Effect of high-frequency low-intensity irradiation on reproductive function in C57Bl/6 and randombred mice

The effect of high-frequency low-intensity radiation on reproductive function was studied on C57Bl/6 and randombred mice. We revealed a progressive decrease in the number of offspring, prevalence of males over females in all generations, and the appearance of stillbirths. The decrease in the number of offspring was probably related to increased number of homozygotes and decreased number of heterozygotes in the population under the influence of nonthermal radiation.Translated from Byulleten Eksperimentalnoi Biologii i Meditsiny, Vol. 138, No. 12, pp. 626–628, December, 2004This revised version was published online in April 2005 with a corrected cover date.     

Abnormal thalamocortical pathfinding and terminal arbors lead to enlarged barrels in neonatal GAP-43 heterozygous mice

GAP-43 has been implicated in axonal pathfinding and sprouting, synaptic plasticity, and neurotransmitter release. However, its effect on cortical development in vivo is poorly understood. We have previously shown that GAP-43 knockout (-/-) mice fail to develop whisker-related barrels or an ordered whisker map in the cortex. Here we used cytochrome oxidase (CO) histochemistry to demonstrate that GAP-43 heterozygous (+/-) mice develop larger than normal barrels at postnatal day 7 (P7), despite normal body and brain weight. Using serotonin transporter (5HT-T) histochemistry to label thalamocortical afferents (TCAs), we found no obvious abnormalities in other somatosensory areas or primary visual cortex of GAP-43 (+/-) mice. However, TCA projections to (+/-) primary auditory cortex were not as clearly defined. To clarify the mechanism underlying the large-barrel phenotype, we used lipophilic (DiI) axon labeling. We found evidence for multiple pathfinding abnormalities among GAP-43 (+/-) TCAs. These axons show increased fasciculation within the internal capsule, as well as abnormal turning and branching in the subcortical white matter. These pathfinding errors most likely reflect failures of signal recognition and/or transduction by ingrowing TCAs. In addition, many DiI-labeled (+/-) TCAs exhibit widespread, sparsely branched terminal arbors in layer IV, reflecting the large-barrel phenotype. They also resemble those found in rat barrel cortex deprived of whisker inputs from birth, suggesting a failure of activity-dependent synaptogenesis and/or synaptic stabilization in (+/-) cortex. Our findings suggest that reduced GAP-43 expression can alter the fine-tuning of a cortical map through a combination of pathfinding and synaptic plasticity mechanisms.     

Parental request for familial carrier testing in early childhood: The genetic counseling perspective

Professional guidelines generally caution against carrier testing in minors, though prior research indicates parents request and providers sometimes facilitate testing for unaffected siblings of a child affected by a genetic disorder. We investigated the perspectives of genetic counselors in North America regarding carrier testing prior to adolescence. Practicing genetic counselors (n = 177) responded to an electronic survey assessing their willingness to facilitate testing in four hypothetical scenarios and their evaluation of parental motivations. Participants did not find parental arguments for testing persuasive, and most were unwilling to facilitate carrier testing in children. A significant interaction effect indicated the presence of nonactionable carrier-associated health risks in adulthood made participants significantly less hesitant when the mode of inheritance was X-linked. Participants considered parental motivations that center the child's interests as significantly more persuasive. This study suggests genetic counselors are resistant to carrier testing for familial disorders in young children and tend to align with current guidelines, yet they recognize nuance in various cases. Further investigation into this topic is warranted to support genetic counselors facing these requests as the ethics of pediatric carrier testing continues to be debated.     

1例新的遗传性高铁血红蛋白血症复合杂合子基因型的鉴定

目的　从分子水平对 1例遗传性高铁血红蛋白血症患者进行确诊。方法　通过RT PCR产物直接测序 ,分析患者和正常对照b5R基因的cDNA编码序列。用PCR 限制性内切酶分析患者、其父母和正常人基因组DNA。结果　患者的一个b5R等位基因第 72位密码子 (位于外显子 3)发生了CTC→CCC突变 ,原来的亮氨酸被脯氨酸替换。患者另一个b5R等位基因第 2 0 3位密码子 (位于外显子 7)发生了TGC→TAC突变 ,原先的半胱氨酸被酪氨酸取代。结论　在中国患者确定了一个新的遗传性高铁血红蛋白血症基因型 ,即L72P/C2 0 3Y。     

采用ROC曲线评价β珠蛋白生成障碍性贫血杂合子血液学指标诊断价值

目的 采用受试者工作特征曲线(ROC曲线)评价β珠蛋白生成障碍性贫血(β地中海贫血,简称β地贫)杂合子血液学指标,确定平均红细胞体积(MCV)、红细胞脆性(EF)、血红蛋白(Hb)A2及HbF的最佳截断值(cutoff值).方法 以基因诊断结果为金标准,采用ROC曲线分析MCV、EF、HbA2及HbF最佳cutoff值;评价单项及多项指标联合检测的诊断价值.结果 与健康对照组比较,β地贫组MCV、EF明显降低,HbA2、HbF明显增高(P<0.05).HbA2、EF、MCV、HbF的ROC曲线下面积依次为0.989、0.926、0.919、0.734,最佳cutoff值分别为3.45%、63.5%、68.25 fl、0.45%,灵敏度分别为98.00%、91.10%、87.10%、77.20%;特异度分别为100.00%、81.10%、84.90%、65.10%.HbA2灵敏度和特异度最高(P<0.05).与单项检测比较,平行联合检测明显提高诊断灵敏度,系列联合检测明显提高特异度(P<0.05).结论 以ROC曲线分析得到的MCV、EF、HbA2最佳cutoff值对β地贫杂合子筛查具有较好的诊断价值,HbA2诊断价值最高.联合检测法可提高诊断灵敏度和特异度.     

四川地区P53 Codon 72多态性与宫颈癌关系的初步研究

目的 探讨抑癌基因P53 Codon 72多态性与HPV有关的宫颈癌的关系。 方法 应用聚合酶链反应法分别对30例卵巢浆液性囊腺癌、50例宫颈鳞状细胞癌和30例正常妇女的P53 Codon 72多态性进行检测。 结果 P53 Arg纯合子、P53 Arg/P53 Pro杂合子和P53Pro纯合子正常妇女对照组分别为33.3％、60％和6.7％;而在卵巢癌组分别为40％、53.3％和6.7％;在宫颈癌组分别为80％、14％和6％。上述人群中,宫颈癌P53 Arg纯合子明显高于卵巢癌组和正常妇女对照组(P<0.05)。 结论 p53 Arg纯合子可作为与HPV感染有关的宫颈癌的危险因素。     

Recurrent moderate-risk mutations in Finnish breast and ovarian cancer patients

Mutations in BRCA1 and BRCA2 genes predispose to breast and ovarian cancer (BC/OC) with a high lifetime risk, whereas mutations in PALB2, CHEK2, ATM, FANCM, RAD51C and RAD51D genes cause a moderately elevated risk. In the Finnish population, recurrent mutations have been identified in all of these genes, the latest being CHEK2 c.319+2T>A and c.444+1G>A. By genotyping 3,156 cases and 2,089 controls, we estimated the frequencies of CHEK2 c.319+2T>A and c.444+1G>A in Finnish BC patients. CHEK2 c.319+2T>A was detected in 0.7% of the patients, and it was associated with a high risk of BC in the unselected patient group (OR = 5.40 [95% CI 1.58–18.45], p = 0.007) and similarly in the familial patient group. CHEK2 c.444+1G>A was identified in 0.1% of all patients. Additionally, we evaluated the combined prevalence of recurrent moderate-risk gene mutations in 2,487 BC patients, 556 OC patients and 261 BRCA1/2 carriers from 109 families. The overall frequency of the mutations was 13.3% in 1,141 BRCA1/2-negative familial BC patients, 7.5% in 1,727 unselected BC patients and 7.2% in 556 unselected OC patients. At least one moderate-risk gene mutation was found in 12.5% of BRCA1 families and 7.1% of BRCA1 index patients, as well as in 17.0% of BRCA2 families and 11.3% of BRCA2 index patients, and the mutations were associated with an additional risk in the BRCA1/2 index patients (OR = 2.63 [1.15–5.48], p = 0.011). These results support gene panel testing of even multiple members of BC families where several mutations may segregate in different individuals.     

Incidence of the Hb E [β26(B8)Glu→Lys,GAG>AAG] Variant In Totos,One of the Smallest Primitive Tribes in the World

Toto is one of the smallest tribes in the world. This primitive sub Himalayan, endogamous tribe lives in a small, isolated village called Totopara in the Jalpaiguri district of West Bengal in India. The tribal communities of West Bengal are vulnerable to various genetic disorders such as β-thalassemia (β-thal). We have studied 443 Totos to define their Hb E [β26(B8)Glu→Lys, GAG>AAG] status. Awareness and screening camps have been organized in various parts of Totopara during the last 2 years. We collected 3 mL peripheral blood from each individual aseptically on which to use the naked eye single tube red cell osmotic fragility test (NESTROFT); complete hemogram and high performance liquid chromatography (HPLC) were done to detect their carrier status. The Hb E variant had been found to be prevalent among the Totos. To confirm the codon 26 (GAG>AAG) mutation in the β-globin gene, amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) was performed. Restriction fragment length polymorphism (RFLP)-PCR was carried out with 44 Hb E alleles to construct the haplotype(s) of the Totos. Our extensive studies have revealed that 49.21% of Totos are Hb E heterozygotes and 19.19% Totos are Hb E homozygotes. The most prevalent haplotype linked with the codon 26 mutation in the Totos is [+ ? ? ? ? ?] (HincII 5′?, HindIII ^Gγ, HindIII ^Aγ, HincII 5′ψβ, HincII 3′ψβ and HinfI 3′β). Consanguineous marriages have resulted in a significant increase of the percentages of heterozygotes and homozygotes of Hb E in the Totos. Genetic counseling is essential and important to prevent the spread of this mutation and hence to save them from having any kind of clinically significant hemoglobinopathy in the future.