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BACKGROUND: Bilateral basal ganglia calcifications (BGCs), if severe, are known hallmarks for idiopathic BGC disease (IBGC), but if milder, are often considered radiological findings of unknown significance. In previous studies, only a minority of patients with BGC had monogenic forms of IBGC. METHODS: We studied consecutive patients from a tertiary neurology clinic with bilateral BGCs of variable severity, and their families. We analyzed known IBGC genes, and an extended panel of genes linked to monogenic stroke and metabolic conditions. Clinical, radiological, and genetic data were collected, including vascular risk factors, cerebrovascular events, imaging findings (total calcification score, white matter hyperintensities, ischemic/hemorrhagic lesions), and relevant family history. RESULTS: Twenty-four families with BGCs and neurological symptoms were analyzed. Disease-causing variants were identified in 14 families (58.3%). Eight patients had IBGC (variants in SLC20A2, PDGFB, MYORG), 4 had mitochondrial disease (MT-TL1), and 2 had monogenic vascular conditions (GAL, MAP3K6). Three variants were novel. BGC severity was highest in IBGC cases, while vascular and mitochondrial cases had milder calcifications. White matter hyperintensities were seen in 94.7% of cases and correlated highly with the total calcification score. Clinical vascular events had occurred in 41.7% cases. No monogenic cause was found in 10 patients, although many of these showed clinical or radiological features suggestive of monogenic disease. CONCLUSIONS: Bilateral BGCs can occur in many neurogenetic disorders apart from IBGCs, and a broader genetic search increases the diagnostic yield. Patients with BGCs frequently had clinical cerebrovascular events, which emphasizes the role of cerebrovascular pathology in BGCs.
N tau-methylhistidine (N tau MH) was used as an index for muscle protein degradation and this index was utilized to evaluate degradation rates in young growing cattle. Initially, two Charolais crossbred heifers, 12 months of age, were used to measure the recovery of radioactivity in the urine for a 120-hour period after intravenous injection of [14C]N tau MH. Of the radioactivity injected into the animals, 89.7% was recovered after 120 hours. With rate and amount of clearance as the criteria, the excretion of N tau MH in urine appears to be a valid index of muscle protein degradation in cattle. Eight steers of two genetic types were used to evaluate the effect of frame size on turnover rates of muscle proteins with N tau MH as an index. Large frame cattle (LG) excreted more N tau MH per day (P less than 0.03) throughout the trial. Total daily creatinine excretion was less for small frame (SM) cattle (P less than 0.02) showing an increase with time (P less than 0.01) in LG and SM cattle. N tau MH-to-creatinine ratios showed a decline with time. Fractional breakdown rates (FBR) and fractional synthesis rates (FSR) appeared to parallel each other with rates tending to decrease with age. No differences were observed between LG and SM cattle for FBR, FSR or fractional growth rate (FGR).
Conditional heterosis associated with two isoallelic forms of octanol dehydrogenase in Drosophila pseudoobscura has been detected in flies that have been (a) inbred for several generations to make the background genotype as homozygous as practicable, and (b) grown on a medium containing a small amount of octanol. The heterosis was first found in inbred males. The possibility that the effect in females was masked by X-linked polymorphic genes affecting the same fitness components as the locus for octanol dehydrogenase was shown to be correct when, on further inbreeding, heterosis was found in the females of one of the lines. The implications of this and other findings for the current understanding of the genetic structure of natural populations is discussed.
Male wap-ras transgenic mice develop adenocarcinomas in salivary and/or mammary tissue by age 1 year. When the wap-ras transgene was bred into the FVB/N strain, males developed multiple mammary tumors between 1.5 and 3 mo. of age, but no salivary tumors. Crosses between ras/FVB mice and other strains produced moderate changes in mammary tumor onset and severity, but no salivary tumors. Histopathological analysis of 62 adenocarcinomas from 18 mice yielded: 14 tumors with areas of squamous metaplasia, many tumors with epithelium-lined cysts, few immune cells in tumors, and no lung metastases. Cyclophosphamide delayed tumor onset and inhibited the growth of established tumors. Our results suggest that wap-ras mice will be useful for studying ras-mediated tumor genetics and should be a good assay system for both preventative and curative anticancer therapies.
The akuA gene encoding the Ku70 component of the nonhomologous end-joining machinery was deleted in the opportunistic pathogen Aspergillus fumigatus. No obvious phenotype could be assessed for the corresponding mutant strain but relative frequencies of homologous recombination were increased as deduced from targeting the laccase-encoding abr2 gene.
Macrophagic myofasciitis (MMF) is a specific histopathologic lesion involved in the persistence for years of aluminum hydroxide [Al(OH)(3)] at the site of previous intramuscular (i.m.) injection. In order to study mechanisms involved persistence of MMF lesions, we set up an experimental model of MMF-lesion in Sprague-Dawley and Lewis rat, by i.m. injections of 10 microL of an Al(OH)(3)-adjuvanted vaccine. An evaluation carried out over a 12-month period disclosed significant shrinkage of MMF lesions with time. A radioisotopic study did not show significant aluminium uptake by Al(OH)(3)-loaded macrophages. A morphometric approach showed that Lewis rats with Th1-biased immunity had significantly smaller lesions than Sprague-Dawley rats with balanced Th1/Th2 immunity. Concluding, our results indicate that genetic determinatives of cytotoxic T-cell responses could interfere with the clearance process and condition the persistence of vaccine-induced MMF-lesions.
The relevance of zinc for proper functioning of the entire immune system is already well documented. However, the identification of individuals who really need zinc supplementation is still debated in view of the fact that excessive zinc may also be toxic. The risk of developing zinc deficiency in people from industrialized countries is relatively low, except for elderly subjects where zinc intake may be suboptimal and inflammation is chronic. Thus, the role of zinc on the immune system and on the health of European elderly people is becoming of paramount importance, considering also that the elderly population is rapidly increasing. In particular, the factors contributing to and the biochemical markers of zinc deficiency in the elderly are still remain to be established. Epidemiological, functional, and genetic studies aimed at formulating a rationale for the promotion of healthy ageing through zinc supplementation was the subject of an International Conference held in Madrid from 11-13 February 2006 (3rd ZincAge Meeting) at the CNIO Institute (local organizer: Maria Blasco, partner of ZincAge).
The endogenously overexpressed c-sis (platelet-derived growth factor (PDGF) B-chain) proto-oncogene and its viral counterpart v-sis effectively transform NIH 3T3 cells by an autocrine mechanism, whereas the PDGF A-chain gene does not. However, PDGF B continuously cultured with confluent NIH 3T3 cells fails to induce phenotypic transformation as would be predicted by the autocrine model. We now have established conditions in which subconfluent, logarithmically growing NIH 3T3 cells are efficiently transformed by exogenous PDGF B but not PDGF A. Clonally selected cells from transformed foci remain transformed when continuously cultured with PDGF B but revert to the non-transformed phenotype without PDGF B or if PDGF A is substituted for PDGF B, suggesting that PDGF B complements a genetically stable NIH 3T3 cell phenotype to induce transformation and initiates a signal different from that of PDGF A required to induce transformation. Neither PDGF A nor PDGF B transform normal rat kidney (NRK) cells under identical conditions of culture. However, we now demonstrate that exogenous PDGF A and PDGF B independently transform NRK cells that endogenously overexpress the anti-apoptotic bcl-2 gene. These results suggest that both PDGF A and PDGF B effectively transform murine fibroblasts with a compatible genotype, that transformation by the PDGF isoforms requires complementation with a compatible genotype in a multistep transformational process, and that the autocrine mechanism is required but not sufficient for transformation of murine fibroblasts by PDGF.
A clinical material of 133 Standardbred horses with palmar/plantar osteochondral fragments (POF) in the metacarpo- and metatarsophalangeal joints were studied. All horses had their fragments removed with arthroscopic surgery. 102 of the horses were 3 years old or younger when surgery was performed. Anatomical localisations of the fragments were in agreement with earlier reports. There was no statistical significant difference in month of birth in the POF--group compared to the total population. Eighty % of the horses that had raced before surgery came back to racing. The racing performance relative to their contemporaries remained the same after the POF operation. 65% of the horses that had not raced before surgery raced after the operation. The breeding index BLUP (Best Linear Unbiased Prediction) was used to evaluate if the POF-horses differed genetically in racing ability from the total population. The average BLUP value of the POF group was 103.4 (+/- 0.65), while the mean BLUP value of the total population was 98.9. This difference was highly significant and indicated that these POF horses belonged to a selected group. A homogeneity test of allele frequencies in blood type systems was performed to evaluate if any genetic difference was persistent between POF horses compared to the total population. The statistical analysis of gene frequencies for alleles in blood type systems indicated a genetic discrimination in blood type systems D and Tf.
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The dbl oncogene, generated by the truncation of the amino-terminal portion of the proto-oncogene sequence, encodes a guanine-nucleotide-releasing factor. The transforming activity of this oncogene has never been demonstrated in vivo or in vitro except in the NIH 3T3 mouse fibroblast cell line. The expression of the proto-dbl transcript is confined to tissues and tumors of neuroectodermal derivation. Therefore, to study the transforming activity of the dbl oncogene in vivo, we have generated transgenic mice that express this oncogene in neuroepithelial tissues. Mice carrying the dbl oncogene did not develop a tumor. Successively, to establish whether dbl interacts with the tumor suppressor gene p53 in tumorigenesis, we have used a p53 deficient mouse strain. The results reported here indicate that dbl is capable of causing tumor formation in vivo when its expression is driven in an appropriate cellular and genetic environment.
Pregnant females C57BL/10JHir-p/p mice crossed with C57BL/10JHir males were whole-body irradiated with a single acute dose of 60Co-gamma-rays to investigate the effect of gamma-radiation on embryonic melanoblasts. The effect was studied by scoring changes in the cutaneous coats of F1 offspring 25 days after birth. White spots were found in mid-ventrum of the animals. Melanoblasts and melanocytes were not observed in the spotted skin. The frequency of the spots increased in a dose-dependent manner. White spots were found in mid-ventrum of (C57BL/6J female x C3H/HeJmsHir male) F1 exposed to gamma-rays. However, the frequency of the spots in (C57BL/6J female x C3H/HeJmsHir male) F1 were extremely lower than that in (C57BL/10JHir-p/p female x C57BL/10JHir male) F1, suggesting the possibility that the frequency of mid-ventral white spots are genetically controlled. Moreover, the highest frequency was found in (C57BL/10JHir-p/p female x C57BL/10JHir male) F1 irradiated at 8.5 days of gestation. This stage corresponds to the stage of initiation of neural-crest cell migration. These results indicate that gamma-radiation affects the differentiation of melanocytes in the skin both with genetical control and with greater effects seen at the stage of initiation of neural-crest cell migration.
Recent studies suggest running wheel activity to be naturally rewarding and reinforcing; considering the shared neuro-behavioural characteristics with drug-induced reward situations, wheel running behaviour gains interest as a tool to study mechanisms underlying reward-sensitivity. Previously, we showed that wheel running has the potential to disrupt the daily organization of home cage behaviour in female C57BL/6 [de Visser L, van den Bos R, Spruijt BM. Automated home cage observations as a tool to measure the effects of wheel running on cage floor locomotion. Behav Brain Res 2005;160:382-8]. In the present study, we investigated the effects of novelty-induced stress on wheel running and its impact on home cage behaviour in male C57BL/6 and DBA/2 mice. Our aim was to determine whether wheel running may be used as a tool to study both genetic and environmentally induced differences in sensitivity to rewarding behaviour in mice. One group of male mice was placed in an automated home cage observation system for 2 weeks with a wheel integrated in the cage. A second group of mice was allowed to habituate to this cage for 1 week before a running wheel was introduced. Results showed a pronounced sensitising effect of novelty on the level of wheel running in C57Bl/6 mice but not in DBA mice. Overall levels of wheel running were higher in DBA/2 mice. Furthermore, wheel running affected circadian rhythmicity in DBA/2 mice but not in C57BL/6 mice. From these findings we tentatively suggest that wheel running behaviour could serve as a tool to study the interaction between genetic and environmental factors in sensitivity to rewarding behaviour in mice. As it is displayed spontaneously and easy to monitor, wheel running may be well suitable to be included in high-throughput phenotyping assays.
Intravascular coagulation is considered a major pathogenetic mechanism for nontraumatic osteonecrosis. The aim of our study was to evaluate the association of thrombophilic factor V G1691A mutation (factor V Leiden) and G20210A prothrombin mutation with the disease. Mutation presence was investigated by polymerase chain reaction techniques in a study population of 72 adult Caucasian patients with osteonecrosis of the femoral head and 300 healthy Caucasian control subjects. The disease was considered idiopathic in 23 patients and secondary in 49. The factor V Leiden mutation was present in 18% of patients, compared with 4.6% of control subjects, resulting in a statistically significant odds ratio of 4.5. The prothrombin mutation was not significantly increased in the idiopathic osteonecrosis subgroup (8.7% versus 2.6%) with an odds ratio of 3.5. Overall, either of these coagulation disorders was present in 22.2% of patients and in 7.3% of control subjects resulting in a significant odds ratio of 3.6. Factor V Leiden, a genetic risk factor for venous thrombosis, is associated with nontraumatic osteonecrosis of the femoral head, supporting the hypothesis that intravascular coagulation is a major pathogenetic mechanism of the disease.
Although the blood-brain barrier and blood cerebrospinal fluid barrier maintain the central nervous system (CNS) as an immunologically privileged site, T lymphocytes can migrate through unstimulated brain endothelium and epithelium to perform immune surveillance or initiate inflammation. Our prior results suggested that early CNS migration of a CD4 Th1 cell line was facilitated by P selectin (CD62P) in (PL/JxSJL/J)F1 mice. Here, quantitative analysis of migration 2 h following adoptive transfer of fluorescently labeled cells revealed a 53-72% decrease in activated splenocyte, CD4 Th1 and CD8 migration, but not CD4 Th2, in CD62P-deficient C57BL6/J mice. Immunohistochemistry revealed constitutive expression of CD62P within the meninges and choroid plexus epithelia in C57BL6/J and SJL/J, but not BALB/cJ, mice. Activated splenocyte migration was approximately three- to four-fold greater in SJL/J as compared to BALB/cJ mice. Anti-CD62P treatment normalized this difference. Based on these results, we hypothesize that genetically determined kinetics of immune surveillance may regulate the phenotype of subsequent CNS inflammation.
The functional division of CD4(+) T cells into Th1 and Th2 subsets is generally accepted but the mechanisms leading to their preferential induction remain elusive. Cytokines are considered the main determining factors in the initial differentiation of precursor T cells into these distinct subsets. Thus, IL-12 drives Th1 cells whereas IL-4 drives Th2 cells. Recently IL-18, originally designated as IFN-gamma-inducing factor, has been reported to synergize with IL-12 in the induction of Th1 cells. We report here that IL-18 can also induce T cells to differentiate into Th2 cells, in the presence of TCR activation, either alone or together with IL-4. This effect of IL-18 is mediated primarily on CD4(+) T cells compared with CD8(+) T cells and is inhibited in the presence of IL-12. IL-18, however, has no effect on functionally committed Th2 cells.( )Moreover, the effect of IL-18 on Th2 cell development is differentially manifest in different mouse strains, suggesting profound underlying genetic influences. BALB/c mice infected with Leishmania major and treated with recombinant IL-18 developed exacerbated disease and enhanced Th2 response compared with untreated controls. These data therefore provide a novel mechanism for Th2 cell development. Thus, IL-18, a cytokine constitutively expressed by cells of the innate response, is capable of inducing Th2 cell differentiation in the absence of IL-4.
Mutations that lead to the emergence of resistance to apoptosis are commonly observed among tumor cells. Some of the proteins affected are integral parts of the apoptotic cascade such as pro- and antiapoptotic members of the Bcl-2 family. F16 is a small molecule that accumulates in mitochondria of a variety of tumor cells and interferes with their physiological function. Because this interference ultimately triggers apoptosis in many affected cell lines, we examined the effect of antiapoptotic Bcl-2 overexpression on the response of cells to F16. Our results showed that high levels of Bcl-2 did not block the ability of F16 to induce cell death. However, unlike the apoptotic response that followed F16 treatment of cells with moderate Bcl-2 levels, cells resistant to a variety of apoptotic stimuli by virtue of Bcl-2 overexpression succumbed to F16 by necrosis. Thus, this dual ability of the mitochondriotoxic compound F16 to induce apoptosis and necrosis may represent an added advantage by expanding its spectrum of action toward genetically altered tumor cells incapable of apoptosis.