta1,2-N-acetylglucosaminyltransferase (POMGnT1) gene on chromosome 1q33. POMGnT1 is a glycosylation enzyme that participates in the synthesis of O-mannosyl glycan. The disease is characterized by altered glycosylation of alpha-dystroglycan. The clinical spectrum of MEB phenotype and POMGnT1 mutations are significantly expanded. We would like to present two cases with MEB disease with POMGnT1 mutations, whose clinical picture shows heterogeneity. The patient with R442H mutation had the classical form of the disease although the one with IVS17-2A-->G homozygous mutation had severe autistic features as the dominating presenting sign. These two cases represent different spectrums of one disorder. To the best of our knowledge, autistic features and stereotypical movements have not been included thus far as a part of broad and heterogeneous MEB spectrum.

Adolescent↗

PubMed2003

ARX mutations in X-linked lissencephaly with abnormal genitalia.

X-linked lissencephaly with abnormal genitalia (XLAG) is a distinct form of lissencephaly associated with absent corpus callosum. Recently, forms of syndromic and nonspecific X-linked mental retardation have been found to be associated with mutations in the Aristaless-related homeobox gene ARX. The authors assessed ARX as a candidate gene for XLAG in a genetic analysis of neuronal migration disorders and found two different point mutations in two XLAG pedigrees affecting the homeodomain of the protein, confirming that ARX is a causative gene for XLAG.

Abnormalities, Multiple↗

PubMed2003

[An unusual complication of coronarography: neuralgia of the internal saphenous].

Many causes of saphenous nerve lesions at the knee or leg level have been reported. Proximal nerve lesions, especially after varicose vein stripping, are uncommon. We report a case of saphenous nerve lesion following catheterization of the femoral artery complicated with arterial spasm. The patient experienced pain for 10 years and only transdermal electroneural stimulation provided sedation. To our knowledge, this is the first published case of such an unusual complication after coronarography, despite the frequency of this procedure. We suggest nerve ischemia could explain the definitive neuralgia.

Adult↗

PubMed2002

[A case report of unusual retinal findings in a patient with Zieve syndrome].

BACKGROUND: The Zieve syndrome is characterized by hemolytic anemia in conjunction with secondary hyperlipidemia in patients suffering from alcohol-related toxic liver damage. So far no retinal changes have been reported due to the Zieve syndrome. CASE REPORT: A 44-year-old diabetic attended a routine control by an ophthalmologist. It was known that he had steatohepatitis due to an abuse of ethanol for years and 1 month previously he had suffered from nausea and vomiting. The visual acuity was found to be good on both sides (1.0/0.8). In the fundus white-colored retinal vessels and peripapillary cotton wool exsudates with isolated hemorrhages were found. An extremely lipemic serum and a severe anemia were present. The patient was referred to the internal department for further investigation and because of the anemia the patient received two blood transfusions. The elevated cholesterol and triglyceride levels in the serum could be substantially reduced by treatment with a cholesterin synthetase inhibitor and a fibrate. The follow-up examination 3 weeks later revealed a regular blood flow and a regression of cotton wool exsudates and 1 month later no pathological retinal findings were detected. CONCLUSIONS: The retinal changes were caused by the combination of severe anemia and hyperlipidemia and these findings played a leading role for deciding further diagnostic procedures. After treatment of the metabolic disorder the retinal changes were completely reversible without functional restrictions.

Adult↗