Characterization of genes encoding translation initiation factor eIF- 2gamma in mouse and human: sex chromosome localization, escape from X- inactivation and evolution

The Delta Sxrb interval of the mouse Y chromosome is critical for spermatogenesis and expression of the male-specific minor transplantation antigen H-Y. Several genes have been mapped to this interval and each has a homologue on the X chromosome. Four, Zfy1 , Zfy2 , Ube1y and Dffry , are expressed specifically in the testis and their X homologues are not transcribed from the inactive X chromosome. A further two, Smcy and Uty , are ubiquitously expressed and their X homologues escape X-inactivation. Here we report the identification of another gene from this region of the mouse Y chromosome. It encodes the highly conserved eukaryotic translation initiation factor eIF-2gamma. In the mouse this gene is ubiquitously expressed, has an X chromosome homologue which maps close to Dmd and escapes X-inactivation. The coding regions of the X and Y genes show 86% nucleotide identity and encode putative products with 98% amino acid identity. In humans, the eIF-2gamma structural gene is located on the X chromosome at Xp21 and this also escapes X-inactivation. However, there is no evidence of a Y copy of this gene in humans. We have identified autosomal retroposons of eIF-2gamma in both humans and mice and an additional retroposon on the X chromosome in some mouse strains. Ark blot analysis of eutherian and metatherian genomic DNA indicates that X-Y homologues are present in all species tested except simian primates and kangaroo and that retroposons are common to a wide range of mammals. These results shed light on the evolution of X-Y homologous genes.      

Gene transfer into the mouse retina mediated by an adeno-associated viral vector

Gene transfer to photoreceptor cells may provide a means for arresting the retinal degeneration that is characteristic of many inherited causes of blindness, including retinitis pigmentosa (RP). However, transduction of photoreceptors has to date been inefficient, and further limited by toxicity and immune responses directed against vector-specific proteins. An alternative vector system based on adeno- associated virus (AAV) may obviate these problems, and may be useful for transduction of neuronal cells. In this study we have demonstrated successful transduction of all layers of the neuroretina as well as the retinal pigment epithelium (RPE) following subretinal injection of recombinant AAV particles encoding lac Z. Furthermore, the efficiency of transduction of photoreceptors is significantly higher than that achieved with an equivalent adenoviral vector. This is the first report showing that AAV is capable of transducing photoreceptor cells and supports the use of this vector system for gene therapy of retinal diseases such as RP.      

Cardiac toxicity of patients on short course trastuzumab in combination with chemotherapy (FinHer Protocol) in breast cancer

FinHer regimen is considered a relatively cardiac safe regimen for Her 2 positive breast cancer in resource-limited settings. There is limited data on cardiotoxicity of this regimen. Out of 1200 patients diagnosed with carcinoma breast during the study period, three hundred Her2-positive early–breast cancer patients received FinHer protocol were included. Among the 300 patients, a total of 71 patients (24%) experienced cardiac toxicity including asymptomatic EF loss in 62 patients (21%) and symptomatic LVEF loss in nine patients (3%). Among patients with symptomatic LVEF loss, six patients had symptomatic cardiac toxicity, one patient (0.3%) had symptoms with fall in EF after completion of treatment, one patient (0.3%) had Congestive cardiac failure (CHF); one patient (0.3%) had non-ST elevation myocardial infarction (NSTEMI). Later, trastuzumab was rechallenged in all 62 patients (24%) with asymptomatic LVEF loss and six patients (2%) with symptomatic LVEF loss. One patient with CHF and NSTEMI was not rechallenged. Hypertension and diabetic mellitus which were the two factors found to have risk on univariate logistic regression analysis although it was not statistically significant. None of these patients further experienced cardiac toxicity at 24 months follow-up except one patient. Although FinHer protocol is considered a cardiac safe protocol, cardiotoxicity associated with trastuzumab which can manifest as an asymptomatic decline in LVEF is more than usually expected in a real-world scenario.     

Needs of disabled children and their families

In the new NHS those who provide services for disabled children need to measure and demonstrate their effectiveness, but there are no easily available outcome measures for use by child development centres and teams. The development of an alternative approach, using a series of statements of good practice, is described. Parents of children with cerebral palsy were asked to participate in semistructured interviews, to ascertain the value and relevance of these quality statements. Parents were most concerned about the standard of news breaking and early follow up, the sharing of information, and the supply and repair of equipment. The findings were used to modify the quality checklist and it is proposed that this should form the basis of a "charter for disabled children and their families'.     

CO2 LASER – A NEW TOOL IN THE SURGEONS ARMAMENTARIUM

One hundred and sixty five patients, treated with carbondioxide (CO₂) laser for benign and malignant lesions of the head and neck were studied. Alveolo-buccal complex (68/165) had the majority of benign and malignant tumors followed by larynx (23/165) and tongue (21/165). All lesions were widely excised, none were reconstructed and all defects healed well with minimal scarring. The post-operative morbidity was minimal and the hospitalization period was 1 to 5 days. Complications were not serious and could be managed easily. This study confirms the usefulness of CO₂ laser surgery for both benign and malignant conditions in head and neck.KEYWORDS: Carbondioxide laser, Head and neck, Malignant neoplasm, Premalignant lesions     

Modern use of clomiphene citrate in induction of ovulation

Clomiphene citrate is the treatment of first choice in the managementof infertility in normally oestrogenized, anovulatory women(WH0 group II). The majority of women with 'pure' anovulatoryinfertility respond to treatment with clomiphene citrate. Therates of pregnancy and miscarriage are close to those expectedin a normal fertile population. Basal hormone concentrationsdo not predict outcome. An increased body mass index is theonly factor which is consistently associated with a decreasedresponse to clomiphene citrate; it follows therefore, that weightreduction should be an important part of therapy in anovulatorywomen. According to our data, only an increased luteinizinghormone value immediately post clomiphene citrate predictedan adverse pregnancy outcome in women who conceived. Clomiphenecitrate, along with other ovulation induction therapies, cancause multiple follicular development, with a risk of ovarianhyperstimulation and multiple pregnancy. Ultrasound monitoringof treatment is important in order to choose the appropriatedose of clomiphene citrate in subsequent cycles and to minimizethe risks of hyperstimulation and multiple pregnancy. When coupleswith other factors contributing to subfertility are excluded,the cumulative conception rate continues to rise after 6 monthsof treatment with clomiphene citrate, reaches a plateau by treatmentcycle 12 and approaches that of the normal population. It hasbeen reported that prolonged use of clomiphene citrate may beassociated with an increased risk of a borderline or invasiveovarian tumour. Taking into consideration these observations,we recommend that anovulatory women responsive to clomiphenecitrate should be treated for at least 6 cycles before consideringmore complex or invasive methods of ovulation induction, andthat treatment should probably be limited to a maximum of 12cycles.     

Localisation of a gene for dominant cone-rod dystrophy (CORD6) to chromosome 17p

We have performed genetic linkage analysis on a four generation British family with cone-rod dystrophy. Significant linkage to the disease gene was obtained with eight marker loci situated on chromosome 17p12-p13. A maximum two-point lod score of 5.93 with no recombination was obtained with marker locus D17S1844. Critical recombinants identified with flanking marker loci placed the disease gene between D17S796/D17S938 and D17S954, an interval estimated to be 8 cM in size. This new localisation for autosomal dominant cone-rod dystrophy (CORD6) overlaps with regions attributed previously to Leber's congenital amaurosis, central areolar choroidal dystrophy and dominant cone dystrophy. Given their differences in phenotype, the most plausible explanation would be that these different retinal disorders are caused by mutations in different genes mapping close together within the genome.      

Evaluation of coronary artery bypass graft patency using three-dimensional re construction and flow study of electron beam tomography

目的　建立并评价电子束CT (EBT)两种方法在冠状动脉搭桥术后 (CABG)随访应用中的价值。方法　本组共 2 14例CABG患者进行了EBT两种方法的扫描 :(1)电子束CT血管造影 (EBA) ,以完成冠状动脉及搭桥血管的三维重建 ;(2 )电子束CT血流扫描 ,以得到冠状动脉及其搭桥血管的血流曲线。结果　本组共分析了 589条冠状动脉搭桥血管 (10条血管因图像伪影而除外 )。 133条动脉材料的血管桥通畅率超过静脉桥 (P <0 0 0 1)。三维重建方法诊断的敏感性、特异性和准确性分别是 97 7%、94 1%和 96 7% ,均高于血流扫描方法 (分别是 88 4 %、82 4 %和 85 2 % )。动脉与静脉血管桥内的平均血流量分别为 4 9± 2 2ml·min 1·g 1和 6 9± 2 8ml·min 1·g 1(P <0 0 0 1)。结论　电子束CT血管造影配合三维重建方法有利于观察冠状动脉及其搭桥血管的解剖 ,而血流扫描方法有利于观察并定量评估搭桥血管内的血流 ,两种方法的结合是理想的冠状动脉搭桥术后随访的无创影像方法     

Characterization of lpd (lipid defect): a novel mutation on mouse chromosome 16 associated with a defect in triglyceride metabolism

Recent epidemiological studies have identified plasma triglyceride as a risk factor for atherogenesis. We have generated a mouse transgenic line that carries a recessive mutation designated lpd (lipid defect). Homozygous lpd mice develop as runts and die by age 10-15 days with striking liver pathology characterized by the presence of numerous lipid-containing vacuoles and extensive accumulation of triglycerides. Cloning of the mutant insertion locus and the wild-type lpd locus have revealed a duplication of host genomic sequences at the site of integration. Mapping of the lpd locus with the Jackson Laboratory BSS interspecific backcross panel of (C57BL/6JEi x SPRET/Ei) F1 x SPRET/Ei placed the lpd locus to the distal part of chromosome 16. These observations suggest that the transgene disrupts a putative gene at the lpd locus and that lpd is a novel locus related to triglyceride metabolism. The lpd mutant mice may serve as models for human disorders of fatty livers or hypertriglyceridemia.