Organ transport temperature box: multicenter study on transport temperature of organs.
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Germany↗
Biomedical subjects
A Abel
Publications and source records attributed to A Abel.
Expression of expanded repeat androgen receptor produces neurologic disease in transgenic mice.
Spinal and bulbar muscular atrophy (SBMA) is a motor neuron disease caused by the expansion of a polyglutamine tract within the androgen receptor. This disease is unusual among the polyglutamine diseases in that it involves lower motor and sensory neurons, with relative sparing of other brain structures. We describe the development of transgenic mice, created with a truncated, highly expanded androgen receptor driven by the neurofilament light chain promoter, which develop many of the motor symptoms of SBMA. In addition, transgenic mice created with the prion protein promoter develop widespread neurologic disease, reminiscent of juvenile forms of other polyglutamine diseases. Thus, in these experiments, the distribution of neurologic symptoms depends on the expression level and pattern of the promoter used, rather than on specific characteristics of androgen receptor metabolism or function. The transgenic mice described here develop neuronal intranuclear inclusions (NIIs), a hallmark of SBMA and the other polyglutamine diseases. We have shown these inclusions to be ubiquitinated and to sequester molecular chaperones, components of the 26S proteasome and the transcriptional activator CREB-binding protein. Apart from the presence of NIIs, evidence of neuropathology or neurogenic muscle atrophy was absent, suggesting that the neurologic phenotypes observed in these mice were the result of neuronal dysfunction rather than neuronal degeneration. These mice will provide a useful resource for characterizing specific aspects of motor neuron dysfunction, and for testing therapeutic strategies for this and other polyglutamine diseases.
Animals↗
Sensitivity and predictive value of criteria for p53 germline mutation screening.
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Adolescent↗
[Li-Fraumeni syndrome: update, new data and guidelines for clinical management].
The Li-Fraumeni syndrome (LFS) is an inherited form of cancer, affecting children and young adults, and characterized by a wide spectrum of tumors, including soft-tissue and bone sarcomas, brain tumours, adenocortical tumours and premenopausal breast cancers. In most of the families, LFS results from germline mutations of the tumor suppressor TP53 gene encoding a transcriptional factor able to regulate cell cycle and apoptosis when DNA damage occurs. Recently, germline mutations of hCHK2 encoding a kinase, regulating cell cycle via Cdc25C and TP53, were identified in affected families. The LFS working group recommendations are the following: (i) positive testing (screening for a germline TP53 mutation in a patient with a tumor) can be offered both to children and adults in the context of genetic counseling associated to psychological support, to confirm the diagnosis of LFS on a molecular basis. This will allow to offer to the patient a regular clinical review in order to avoid a delay to the diagnosis of another tumor; (ii) the 3 indications for positive testing are: a proband with a tumor belonging to the narrow LFS spectrum and developed before age 36 and, at least, first- or second-degree relative with a LFS spectrum tumor, before age 46, or a patient with multiple primary tumors, 2 of which belonging to the narrow LFS spectrum, the first being developed before 36 or a child with an adenocortical tumour; (iii) presymptomatic testing must be restricted to adults; (iv) the young age of onset of the LFS tumors the prognosis of some tumors, the impossibility to ensure an efficient early detection and the risk for mutation carriers to develop multiple primary tumors justify that prenatal diagnosis might be considered in affected families.
Adult↗
Cell cycle-dependent coupling of the vasopressin V1a receptor to different G proteins.
Arginine vasopressin (AVP) regulates biological processes by binding to G protein-coupled receptors. In Swiss 3T3 fibroblasts, expressing the V(1a) subtype of vasopressin receptors, AVP mobilizes calcium from intracellular stores. In proliferating cells, the AVP-induced increase in intracellular calcium concentration ([Ca(2+)](i)) was mediated by G proteins of the G(q) family, which are insensitive to pertussis toxin (PTX) pretreatment of the cells. In quiescent cells, the AVP-induced increase in [Ca(2+)](i) was partially PTX-sensitive, suggesting an involvement of G(i) proteins. We confirmed this by photoaffinity labeling of G proteins in Swiss 3T3 cell membranes activated by AVP. In Swiss 3T3 cells arrested in the G(0)/G(1) phase of the cell cycle, the AVP-induced increase in [Ca(2+)](i) was also partially PTX-sensitive but was PTX-insensitive in cells arrested in other phases of the cell cycles. The blocking effect of PTX pretreatment in G(0)/G(1) cells was mimicked by microinjection of antisense oligonucleotides suppressing the expression of the Galpha(i3) subunits. These results were confirmed by microinjection of antibodies directed against the C terminus of G protein alpha-subunits. The data presented indicate that in Swiss 3T3 fibroblasts synchronized in the G(0)/G(1) phase of the cell cycle the V(1a) receptor couples to G(q/11) and G(i3) to activate the phospholipase C-beta, leading to release of intracellular calcium.
3T3 Cells↗
A gene for autosomal dominant juvenile amyotrophic lateral sclerosis (ALS4) localizes to a 500-kb interval on chromosome 9q34.
Amyotrophic lateral sclerosis (ALS) denotes a heterogeneous group of neurodegenerative disorders affecting upper and lower motor neurons. ALS4 is a juvenile-onset, autosomal dominant form of ALS that is characterized by slow progression, distal limb weakness and amyotrophy, and pyramidal signs associated with severe loss of motor neurons in the brain and spinal cord. The ALS4 locus was recently mapped by linkage analysis to a large genetic interval on chromosome 9q34. By undertaking extensive genetic linkage analysis, we have significantly refined the ALS4 locus to a critical interval of less than 3 cM, flanked by D9S149 and D9S1198. Previous physical mapping in this region has indicated that this critical interval spans approximately 500 kb. Seventeen putative transcripts have been localized within this interval including 7 characterized genes, 2 partially characterized genes, and 8 "anonymous" expressed sequence tags . These are therefore positional candidate genes for the ALS4 locus. We have also undertaken mutation analysis and genetic mapping to investigate and exclude candidate genes, including RING3L/ORFX and RALGDS, from a pathogenic role in ALS4.
Age of Onset↗
P53 germline mutations in childhood cancers and cancer risk for carrier individuals.
The family history of cancer in children treated for a solid malignant tumour in the Paediatric Oncology Department at Institute Gustave-Roussy, has been investigated. In order to determine the role of germline p53 mutations in genetic predisposition to childhood cancer, germline p53 mutations were sought in individuals with at least one relative (first- or second-degree relative or first cousin) affected by any cancer before 46 years of age, or affected by multiple cancers. Screening for germline p53 mutation was possible in 268 index cases among individuals fulfilling selection criteria. Seventeen (6.3%) mutations were identified, of which 13 were inherited and four were de novo. Using maximum likelihood methods that incorporate retrospective family data and correct for ascertainment bias, the lifetime risk of cancer for mutation carriers was estimated to be 73% for males and nearly 100% for females with a high risk of breast cancer accounting for the difference. The risk of cancer associated with such mutations is very high and no evidence of low penetrance mutation was found. These mutations are frequently inherited but de novo mutations are not rare.
Adult↗
X-linked Charcot-Marie-Tooth disease and connexin32.
X-linked Charcot-Marie-Tooth disease is caused by mutations in the gene for the gap junction protein connexin32. This protein is expressed in peripheral nerve and present in noncompacted myelin, where it likely forms channels around and across the myelin sheath. Studies in cell culture and in transgenic mice show that connexin32 mutations can cause a loss of channel function or a gain of toxic effects on myelinating Schwann cells or both, with resulting peripheral nerve degeneration.
Animals↗
Androgen receptor mutation in Kennedy's disease.
Kennedy's disease is an X-linked form of motor neuron disease caused by an expanded polyglutamine repeat in the androgen receptor. While the expansion mutation causes some loss of transcriptional activity by the androgen receptor, the predominant effect of expansion is probably a toxic gain of function, similar to the mechanism of other polyglutamine expansion diseases. Features of the neurodegenerative phenotype of Kennedy's disease have now been reproduced in transgenic animals and neuronal cell culture. Nuclear inclusions of mutant androgen receptor protein are found in these model systems and in autopsy samples from patients with Kennedy's disease.
Animals↗
The role of the gap junction protein connexin32 in the pathogenesis of X-linked Charcot-Marie-Tooth disease.
Mutations in the gene encoding the gap junction protein connexin32 (Cx32; beta 1) cause the X-linked form of Charcot-Marie-Tooth disease (CMTX), a common form of inherited demyelinating neuropathy. Cx32 is localized to the paranodes and incisures of myelinating Schwann cells, and probably participates in the formation of gap junctions at these locations, thereby allowing the diffusion of ions and small molecules directly across the myelin sheath. In transfected cells different CMTX mutations have different effects on the ability of the mutant protein to form functional gap junctions; some mutant proteins cannot be detected within the cell, other mutant proteins accumulate within the cell but do not reach the cell membrane, while other mutants reach the cell membrane and some of these form functional gap junctions. In transgenic mice two mutants, R142W and 175 frameshift, have similar effects on protein trafficking as in transfected cells: the R142W mutant protein remains in the perinuclear region and does not reach the paranodes or incisures, and the 175 frameshift protein cannot be detected. Thus, different CMTX mutations have different effects on Cx32 protein, and these differences may help to explain the phenotypic differences seen in CMTX kindreds.
Amino Acid Sequence↗
Promiscuity and fidelity in receptor-G-protein coupling: cell cycle-dependent coupling of the vasopressin V1 receptor.
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Animals↗
Studies in transgenic mice indicate a loss of connexin32 function in X-linked Charcot-Marie-Tooth disease.
X-linked Charcot-Marie-Tooth disease (CMTX) is an inherited demyelinating neuropathy caused by mutations in the gene encoding the gap junction protein connexin32 (Cx32). Despite the identification of over 160 different mutations in the Cx32 coding sequence, it is not known whether the mutations cause the disease manifestations through a loss of Cx32 function or through toxic effects on peripheral nerve. We created transgenic mice with a frameshift mutation at codon 175 (175fs), identified in a large CMTX pedigree. Light microscopic examination of the peripheral nerves from adult transgenic animals showed no pathological features. Western blotting did not show transgenic Cx32 protein in any of the 26 lines, although expression of transgenic messenger RNA was detected by reverse-transcriptase polymerase chain reaction and by ribonuclease protection assay. Our findings indicate that the 175fs mutation results in a loss of Cx32 function, without additional toxic effects.
Animals↗
[Noninvasive intermittent self-ventilation as a palliative measure in amyotrophic lateral sclerosis].
Almost all patients with amyotrophic lateral sclerosis (ALS) experience symptoms of nocturnal hypoventilation during the course of the illness. These symptoms can develop years before death and may severely affect quality of life. Non-invasive intermittent home mechanical ventilation (HMV) via mask is a possible palliative measure for these symptoms, which is not often used in Germany. We report on our experience with HMV in 24 patients with ALS. Our data show a good palliative effect in 17 of 24 treated patients. Severe complications did not occur. The mean ventilation time at present is 14 months. Available options and their consequences need to be discussed in detail with patients and relatives before HMV is initiated.
Adult↗
Pulmonary tuberculosis presenting as mass lesions and simulating neoplasms in adults.
In a review of the chest X-rays and medical records of 597 cases of culture- or biopsy-proven pulmonary tuberculosis (PTB; age range 1.5-72 years), seen over a period of 6 years (1991-97), 26 patients had radiographic patterns unusual for PTB. These patterns were mass-like densities simulating neoplasms, chronic lower lobe airspace opacities without adenopathy, mediastinal adenopathy without parenchymal airspace opacities and bronchopleural fistula without other radiographic abnormalities. The most common of these unusual radiographic patterns was mass-like densities, most of which were initially and mistakenly diagnosed as neoplasms. These masses, seen in 11 adult patients, form the basis of this report. Two children aged 1.5 and 2 years also had tuberculous mass densities initially diagnosed as neurogenic tumour and round pneumonia, respectively. They have been excluded from the present series, and form the subject of another report. The masses were lower lobe predominant and were not usually associated with fibro-productive satellite lesions or with calcification or cavitation. In view of the recent resurgence of PTB and the importance of chest X-rays in its diagnosis and management, this rare radiographic pattern needs to be emphasized.
Adult↗
Dopaminergic deficit in amyotrophic lateral sclerosis assessed with [I-123] IPT single photon emission computed tomography.
Dopamine transporter imaging was performed in 18 patients with sporadic amyotrophic lateral sclerosis (ALS) and 11 age matched controls with [I-123] IPT (N-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta(4-chlorophen yl)-tropane), a new cocaine analogue that selectively binds to the dopamine transporter located on dopaminergic nerve terminals. Image analysis showed that striatal IPT binding was moderately but significantly reduced in the ALS group compared with controls (p<0.01). The reduction of IPT binding was similar for patients with bulbar onset compared with those with limb onset. There was no correlation between values for uptake of striatal IPT and the age of the patients or the duration of the disease. These data indicate that nigrostriatal dopaminergic neurons are subclinically affected in a subset of patients with sporadic ALS.
Adult↗
Schistosomiasis Acquired in Lake Malawi.
Background: Schistosomiasis is second only to Malaria in its prevalence in the tropics. The mode of transmission of this disease is unknown to many travelers, whereas other travelers consciously choose to ignore recommendations offered by travel clinics. Methods: We present a descriptive analysis of 22 patients who presented with S. haematobium (SH) infection to two travel clinics in Israel during 1993 and 1994. Results: All 22 patients (mean age 24.2 yrs) apparently acquired SH in lake Malawi. The group contained seven couples, which indicates a very high attack rate. Three of the cases were asymptomatic, thereby causing a diagnostic delay of up to 52 weeks. Diagnosis was established in 18 cases by finding eggs in the urine, and in eight cases, by serology. Conclusion: All cases of SH diagnosed at two medical centers in Israel in 1993 and 1994 were acquired in Lake Malawi. A few of the cases were totally asymptomatic, which raises the question of routine screening. Travel clinics should warn travelers to the Lake Malawi region of this specific hazard.
Journal Article↗
[X chromosomal bulbospinal neuropathy (X-BSN, Kennedy syndrome): an illness with repetitive triplet sequences. Case report, differential diagnosis and molecular genetics aspects].
X-chromosomal recessive bulbospinal neuronopathy (X-BNS, Kennedy's disease) is an important differential diagnosis of amyotrophic lateral sclerosis. We present the data of ten own patients along with a review of the literature on this uncommon disease which is caused by an expanded CAG-repeat in the androgen receptor gene. This mutation probably affects the transcription regulating activity of the androgen receptor in neurons. Signs and symptoms of X-BSN can be derived from partial insensitivity for androgens and a mixed, mainly motor neuronopathy. The clinical diagnosis is based on: 1. lower motor neuron weakness of bulbar and proximal limb muscles with onset in the third to fifth decade, 2. cramps and pronounced fasciculations, particularly of facial muscles, 3. postural tremor, 4. diminished or absent sensory action potentials inspite of only minor sensory impairment, 5. gynecomastia, and 6. infertility, diabetes mellitus and hyperlipoproteinemia in a minority of cases. Unlike amyotrophic lateral sclerosis, disease progression is slow with barely shortened life expectancy, which should be stressed in patient counselling. Causal treatment is as yet unavailable but several aspects of palliative medicine should be considered.
Amyotrophic Lateral Sclerosis↗
Cancers in relatives of children with non-Hodgkin's lymphoma.
We undertook a family study of children treated at the Institute Gustave-Roussy in France to investigate a familial aggregation of cancer in the families of children with non-Hodgkin's lymphoma (NHL). We obtained family dat for 284 children with NHL. Using the Standardized Incidence Ratio, we compared the observed and expected number of families with at least one proband relative affected by cancer at a young age (before 46 years). We found a small but non-significant excess of all tumors in first-degree relatives (SIR = 1.3, 95% CI = 0.7-2.3) explained by a small but non-significant excess of hematological malignancies (SIR = 1.5, 95% CI = 0.2-5.5), particularly Hodgkin's disease and leukemia, and of osteosarcoma (SIR = 7.5, 95% CI = 0.1-41.4). This is probably a lower bound of the SIR, because the expected number of families was estimated from cancer incidence in France between 1978 and 1982, whereas most cancers occurred before this period. Other tumors were not in excess in first-degree relatives.
Adolescent↗