The KL-VS sequence variant of Klotho and cancer risk in BRCA1 and BRCA2 mutation carriers

Klotho (KL) is a putative tumor suppressor gene in breast and pancreatic cancers located at chromosome 13q12. A functional sequence variant of Klotho (KL-VS) was previously reported to modify breast cancer risk in Jewish BRCA1 mutation carriers. The effect of this variant on breast and ovarian cancer risks in non-Jewish BRCA1/BRCA2 mutation carriers has not been reported. The KL-VS variant was genotyped in women of European ancestry carrying a BRCA mutation: 5,741 BRCA1 mutation carriers (2,997 with breast cancer, 705 with ovarian cancer, and 2,039 cancer free women) and 3,339 BRCA2 mutation carriers (1,846 with breast cancer, 207 with ovarian cancer, and 1,286 cancer free women) from 16 centers. Genotyping was accomplished using TaqMan^® allelic discrimination or matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Data were analyzed within a retrospective cohort approach, stratified by country of origin and Ashkenazi Jewish origin. The per-allele hazard ratio (HR) for breast cancer was 1.02 (95% CI 0.93–1.12, P = 0.66) for BRCA1 mutation carriers and 0.92 (95% CI 0.82–1.04, P = 0.17) for BRCA2 mutation carriers. Results remained unaltered when analysis excluded prevalent breast cancer cases. Similarly, the per-allele HR for ovarian cancer was 1.01 (95% CI 0.84–1.20, P = 0.95) for BRCA1 mutation carriers and 0.9 (95% CI 0.66–1.22, P = 0.45) for BRCA2 mutation carriers. The risk did not change when carriers of the 6174delT mutation were excluded. There was a lack of association of the KL-VS Klotho variant with either breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.     

The M-OVIN study: does switching treatment to FSH and / or IUI lead to higher pregnancy rates in a subset of women with world health organization type II anovulation not conceiving after six ovulatory cycles with clomiphene citrate – a randomised controlled trial

Background

Clomiphene citrate (CC) is first line treatment in women with World Health Organization (WHO) type II anovulation and polycystic ovary syndrome (PCOS). Whereas 60% to 85% of these women will ovulate on CC, only about one half will have conceived after six cycles. If women do not conceive, treatment can be continued with gonadotropins or intra-uterine insemination (IUI). At present, it is unclear for how many cycles ovulation induction with CC should be repeated, and when to switch to ovulation induction with gonadotropins and/or IUI.

Methods/Design

We started a multicenter randomised controlled trial in the Netherlands comparing six cycles of CC plus intercourse or six cycles of gonadotrophins plus intercourse or six cycles of CC plus IUI or six cycles of gonadotrophins plus IUI.Women with WHO type II anovulation who ovulate but did not conceive after six ovulatory cycles of CC with a maximum of 150 mg daily for five days will be included.Our primary outcome is birth of a healthy child resulting from a pregnancy that was established in the first eight months after randomisation. Secondary outcomes are clinical pregnancy, miscarriage, multiple pregnancy and treatment costs. The analysis will be performed according to the intention to treat principle. Two comparisons will be made, one in which CC is compared to gonadotrophins and one in which the addition of IUI is compared to ovulation induction only. Assuming a live birth rate of 40% after CC, 55% after addition of IUI and 55% after ovulation induction with gonadotrophins, with an alpha of 5% and a power of 80%, we need to recruit 200 women per arm (800 women in total).An independent Data and Safety Monitoring Committee has criticized the data of the first 150 women and concluded that a sample size re-estimation should be performed after including 320 patients (i.e. 80 per arm).

Discussion

The trial will provide evidence on the most effective, safest and most cost effective treatment in women with WHO type II anovulation who do not conceive after six ovulatory cycles with CC with a maximum of 150 mg daily for five days. This evidence could imply the need for changing our guidelines, which may cause a shift in large practice variation to evidence based primary treatment for these women.

Trial registration number

Netherlands Trial register NTR1449

     

Snuff use and smoking among senior high school students: effects of a snuff sales ban

OBJECTIVES: The popularity of snuff especially among adolescents is rising. The association between long-term snuff use and oral cancer discovered in epidemiological studies has prompted a variety of preventive measures to be taken to reduce snuff use and prevent adoption of the habit. In this study, the effect of a recent (I March, 1995) snuff sales ban introduced in Finland was investigated. Further, the rates of smoking, snuff use, alcohol use and drug experimenting were investigated before the introduction of the ban to characterize the study population.
DESIGN AND SUBJECTS: Two questionnaire studies were carried out. The first was carried out 3 months prior to the ban in 1994 and the second 9 months after the ban in 1995 in a senior high school population in southwestern Finland. The participants were 793 students (aged 15–22 years) in the first survey and 545 students (aged 16–23) in the second. Associations between variables were analyzed using cross-tabulation and stepwise logistic regression. The effects of the ban were determined on the basis of direct questions in the second questionnaire relating to the snuff sales ban.
RESULTS: Snuff was used by 9% of the students participating in the first study. The results of the second questionnaire indicate that the implementation of the snuff sales ban reduced the rate of snuff use by 1% in the study population. The majority of the snuff users (76%) reported that they had maintained their snuff habit. Of those reporting that they were snuff users before implementation of the snuff sales ban, 12% had switched to smoking and 5% to drugs.
CONCLUSIONS: The results of the present study suggest that the snuff sales ban in this population with a high rate of snuff use had little effect on snuff use rates and may have some short-term negative consequences as some snuff users switch to other substitutes, such as smoking, with known adverse health effects.     

The membrane mucin MUC4 is elevated in breast tumor lymph node metastases relative to matched primary tumors and confers aggressive properties to breast cancer cells

Introduction

Previous studies indicate that overexpression of the membrane-associated mucin MUC4 is potently anti-adhesive to cultured tumor cells, and suppresses cellular apoptotic response to a variety of insults. Such observations raise the possibility that MUC4 expression could contribute to tumor progression or metastasis, but the potential involvement of MUC4 in breast cancer has not been rigorously assessed. The present study aimed to investigate the expression of the membrane mucin MUC4 in normal breast tissue, primary breast tumors and lymph node metastases, and to evaluate the role of MUC4 in promoting the malignant properties of breast tumor cells.

Methods

MUC4 expression levels in patient-matched normal and tumor breast tissue was initially examined by immunoblotting lysates of fresh frozen tissue samples with a highly specific preparation of anti-MUC4 monoclonal antibody 1G8. Immunohistochemical analysis was then carried out using tissue microarrays encompassing patient-matched normal breast tissue and primary tumors, and patient-matched lymph node metastases and primary tumors. Finally, shRNA-mediated knockdown was employed to assess the contribution of MUC4 to the cellular growth and malignancy properties of JIMT-1 breast cancer cells.

Results

Immunoblotting and immunohistochemistry revealed that MUC4 levels are suppressed in the majority (58%, p < 0.001) of primary tumors relative to patient-matched normal tissue. On the other hand, lymph node metastatic lesions from 37% (p < 0.05) of patients expressed higher MUC4 protein levels than patient-matched primary tumors. MUC4-positive tumor emboli were often found in lymphovascular spaces of lymph node metastatic lesions. shRNA-mediated MUC4 knockdown compromised the migration, proliferation and anoikis resistance of JIMT-1 cells, strongly suggesting that MUC4 expression actively contributes to cellular properties associated with breast tumor metastasis.

Conclusions

Our observations suggest that after an initial loss of MUC4 levels during the transition of normal breast tissue to primary tumor, the re-establishment of elevated MUC4 levels confers an advantage to metastasizing breast tumor cells by promoting the acquisition of cellular properties associated with malignancy.     

Prospective study of a noninvasive treatment for two common congenital toe abnormalities (curly/varus/underlapping toes and overlapping toes)

OBJECTIVE

To assess, in the newborn, the efficacy of a standard taping treatment used in children for two selected congenital toe abnormalities (curly/varus/underlapping toes and overlapping toes), and compare the outcome with the available world literature.

METHODS

All children referred by their family physician between January 2004 and January 2006 were included. The newborns were reviewed by one author (WGS) within 10 days of birth, assessed for severity, and the toes were taped in a standard manner if the abnormalities met the study criteria. After one and two months, the same author reviewed the children, and retaped the toes. The children’s toes were photographed before the taping and then after three months when the tape was removed permanently. After six months, the children, with their pictures, were sent to a second author (JTS), and were scored for the grade of severity and improvement using standard criteria.

RESULTS

The world literature and standard textbooks indicate a 25% spontaneous improvement of these abnormalities. The recommendation is for surgical correction at a later date because intervention with taping has not shown success after the newborn period. No prior studies have been undertaken in the newborn. In the present study of 84 toes, the abnormality occurred in 2.8% of newborns, and 94% of the toes were improved or cured with no complications related to the technique.

CONCLUSION

A simple, office-friendly technique of taping underlapping and overlapping toes in the newborn proved successful in 94% of the toes.     

Undergraduate ophthalmology education survey of New Zealand ophthalmologists, general practitioners and optometrists

Aim : To determine what New Zealand ophthalmologists, general practitioners and optometrists consider important ophthalmic topic areas requiring emphasis in the medical undergraduate curriculum. Method : A total of 793 questionnaires related to the content and teaching of undergraduate ophthalmology were sent to ophthalmologists, general practitioners and optometrists. Results were analysed separately for the three respondent groups and as a whole. Results : Four hundred and fourteen questionnaires were returned (52% return rate). Overall responses of the three participant groups were similar and agreed favourably with the current curriculum. The ability to measure visual acuity (97%) and pupillary reflexes (93%), perform ophthalmoscopy (92%), and assess visual fields (68%) were regarded as ‘important or essential’ by the majority of respondents. Only 53% of respondents consider the ability to diagnose chronic open angle glaucoma as important. The respondents stressed the importance of the diagnosis of predominantly anterior segment disease contrasting with the traditional bias towards the teaching of ophthalmoscopy and posterior segment disease. The majority of respondents stressed the importance of graduating medical students being able to treat bacterial and allergic conjunctivitis, styes, blepharitis, corneal abrasion, and corneal and conjunctival foreign bodies, areas present but not normally emphasized in current curricula. Conclusion : The findings of this study provided additional data to facilitate curriculum design and illustrated the value of an integrated problem‐based learning approach in ophthalmology undergraduate teaching.     

溃结Ⅰ号的制备与稳定性考察

目的提高医院临时处方溃结Ⅰ号保留灌肠剂的稳定性,并对其中的主要成分含量进行控制。方法制备时加入助悬剂,用沉降容积比和再分散性选择适宜的助悬剂及其最佳助悬浓度,并用紫外分光光度法对主要成分柳氮磺吡啶的含量进行测定。结果在制剂中加入卡波母作为助悬剂0.15%就可以达到良好的助悬效果,而且制备的制剂再分散性好。结论加入卡波母作为助悬剂制备的制剂稳定,再分散性好,便于使用和保存。     

Variable compensation technique for digital radiography of the chest

The authors describe a new technique, variable compensation (VC) radiography, for digital radiography of the chest. It permits retrospective adjustment of image display while maintaining improved mediastinal signal-to-noise ratio (S/N) from aggressive x-ray equalization. A fraction of a logarithmic image representing the profile of the beam intensity incident on the patient is subtracted from a logarithmic equalized image. VC images of a chest phantom were generated with various weightings of the beam-profile image. Edge artifacts were substantially reduced with a weighting of greater than 0.5 and eliminated with a weighting of 1.0. The S/N properties of VC images were measured with a series of plastic squares placed over various regions of the chest phantom. The S/N of the squares in the dense sub-diaphragm were improved twofold compared with the S/N on unequalized radiographs, whereas the S/N in the lung was reduced by 30%. Studies of a volunteer revealed the ability to render images with aggressive equalization (for improved mediastinal visualization) and images with the appearance of traditional chest radiographs.     

Infectious disease complications of simultaneous pancreas kidney transplantation

BACKGROUND: Although technical success rate of simultaneous pancreas kidney (SPK) transplantation in insulin-dependent diabetes mellitus (IDDM) patients with diabetic nephropathy has improved, morbidity remains high due to infection and rejection. The purpose of this study was to analyse infections encountered in our series of SPK transplants, using a restrictive antibiotic prophylaxis policy. METHODS: We reviewed all infectious diseases after 66 consecutive bladder-drained SPK transplantations in 64 IDDM patients with end-stage renal disease due to diabetic nephropathy. During follow-up, the perioperative antibiotic regimen was altered (from 5 days preemptive therapy with multiple drugs to 1 day prophylaxis with cefamandole), and long-term viral prophylaxis (high-dose aciclovir) was introduced. For post-operative urinary tract or opportunistic infection, no prophylaxis was given. RESULTS: Overall mean infection rate was 2.9 infections/ patient/year after a mean follow-up of 2.3 years. Surgical site infections (SSI) were seen in 30% of the patients, with Enterococci present in 47%. Logistic regression showed one day cefamandole prophylaxis to be associated with SSI, but there was no significant influence of SSI on either graft or patient survival. Forty-eight percent of all infections were lower urinary tract infections (UTI). There were 59 first UTIs (89%), probably related to long-term Foley catheter use, and 47 second UTIs (71%). Subsequent UTIs were not microbiologically related to first UTIs. Cytomegalovirus (10 patients) and other opportunistic agents did not cause mortality or graft loss. Five grafts were lost due to infection (SSI three times, post-transplant lymphoproliferative disease twice). Only one patient died because of infection (2%). CONCLUSIONS: Infectious diseases after SPK transplantation caused significant morbidity but did not influence either patient or graft survival. A change in prophylactic policy for both SSI as well as recurrent UTI, combined with earlier Foley removal, may lower incidences of these infections.      

Induction of tumor-specific T cell response by cognating tumor cells with foreign antigen-primed Th cells

Sufficient CD4+ T cell help is very important in generating specific cytotoxic T cell responses. The inadequate activation of tumor-specific Th cells leads to failure of antitumor immunity. In general, each individual consists of some primed Th cells responding to certain antigens. If these tumor non-specific pre-primed Th cells can provide sufficient help, the generation of tumor-specific T cells may be enhanced. In the present study, we tested this hypothesis by cognating and reactivating pre-primed ovalbumin (OVA)-specific Th cells with OVA- pulsed tumor cells which could simultaneously present both OVA and tumor-associated antigen on the same cell. We clearly demonstrated that immunization of OVA-sensitized mice with OVA-pulsed P388 cells, but not unpulsed P388 cells, led to the induction of P388-specific cytotoxicity and tumor resistance. Both CD4+ and CD8+ tumor-specific cytotoxic T cells were detected in vitro, but only CD8+ T cells played the major effector role in preventing the growth of challenged tumor in vivo. Taken together, our study demonstrated that the immunogenicity of tumor cells can be enhanced effectively by cognating pre-primed foreign antigen-specific Th cells with tumor cells. These findings have potential implications in developing methods to control tumor growth.