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Biomedical subjects

G Utermann

Publications and source records attributed to G Utermann.

At least 37 records · Page 2Linked to original sources
PubMed2001

Combined study of prostatic carcinoma by classical cytogenetic analysis and comparative genomic hybridization.

Conventional cytogenetic analysis of prostatic carcinoma (PC) is characterized by inefficient growth of tumor cells during in vitro culture, leading to a lack of aberrant karyotypes in many of investigated tumors. In this study we have combined a modified short-term tissue culture method for conventional banding analysis and comparative genomic hybridization (CGH) to examine genetic changes in PC, and to evaluate the effect of the in vitro culture on chromosomal changes by comparing results of the two methods. Cytogenetic analysis was performed on 34 PCs using both, conventional and molecular methods. Tumor tissues were obtained predominantly from untreated primary tumors from 48 patients. For karyotyping all tumor samples were short-term cultured using a feeder layer technique. Additionally DNA from uncultured tumor material from 17 of those patients was isolated and screened for copy number changes using CGH. Conventional banding analysis: clonal aberrations were detected in 65% of the tumor samples. Most of the chromosomal findings were numerical changes, including loss of chromosomes Y (32%), 18, 19 and 21 (each 12%). Less frequent, trisomy of chromosome 7 and monosomy of chromosomes 9, 12 and 22 (each 9%) was found. Additionally an inversion of chromosome 9p and a deletion at chromosome 7q was found in two cases. In 35% no clonal aberrations could be detected. CGH: DNA copy number changes were detected in 65% of the analyzed tumors. Predominantly losses of DNA sequences were found. The most common losses were found at chromosome regions 13q21q33 (29%), 6q11q23 (24%), 16q, and 18 (each 18%), and the most common gains at 19 (18%). In six tumors no copy number changes were found. Both methods showed a similar aneuploidy rate, suggesting that the feeder layer technique is quite a suitable method for in vitro culture of PC cells. However, the two techniques produced substantially differing results for most of the tumor samples, and in some cases the discrepancies are quite striking. Therefore eventual culture effects need to be taken into account when comparing results from conventional cytogenetics and CGH. Some contrary findings from the two methods are discussed.

Aged↗
PubMed2000

Mapping of a minimal apolipoprotein(a) interaction motif conserved in fibrin(ogen) beta - and gamma -chains.

Lipoprotein(a) (Lp(a)) is a major independent risk factor for atherothrombotic disease in humans. The physiological function(s) of Lp(a) as well as the precise mechanism(s) by which high plasma levels of Lp(a) increase risk are unknown. Binding of apolipoprotein(a) (apo(a)) to fibrin(ogen) and other components of the blood clotting cascade has been demonstrated in vitro, but the domains in fibrin(ogen) critical for interaction are undefined. We used apo(a) kringle IV subtypes to screen a human liver cDNA library by the yeast GAL4 two-hybrid interaction trap system. Among positive clones that emerged from the screen, clones were identified as fibrinogen beta- and gamma-chains. Peptide-based pull-down experiments confirmed that the emerging peptide motif, conserved in the carboxyl-terminal globular domains of the fibrinogen beta and gamma modules specifically interacts with apo(a)/Lp(a) in human plasma as well as in cell culture supernatants of HepG2 and Chinese hamster ovary cells, ectopically expressing apo(a)/Lp(a). The influence of lysine in the fibrinogen peptides and of lysine binding sites in apo(a) for the interaction was evaluated by binding experiments with apo(a) mutants and a mutated fibrin(ogen) peptid. This confirmed the lysine binding sites in kringle IV type 10 of apo(a) as the major fibrin(ogen) binding site but also demonstrated lysine-independent interactions.

Amino Acid Sequence↗
PubMed2000

Homozygosity for the W151X stop mutation in the delta7-sterol reductase gene (DHCR7) causing a lethal form of Smith-Lemli-Opitz syndrome: retrospective molecular diagnosis.

Smith-Lemli-Opitz syndrome (SLOS) is a multiple congenital anomalies syndrome caused by an abnormality in cholesterol metabolism. The clinical severity may vary from very mild to lethality in utero, making diagnosis difficult at both ends of the spectrum. Patients with severe SLOS might often escape diagnosis because they die before the correct diagnosis is made. We describe an Austrian family whose first child died neonatally with multiple congenital anomalies. The second pregnancy was terminated because the fetus showed similar severe anomalies ultrasonographically. A further pregnancy ended in a spontaneous first trimester abortion. Clinical diagnosis of SLOS was not considered until the autopsy of the fetus of the terminated pregnancy. Because no material for biochemical testing was available we performed mutational analysis of the DHCR7 gene from paraffin-embedded tissue and a Guthrie card focusing on mutations known to cause a severe SLOS phenotype. This demonstrated homozygosity for the mutation W151X, which has been demonstrated to be a functional null mutation. Our data confirm the concept that homozygosity for functional null alleles of the DHCR7 locus results in intrauterine or perinatal lethality. Furthermore, our findings suggest the usefulness of molecular studies of stored material in similarly affected cases where no material for biochemical analysis is available.

Abnormalities, Multiple↗
PubMed2000

Mental and psychomotoric retardation in two brothers with pure partial trisomy 7q32-q34 due to a maternal insertion (14;7).

We present two brothers with mental retardation, seizures disorder, generalized muscular hypertonia, kyphoscoliosis, minor anomalies and a prominent midface. GTG-banded chromosome analysis showed a derivative chromosome 14 without clues toward the origin of the rearrangement. Microdissection of the derivative chromosome 14 and subsequent reverse painting demonstrated partial trisomy 7q32-q34 as the unbalanced product of a maternal insertion (14;7). Thus, we identified two cases with pure trisomy 7q32-q34 that allowed further delineation of this aneusomy syndrome.

Adult↗
PubMed2000

T cell expressed PKCtheta demonstrates cell-type selective function.

T lymphocyte stimulation leading to interleukin-2 (IL-2) expression requires activation of protein kinase C (PKC); however, the relevant PKC isoform(s) have not yet been systematically defined. Here we examine seven major T cell expressed PKC isoforms (PKCalpha, delta, epsilon, zeta, nu, theta and iota) and identify PKCtheta to be essential for IL-2 expression (via the critical NF-AT and NF-kappaB enhancer) in Jurkat T cells. Employing a conditionally activated PKCtheta estrogen-receptor fusion mutant, a de novo synthesis-independent transactivation of JNK2 was established. Based on mRNA in situ hybridization to mouse whole body sections, PKCtheta was found to be highly expressed in lymphoid organs but also skeletal muscle and the nervous system. PKCtheta function appears to be cell-type specific, since its isoenzyme-selective function was not observed in ectopic expression studies, employing COS-1 or NIH3T3 cells. These results confirm PKCtheta to be the prime target for the activating effect of phorbol ester in T cell signaling and suggest that gene expression as well as gene function of PKCtheta is strictly controlled by the cell type.

3T3 Cells↗
PubMed2000

Mutation analysis in glycogen storage disease type 1 non-a.

We report molecular and clinical findings in 13 patients with rare types of glycogen storage disease 1 (GSD1 non-a). Analysis of G6PT encoding a microsomal transporter protein has revealed mutations on both chromosomes in each case, four of which are novel. Diagnosis has been confirmed in three patients suspected of having GSD1 non-a without enzymatic studies involving liver biopsy, thus emphasising the advantage of G6PT mutation analysis for all GSD1 non-a patients.

Adolescent↗
PubMed2000

Mutational spectrum in the Delta7-sterol reductase gene and genotype-phenotype correlation in 84 patients with Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS), an autosomal recessive malformation syndrome, ranges in clinical severity from mild dysmorphism and moderate mental retardation to severe congenital malformation and intrauterine lethality. Mutations in the gene for Delta7-sterol reductase (DHCR7), which catalyzes the final step in cholesterol biosynthesis in the endoplasmic reticulum (ER), cause SLOS. We have determined, in 84 patients with clinically and biochemically characterized SLOS (detection rate 96%), the mutational spectrum in the DHCR7 gene. Forty different SLOS mutations, some frequent, were identified. On the basis of mutation type and expression studies in the HEK293-derived cell line tsA-201, we grouped mutations into four classes: nonsense and splice-site mutations resulting in putative null alleles, missense mutations in the transmembrane domains (TM), mutations in the 4th cytoplasmic loop (4L), and mutations in the C-terminal ER domain (CT). All but one of the tested missense mutations reduced protein stability. Concentrations of the cholesterol precursor 7-dehydrocholesterol and clinical severity scores correlated with mutation classes. The mildest clinical phenotypes were associated with TM and CT mutations, and the most severe types were associated with 0 and 4L mutations. Most homozygotes for null alleles had severe SLOS; one patient had a moderate phenotype. Homozygosity for 0 mutations in DHCR7 appears compatible with life, suggesting that cholesterol may be synthesized in the absence of this enzyme or that exogenous sources of cholesterol can be used.

Adolescent↗
PubMed2000

Lipoprotein(a) in homozygous familial hypercholesterolemia.

Lipoprotein(a) [Lp(a)] is a quantitative genetic trait that in the general population is largely controlled by 1 major locus-the locus for the apolipoprotein(a) [apo(a)] gene. Sibpair studies in families including familial defective apolipoprotein B or familial hypercholesterolemia (FH) heterozygotes have demonstrated that, in addition, mutations in apolipoprotein B and in the LDL receptor (LDL-R) gene may affect Lp(a) plasma concentrations, but this issue is controversial. Here, we have further investigated the influence of mutations in the LDL-R gene on Lp(a) levels by inclusion of FH homozygotes. Sixty-nine members of 22 families with FH were analyzed for mutations in the LDL-R as well as for apo(a) genotypes, apo(a) isoforms, and Lp(a) plasma levels. Twenty-six individuals were found to be homozygous for FH, and 43 were heterozygous for FH. As in our previous analysis, FH heterozygotes had significantly higher Lp(a) than did non-FH individuals from the same population. FH homozygotes with 2 nonfunctional LDL-R alleles had almost 2-fold higher Lp(a) levels than did FH heterozygotes. This increase was not explained by differences in apo(a) allele frequencies. Phenotyping of apo(a) and quantitative analysis of isoforms in family members allowed the assignment of Lp(a) levels to both isoforms in apo(a) heterozygous individuals. Thus, Lp(a) levels associated with apo(a) alleles that were identical by descent could be compared. In the resulting 40 allele pairs, significantly higher Lp(a) levels were detected in association with apo(a) alleles from individuals with 2 defective LDL-R alleles compared with those with only 1 defective allele. This difference of Lp(a) levels between allele pairs was present across the whole size range of apo(a) alleles. Hence, mutations in the LDL-R demonstrate a clear gene-dosage effect on Lp(a) plasma concentrations.

Adult↗
PubMed2000

Hypermetaphase and interphase fluorescence in situ hybridisation for monitoring of remission status in Philadelphia chromosome positive chronic myeloid leukaemia.

Interferon (IFN) alone or in combination with cytostatic drugs, can induce major and durable cytogenetic remissions in chronic myelogenous leukaemia (CML) patients. Hypermetaphase (HMF) and interphase (IPF) fluorescence in situ hybridisation (FISH) have been described to be suitable for remission assessment. In the present study we applied HMF and IPF simultaneously to bone marrow (BM) probes from Ph-positive CML patients. As conventional cytogenetics (CC) is still deemed to be the for remission analysis we studied a group of patients analysed with this method as control. A mean of 50 metaphases was available for HMF analysis, whereas only an average of 18.7 metaphases could be analysed by CC. Remission assessment was frequently impossible by CC or HMF due to lack of metaphases, but always possible by applying IPF. Our results show that HMF should replace CC for routinely monitoring the remission status in Ph-positive CML patients and that in case of lack or insufficient number of metaphases in the majority of cases IPF is suitable for remission assessment.

Adolescent↗
PubMed2000

Lipoprotein(a) determination and risk of cardiovascular disease in South African patients with familial hypercholesterolaemia.

OBJECTIVE: A raised plasma level of lipoprotein(a) (Lp(a)) is an established genetic risk factor for coronary heart disease (CHD), particularly in patients with concomitant elevation of low-density lipoprotein (LDL) cholesterol. The current study focused on the comparison of two commercially available Lp(a) assay kits to determine whether differences observed in measured Lp(a) levels could be deemed negligible in CHD risk assessment in familial hypercholesterolaemic (FH) patients. DESIGN: To compare results obtained on duplicate plasma samples using two commercially available Lp(a) measuring kits, the immunoradiometric assay (RIA) and the enzyme-linked immunoabsorbent assay (ELISA). SETTING: Division of Human Genetics, Department of Obstetrics and Gynaecology, University of Stellenbosch, Tygerberg, South Africa and the Institute for Medical Biology and Human Genetics, University of Innsbruck, Austria. SUBJECTS: Plasma samples were obtained from 146 family members of 65 molecularly characterised South African FH families for comparative analysis. RESULTS: Using the RIA method, 34 samples (23%) considered to be in the normal range by the ELISA technique, were placed in the high-risk group (> 30 mg/dl). Only one sample, considered to have a normal Lp(a) level with the RIA method, was categorised by the ELISA technique as high risk. CONCLUSION: Our data demonstrate that measurements of Lp(a) using the RIA method (the only assay available in South Africa at the time of this study) differ significantly from those obtained by the reference ELISA technique, suggesting that misclassification could lead to inaccurate CHD risk assessment. This is an important consideration in Afrikaner FH families, where plasma levels of Lp(a) have been shown to be elevated significantly in FH patients compared with non-FH individuals.

Adult↗
PubMed1999

Role of lipoprotein(a) and apolipoprotein(a) phenotype in atherogenesis: prospective results from the Bruneck study.

BACKGROUND: Experimental studies have suggested both atherogenic and thrombogenic properties of lipoprotein(a) [Lp(a)], depending on Lp(a) plasma concentrations and varying antifibrinolytic capacity of apolipoprotein(a) [apo(a)] isoforms. Epidemiological studies may contribute to assessment of the relevance of these findings in the general population. METHODS AND RESULTS: This study prospectively investigated the association between Lp(a) plasma concentrations, apo(a) phenotypes, and the 5-year progression of carotid atherosclerosis assessed by high-resolution duplex ultrasound in a random sample population of 826 individuals. We differentiated early atherogenesis (incident nonstenotic atherosclerosis) from advanced (stenotic) stages in atherosclerosis that originate mainly from atherothrombotic mechanisms. Lp(a) plasma concentrations predicted the risk of early atherogenesis in a dose-dependent fashion, with this association being confined to subjects with LDL cholesterol levels above the population median (3.3 mmol/L). Apo(a) phenotypes were distributed similarly in subjects with and without early carotid atherosclerosis. In contrast, apo(a) phenotypes of low molecular weight emerged as one of the strongest risk predictors of advanced stenotic atherosclerosis, especially when associated with high Lp(a) plasma concentrations (odds ratio, 6.4; 95% CI, 2.8 to 14. 9). CONCLUSIONS: Lp(a) is one of the few risk factors capable of promoting both early and advanced stages of atherogenesis. Lp(a) plasma concentrations predicted the risk of early atherogenesis synergistically with high LDL cholesterol. Low-molecular-weight apo(a) phenotypes with a putatively high antifibrinolytic capacity in turn emerged as one of the leading risk conditions of advanced stenotic stages of atherosclerosis.

Adult↗
PubMed1999

Protein kinase Ctheta, a selective upstream regulator of JNK/SAPK and IL-2 promoter activation in Jurkat T cells.

The predominant expression of protein kinase C (PKC) theta in T cells (J. Biol. Chem. 1993. 268: 4997-5004), its isoenzyme-specific ability to stimulate AP-1 transcriptional activity (Mol. Cell. Biol. 1996. 16: 1842-1850) and the recent discovery of its selective and antigen-dependent colocalization with the contact region between T cells and antigen-presenting cells (Nature 1997. 385: 83-89) suggest that, among the PKC family members, PKCtheta plays a specialized role in T cell activation. By investigating the downstream effectors of PKCtheta we now demonstrate a direct and isoenzyme-specific contribution of PKCtheta to c-Jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK) but not extracellular regulated kinase (ERK) activation. Expression of a constitutively active (CA) form of PKCtheta (but not CA-PKCalpha, epsilon and lambda/iota) resulted in strong activation of JNK/SAPK and expression of a dominant-negative form of PKCtheta interfered with the endogenous activation signal for JNK/SAPK. Importantly, Ca2+ ionophore and CA-PKCtheta (but not CA-PKCalpha, epsilon and lambda/iota) caused synergistic activation of the IL-2 promoter. Together, these data establish that PKCtheta is required for activation of JNK/SAPK signaling leading to IL-2 promoter transcription in T lymphocytes.

Anisomycin↗
PubMed1999

Is apolipoprotein(a) a susceptibility gene for type I diabetes mellitus and related to long-term survival?

AIMS/HYPOTHESIS: High lipoprotein(a) [Lp(a)] plasma concentrations are a genetically determined risk factor for atherosclerotic complications. In healthy subjects Lp(a) concentrations are mostly controlled by the apolipoprotein(a) [apo(a)] gene locus which determines a size polymorphism with more than 30 alleles. Subjects with low molecular weight apo(a) phenotypes on average have higher Lp(a) concentrations than those with high molecular weight apo(a) phenotypes. There are many opinions about whether and why Lp(a) is raised in patients with Type I diabetes (insulin-dependent) mellitus. METHODS: We investigated Lp(a) plasma concentrations and apo(a) phenotypes in 327 patients with Type I diabetes mellitus (disease duration 1-61 years) and in 200 control subjects matched for age and sex. RESULTS: Patients with a disease duration of up to 15 years had significantly higher Lp(a) concentrations (24.3 +/- 34.0 mg/dl vs 16.7 +/- 22.6 mg/dl, p = 0.014) compared with control subjects. This increase can be explained by a considerably higher frequency of low molecular weight apo(a) phenotypes (38.9% vs 23.5%, p < 0.005). The frequency of low molecular weight apo(a) phenotypes decreased continuously with disease duration from 41.7% in those with disease duration of up to 5 years to 18.2% in those with the disease lasting more than 35 years. CONCLUSIONS/INTERPRETATION: Our data show that an increase of Lp(a) in Type I diabetic patients can only be observed in groups with short diabetes duration and that this elevation is genetically determined. Therefore, the apo(a) gene, located at 6q26-27, might be a susceptibility gene for Type I diabetes mellitus which is supported by recently published studies reporting evidence for linkage of this region (6q27) with Type I diabetes mellitus. Furthermore, the decreasing frequency of low molecular weight apo(a) phenotypes with disease duration suggests a survivor effect.

Adult↗
PubMed1999

Lipoprotein(a) plasma concentrations after renal transplantation: a prospective evaluation after 4 years of follow-up.

The highly atherogenic lipoprotein(a) [Lp(a)] is significantly elevated in patients with renal disease. It is discussed controversially whether Lp(a) concentrations decrease after renal transplantation and whether the mode of immunosuppressive therapy influences the Lp(a) concentrations. In a prospective study the Lp(a) concentrations before and on average 48 months after renal transplantation were measured in 145 patients. The determinants of the relative changes of Lp(a) concentrations were investigated in a multivariate analysis. Patients treated by CAPD showed a larger decrease of Lp(a) than hemodialysis patients, reflecting their markedly higher Lp(a) levels before transplantation. The relative decrease of Lp(a) was higher with increasing Lp(a) concentrations before transplantation in combination with an increasing molecular weight of apolipoprotein(a) [apo(a)]. That means that the relative decrease of Lp(a) is related to the Lp(a) concentration and the apo(a) size polymorphism. With increasing proteinuria and decreasing glomerular filtration rate, the relative decrease of Lp(a) became less pronounced. Neither prednisolone nor cyclosporine (CsA) had a significant impact on the Lp(a) concentration changes. Azathioprine (Aza) was the only immunosuppressive drug which had a dose-dependent influence on the relative decrease of Lp(a) levels. These data clearly demonstrate a decrease of Lp(a) following renal transplantation which is caused by the restoration of kidney function. The relative decrease is influenced by Aza but not by CsA or prednisolone.

Adult↗
PubMed1999

Cytogenetic characterization of 22 human renal cell tumors in relation to a histopathological classification.

In this study, cytogenetic and fluorescence in situ hybridization analyses were performed on 22 sporadic, unilateral primary renal cell tumors. The tumors were classified according to cell types, growth patterns, and grades of malignancy. A feeder layer technique was used for the cell culture of 13 clear-cell carcinomas, 4 chromophilic carcinomas, 3 chromophobe carcinomas, 1 oncocytoma, and 1 spindle-shaped pleomorphic carcinoma. Eighty-six percent (19/22) of renal tumors showed clonal abnormalities. The most frequent finding in the 15 male patients was loss of chromosome Y (9/15). In 3/15, it was the only observed aberration. The second most visible aberration was regional loss or entire loss of chromosome 9, which was detected in 36% (8/22) of the cases. Four cases showed loss of chromosome 9 and 4 cases a deletion of the short arm with breakpoints on 9p11 and 9p21. Loss of 3p material was observed in 32% (7/22) of the cases but only in 2/13 patients with clear-cell carcinoma. Gain of chromosome 12 or 12p was observed in 27% (6/22). In 23% (5/22) of the patients, gain of whole or partial chromosomes 2, 5, and 7 was found. Less-frequent findings were loss of chromosomes 8, 14, and 21; gain of chromosome 16; and structural abnormalities of chromosome 1 (each 18%; 4/22). Only some of the karyotypes described as typical for the various renal tumor types were confirmed. In contrast with previous reports, chromosome 3 and 9 aberrations did not allow differentiation between tumor types in our study.

Aged↗
PubMed1999

Switch from antagonist to agonist of the androgen receptor bicalutamide is associated with prostate tumour progression in a new model system.

Advanced prostate cancer is treated by androgen ablation and/or androgen receptor (AR) antagonists. In order to investigate the mechanisms relevant to the development of therapy-resistant tumours, we established a new tumour model which closely resembles the situation in patients who receive androgen ablation therapy. Androgen-sensitive LNCaP cells were kept in androgen-depleted medium for 87 passages. The new LNCaP cell subline established in this manner, LNCaP-abl, displayed a hypersensitive biphasic proliferative response to androgen until passage 75. Maximal proliferation of LNCaP-abl cells was achieved at 0.001 nM of the synthetic androgen methyltrienolone (R1881), whereas 0.01 nM of this compound induced the same effect in parental cells. At later passages (> 75), androgen exerted an inhibitory effect on growth of LNCaP-abl cells. The non-steroidal anti-androgen bicalutamide stimulated proliferation of LNCaP-abl cells. AR protein expression in LNCaP-abl cells increased approximately fourfold. The basal AR transcriptional activity was 30-fold higher in LNCaP-abl than in LNCaP cells. R1881 stimulated reporter gene activity in LNCaP-abl cells even at 0.01 nM, whereas 0.1 nM of R1881 was needed for induction of the same level of reporter gene activity in LNCaP cells. Bicalutamide that acts as a pure antagonist in parental LNCaP cells showed agonistic effects on AR transactivation activity in LNCaP-abl cells and was not able to block the effects of androgen in these cells. The non-steroidal AR blocker hydroxyflutamide exerted stimulatory effects on AR activity in both LNCaP and LNCaP-abl cells; however, the induction of reporter gene activity by hydroxyflutamide was 2.4- to 4-fold higher in the LNCaP-abl subline. The changes in AR activity were associated neither with a new alteration in AR cDNA sequence nor with amplification of the AR gene. Growth of LNCaP-abl xenografts in nude mice was stimulated by bicalutamide and repressed by testosterone. In conclusion, our results show for the first time that the nonsteroidal anti-androgen bicalutamide acquires agonistic properties during long-term androgen ablation. These findings may have repercussions on the natural course of prostate cancer with androgen deprivation and on strategies of therapeutic intervention.

Androgen Antagonists↗
PubMed1999

Molecular cytogenetic detection of 9q34 breakpoints associated with nail patella syndrome.

The nail patella syndrome (NPS1) is an autosomal dominant disorder characterised by dysplasia of the finger nails and skeletal abnormalities. NPS1 has been mapped to 9q34, to a 1 cM interval between D9S315 and the adenylate kinase gene (AK1). We have mapped the breakpoints within the candidate NPS1 region in two unrelated patients with balanced translocations. One patient [46,XY,t(1;9)(q32.1;q34)] was detected during a systematic survey of old cytogenetic files in Denmark and southern Sweden. The other patient [46,XY,t(9;17)(q34.1;q25)] was reported previously. D9S315 and AK1 were used to isolate YACs, from which endclones were used to isolate PACs. Two overlapping PAC clones span the 9q34 breakpoints in both patients, suggesting that NPS1 is caused by haploinsufficiency due to truncation or otherwise inactivation of a gene at or in the vicinity of the breakpoints.

Chromosome Fragility↗