Predictive genetic screening for type-1 diabetes in the Hungarian population

INTRODUCTION: In the modern genetic era the principles of genetic screening are being changed. In addition to diagnostic screening for rare monogenic diseases, predictive screening for common polygenic conditions, like type 1 diabetes, will be more widely implemented. The majority of the genetic background of type 1 diabetes is encoded by the HLA DQ and DR genes, selected variants of which could be used as screening markers. However, risk conferred by various HLA genotypes shows considerable ethnic variation, therefore population-specific screening markers need to be established. AIMS: The aim of this study was to describe a screening strategy based on risk-defining HLA DRB1-DQA1-DQB1 markers to identify individuals at risk for type 1 diabetes in the Hungarian population. METHODS: HLA genotypes of 149 consecutively diagnosed children with type 1 diabetes (age at diagnosis 0-14, mean 8.8 +/- 4.2 years) and 177 randomly selected healthy schoolchildren were studied. Allele-specific polymerase chain reaction method was used for HLA typing. The diagnostic sensitivity, specificity and predictive value of diabetes associated DRB1-DQA1-DQB1 alleles were analysed in a step-wise strategy. RESULTS: The highest diagnostic sensitivity was detected when DQB1 typing was complemented by DQA1 typing on DQB1*0201 positive samples with additional DRB1*04 subtyping in DQB1*0302 carriers. The combination of the following markers gave a relative risk of 28.9 (95% confidence interval: 15.9-52.7, p = 10(-6): DQB1*0201/0302-DQA1*0301,0501-b (b not equal to DRB1* 0403), DQB1*0302/x-DRB1*0401,0402 (not equal to DQB1*0201, 0301,0602,0603), DQB1*0301/0302-DRB1*0401,0404, DQB1*0304/s (s = any DQB1 alleles), DQB1*0201/y-DQA1*0501/a (y not equal to DQB1*0301,0302,0602, 0603,0604, a not equal to DQA1*0201). The diagnostic sensitivity, specificity and positive predictive values for this marker combination were 79.2%, 88.7%, and 1.1%, respectively. CONCLUSIONS: Using HLA DRB1-DQA1-DQB1 markers predictive genetic screening for type 1 diabetes is feasible in the Hungarian population with high diagnostic sensitivity and specificity. At present, such a screening for individuals at risk for type 1 diabetes in the general population is recommended only as part of prospective studies on the natural history or prevention of disease. To increase the positive predictive value of the model, pancreas beta-cell autoantibodies need to be measured and followed in the high-risk cohort.     

Deaths due to suicide: the effects of certification and coding practices in Australia

OBJECTIVE: To highlight issues relating to suicide coding that have an impact on the final reported mortality data by the Australian Bureau of Statistics. METHOD: This paper presents an outline of the way in which the official Australian suicide data is captured and coded and highlights issues relating to the classification used, coronial processes, documentation requirements and data sources that have an impact on the final reported data, especially deaths associated with coronial investigations. RESULTS: Issues related to the coding of Australian suicide data are: *Disparity between jurisdictions due to differences in documentation about accidental or undetermined causes of death. *Lack of standardisation in the way that coronial deaths are reported across Australia. *Lack of a standard form for police reports. *Administrative processes that cause delays in reporting the results of coronial investigations. *Reluctance on the part of some coroners to report deaths as suicides. CONCLUSIONS: Researchers and policy makers need to be aware of the constraints under which suicide can be reported as such in the official data before interpreting time trends.     

Teleradiology--an integrated solution

Successful and clinically relevant teleradiology requires robust technology coupled with expert specialist opinion. It also places significant demands on ships' medical personnel to produce images of diagnostic quality. There is the corresponding need for crew training and continuous quality management to ensure that the benefits of an innovative service are maintained and maximised. In the context of services provided by the Telemedical partnership, this paper will discuss: * Maritime Radiography and Information Technology (IT) * Crew Training--shore and computer based * Radiation Protection--recent legislation * Quality Standards--medical audit and clinical governance. It will demonstrate how a high quality clinical service can be developed and sustained by applying an integrated approach to these essential components. (This subject was presented to the 6th International Symposium on Maritime Health in Manila, Philippines, in November 2001).     

Home is where recovery begins

* Let's try to learn from our less creative approaches and not repeat our mistakes. We've learned a lot about what didn't work with the continuum of care concept, so let's move on to recovery-oriented housing opportunities for the people who use our services. * Let's move away from the concept of "placing" people. Let's ask people to decide where they want to live, and help them get there. The more involved they are in the planning and selection of their living plan, the more meaning it will have for them-and the more involved and invested they will be in maintaining it. * Let's not assume people need to be moved up and down a continuum. The less we move people the easier it will be for them to develop relationships and support systems that will help them maintain recovery. If there is any moving to do, let's move the staff instead. * Let's provide recovery-centered education that honors and respects people's strengths and ideas while building on their knowledge and skills for community living success.     

Haplogroup analysis of vitamin-K epoxide reductase (VKORC1) gene: novel element in the optimization of anticoagulant therapy

Warfarin and acenocoumarols are the most commonly prescribed anticoagulants that is difficult to use because of the wide intra- and interpatient variation in the dose requirements, the narrow therapeutic range and the risk of serious bleeding. Vitamin K epoxide reductase (VKORC1) is the site of inhibition by coumarins. Mutations in the VKORC1 gene affect the sensitivity of the epoxy reductase enzyme for warfarin. The three main haplotypes of VKORC1 gene, *2, *3, *4, explain most of the genetic variability in warfarin dose among Caucasians. In the current paper we focus on this subject in view of our experience gained during molecular genetic tests for the main VKORC1 haplotypes in Hungarian patients with anticoagulant therapy and unusual clinical response. A total of 28 selected cases were characterized for VKORC1 G-1639A, G9041A and C6009T alleles. Genotyping has been carried out by molecular biology techniques, including PCR-RFLP assay and direct sequencing. In patients undergoing anticoagulant therapy we could identify VKORC1 *1*2, *2*2, *2*3, *1*4, *2*4 and *3*4 haplotypes. Patients with A haplotype group (14% of the studied patients) require much lower warfarin doses than other patients (2.7+/-0.2 mg/day). In our patients we found some with B haplotype group (25%) who require high warfarin dose (6.2+/-0.3 mg/day). There were also subjects bearing the A/B haplotype group (61%) with intermediate warfarin dose (4.9+/-0.2 mg/day), estimated by the haplotype analyses of the VKORC1 gene. Results presented here underline the need of VKORC1 haplotyping in anticoagulated patients with unusual clinical anticoagulant response, and the examination can have further therapeutic consequences.     

Biological Monitoring of Bisphenol A in a Korean Population

To conduct proper biological monitoring of environmental exposure to bisphenol A (BPA), the variation in host susceptibility need to be investigated. For this purpose, we studied effects of genetic polymorphism in sulfotransferase (SULT) 1A1 on urinary BPA, a biomarker for BPA exposure, in 73 Koreans (male, 34; female, 39; age, 48.9 ± 11.9 yrs). We used reverse phase-HPLC/FD for analysis of urinary BPA and obtained information from each subject on lifestyle, environment, and potential exposure to BPA via food. The HPLC/FD method showed good reproducibility (CVs < 0.1) and a relatively sensitive detection limit of 0.012 μg/L. These methods yielded a geometric mean of urinary BPA as 9.54 μg/L (8.91 μg/g creatinine), with a geometric standard deviation of 8.32 μg/L. Among potential routes for BPA exposure, only “vinyl wrapping of microwave heating” indicated a borderline positive association with urinary BPA level (p = 0.1). After PCR-RFLP, we found the allele frequencies of SULT1A1*1 and SULT1A1*2 were 0.89 and 0.11, respectively within the subjects. As the SULT1A1*1 allele of SULT1A1 is known to be a rapid sulfonylation-allele, the presence of SULT1A1*1 is suspected to rapidly dispose of environmental BPA. However resultant, urinary BPA levels were not significantly different between the SULT1A1*1/*1 identified subjects and the SULT1A1*1/*2 subjects. Therefore, to clarify host variability in urinary BPA level, different genetic polymorphisms in BPA metabolic enzymes other than SULT1A1 should be further studied. Received: 21 June 2002/Accepted: 29 October 2002     

Genetic polymorphism of alcohol dehydrogenase 3 in alcohol liver cirrhosis and in alcohol chronic pancreatitis

AIM: To find the ADH3 genotypes in the Polish population likely to be responsible for higher susceptibility to alcohol disease of the liver and chronic alcohol pancreatitis. METHOD: The ADH3 genotype and ADH3*1 and ADH3*2 alleles frequencies were examined in 198 patients. Genotyping of the ADH3 was performed using PCR-restriction fragment length polymorphism methods on a white cell DNA. RESULTS: The genotype ADH3*1/ADH3*1 was found to be significantly more frequent in alcohol abusers compared with non-drinkers. The examinations of the group of alcohol abusers showed that the genotype ADH3*2/ADH3*2 occurred statistically significantly less frequently in patients with chronic pancreatitis than in those without alimentary lesions (healthy drinkers). The alleles ADH3*1 and genotype ADH3*1/ADH3*1 were significantly more frequent in men than in women, whereas alleles ADH3*2 and genotype ADH3*2/ADH3*2 were more common in women. CONCLUSIONS: The genotype ADH3*2/ADH3*2 is likely to be a protective factor for chronic pancreatitis. Variations in ADH3 genotypes may account for some of the differences in prevalence of alcohol dependence between genders in the Polish population.     

Male urinary incontinence

*Urinary incontinence in males is gaining increasingly more attention. *Male urinary incontinence can be classified as storage incontinence due to overactive bladder syndrome or stress incontinence due to urethral sphincter dysfunction. *Most patients benefit from the currently available treatment options for overactive bladder, which include physiotherapy, medication, botulinum A toxin injections and neuromodulation techniques. *The number of radical prostatectomies performed for prostate cancer is increasing; this intervention can lead to stress incontinence due to sphincter weakness. *Various treatment options are available for stress incontinence due to sphincter weakness. *In addition to physiotherapy, treatment options also include the artificial urinary sphincter, which has been available for decades. *New treatments include para-urethral balloons and male slings. The value of these approaches must be proven in the coming years.     

You'll need this data on patient QI involvement

* Patients should be included in hospital committees and advisory boards. * Including patients in quality improvement is a new trend in health care. * Outcomes data should be collected to determine the impact of patients' involvement.     

An integrative framework for HIPAA-compliant I*IQ healthcare information systems

Currently the healthcare industry in the US is not only contending with relentless pressures to lower costs while maintaining and increasing the quality of service but is also under a stringent timeline to become compliant with the health insurance, portability and accountability act (HIPAA) regulatory requirements. Robust healthcare information systems (HCIS) become critical to enabling healthcare organizations address these challenges. Hence, it becomes an imperative need that the information that is captured, generated and disseminated by these HCIS be of the highest possible integrity and quality as well as compliant with regulatory requirements. This paper addresses this need by proposing an integrative framework for HIPAA compliant, I*IQ HCIS. It bases this framework on an integration of the requirements for HIPAA compliance, the principles of information integrity, as well as the healthcare quality aims set forth by the Committee on the Quality of Healthcare in America.     

Effects of rotavirus NSP4 protein on the immune response and protection of the SR69A-VP8* nanoparticle rotavirus vaccine

Rotavirus causes severe diarrhea and dehydration in young children. Even with the implementation of the current live vaccines, rotavirus infections still cause significant mortality and morbidity, indicating a need for new rotavirus vaccines with improved efficacy. To this end, we have developed an S_R69A-VP8*/S₆₀-VP8* nanoparticle rotavirus vaccine candidate that will be delivered parenterally with Alum adjuvant. In this study, as parts of our further development of this nanoparticle vaccine, we evaluated 1) roles of rotavirus nonstructural protein 4 (NSP4) that is the rotavirus enterotoxin, a possible vaccine target, and an immune stimulator, and 2) effects of CpG adjuvant that is a toll-like receptor 9 (TLR9) ligand and agonist on the immune response and protection of our S_R69A-VP8*/S₆₀-VP8* nanoparticle vaccine. The resulted vaccine candidates were examined for their IgG responses in mice. In addition, the resulted mouse sera were assessed for i) blocking titers against interactions of rotavirus VP8* proteins with their glycan ligands, ii) neutralization titers against rotavirus replication in cell culture, and iii) passive protection against rotavirus challenge with diarrhea in suckling mice. Our data showed that the Alum adjuvant appeared to work better with the S_R69A-VP8*/S₆₀-VP8* nanoparticles than the CpG adjuvant, while an addition of the NSP4 antigen to the S_R69A-VP8*/S₆₀-VP8* vaccine may not help to further increase the immune response and protection of the resulted vaccine.     

The succession procedure for interim analysis: Extensions for early acceptance of h0 and for flexible times of analysis

The succession procedure is a new method for group sequential analysis based on a succession of significant tests. In this paper, the procedure is extended by the addition of a lower boundary, which allows the early acceptance of the null hypothesis H₀ according to the stochastic curtailing approach. The succession procedure is also adapted to the type I error spending rate function α*(t), leading to the method of semisequential analysis for which the times of analysis need not be specified in advance.     

肠外营养与肠内营养的比较

Summary Inappropriate emphasis has been given to conflictingcamps in the debate over enteral nutrition versus parenteral nutrition.It is not a question of one or the other,but a question of finding the right balance between parenteral and enteral nutrition using both EN and PN to achieve the daily caloric needs of the patient.Not uncommonly,paitents receive inadequate nutrition support during the ramp-up of enteral feedings over several days under the perception that parenteral nutrition carries a high risk of complications,and therefore should be avoided.Properly administered parenteral nutrition is both safe and effective,especially when used with a “background patter”of enteral nutrition.Just a small amount of enteral nutrition significantly reduces the potential complications from parenteral nutrition associated with lack of gut barrier function and inadequate stimulation of the enteral-hepatic circulation.A small amount of background enteral nutrition paves the way for safe administration of apropriate parenteral nutrition to meet the caloric needs and achieve the necessary macro-and micro-nutrient balance to accelerate the recovery of medical and surgical patients otherwise suffering from nutritional compromise.Ⅰ.PN vs.EN Not either-or,but…BOTHⅡ.Risk Factors for EN*Mechanical*Septic*Obtunded patient*Gastroparesis*Frequently occurs for 1-3 days post op*More common and severe with diabetes*Uneven GI function*Stomach-jejunum-ileum-colon*Improperly placed feeding tube*Naso-gastric*Naso-jejunal*Importance of decompressing the stomach*Acquired lactase deficiency*Diarrhea*Constipation*Mechanical-related to insertion and maintenance of IV line*Septic-related to sterile technique,potential for bacterial contamination*Metabolic-issues of fluid balance and nutrition:electrolytes,fat,carbohydrate,protein,vitamins,trace elementsⅢ.Goals *Maintain appropriate level of nutrition support*Avoid complicationsⅣ.Keys to Success *Nutritional Assessment*Keep it simple*Base line*Ongoing*Understand the physiologic state of your patient*If the gut works.use it!*Give a combination of PN and EN*“Mix and Match”*Team approach:*One person in charge*Transition from PN to EN Ⅴ.Transition from PN to EN (see graph)Ⅵ.Pearls for PN *Protocol approach*Sterile technique*Expert line placement*Disciplined line-dressing changes*20-50% of daily calories as fat*Use only 20% lipid emulsion*Use MCT/LCT fat emulsion if available*Always give some ENAs little as 1-2cc/hr provides physiologic protection *Healthy gut with mucous production:minimizes bacterial translocation*Entero-hepatic circulation:minimizes fatty liver and cholestasis*Administer fat and blucose-amino acid solutions together*Add 1 IU/cc heparin to glucose-amino acid solution*Restrict osmolarity to <600 mosm*Ongoing fever work up*Ongoing global assessmentEN and PN *Set nutritional therapy goal*Give “background patter”of EN*Give the balance of calories-electrolytes-vitamins-trace elements as PNⅦ.Keep it Physiologic Keep it Simple     

矽肺与人类白细胞抗原-DRB1·和-DQB1·基因相关性的研究

目的 探讨我国北方汉族人矽肺的易感性与人类白细胞抗原（HLA）－DRB1＊、DQB1＊位点等位基因多态的相关性。方法 用序列特异性引物的聚合酶链式反应（PCR－SSP）方法，分析48名汉族矽肺患者及100名汉族无血缘关系对照者（均为有过14年以上接尘史的井下凿岩工）HLA－DRB1＊、DQB1＊位点的基因频率分布，以相对危险度（RR）代表相关程度。结果 在矽肺患者组中，DRB1＊1401、DQB1＊05的等位基因频率明显高于对照组，经统计学处理，两组间差异具有显著性（χ^2=5.61,P=0.0066,RR=17.40;χ^2=10.70,P=0.0011,RR=3.81)；而DRB1＊09的等位基因频率则明显低于对照组，差异有显著性（χ^2=5.70,P=0.0187,RR=0.21)；其他等位基因频率的分布差异无显著性（P＞0．05）。结论 HLA－DRB1＊1401、DQB1＊05可能与矽肺的易感性有关，而DRB1＊09则可能与机体抗矽肺的保护性有关。HLA－DR位点与机体易感及保护的双重作用有关，等位基因之间的共同作用可能是影响矽肺发生的原因之一。     

Nonfunctioning pituitary macroadenomas: diagnosis, treatment and follow-up

*Nonfunctioning pituitary adenomas are benign tumours characterised by the absence of hormone overproduction. *Clinical symptoms are caused by the mass effects of the tumour. The main symptoms are pituitary insufficiency, visual field defects, vision impairment and headache. *Treatment is unnecessary for tumours less than 1 cm, and an expectative approach can be used for some patients with larger tumours but no visual field defects. *Transsphenoidal surgery is indicated for patients with visual field defects. *Because nonfunctioning adenomas can recur, lifelong follow-up after treatment is necessary. *Poor quality of life has been reported in treated patients with nonfunctioning pituitary adenomas, which may be due to the intrinsic imperfections of hormonal replacement therapy.     

The integration ladder: a tool for curriculum planning and evaluation

Integration has been accepted as an important educational strategy in medical education. Discussions about integration, however, are often polarized with some teachers in favour and others against integrated teaching. This paper describes 11 points on a continuum between the two extremes. * Isolation * Awareness * Harmonization * Nesting * Temporal co-ordination * Sharing * Correlation * Complementary * Multi-disciplinary * Inter-disciplinary * Trans-disciplinary As one moves up the ladder, there is less emphasis on the role of disciplines, an increasing requirement for a central curriculum, organizational structure and a requirement for greater participation by staff in curriculum discussions and planning. The integration ladder is a useful tool for the medical teacher and can be used as an aid in planning, implementing and evaluating the medical curriculum.     

CMS proposes a vast expansion of its quality measures program

* They may be called 'never' events, but not all of them are preventable. * Quality managers will have to 'staff up' to meet new CMS requirements. * Even electronic documentation systems may require some re-tooling.     

ADH1B与ALDH-2基因多态性与中国人群食管癌发病风险的Meta分析

目的探讨中国人乙醇脱氢酶1B(ADH1B)和乙醛脱氢酶-2(ALDH-2)的基因多态性与食管癌发病风险的关系。方法检索中外文数据库,获得有关ADH1B和ALDH-2位点的多态性与食管癌发病风险的病例-对照研究资料,对各位点以及与饮酒的交互作用进行Meta分析,得到合并的OR值及其95%CI。结果等位基因ADH1B*1和ALDH-2*2可增加食管癌的发病风险。基因型ADH1B*1/*2和ADH1B*1/*1的OR值分别为1.24(95%CI 1.10-1.41)和3.05(95%CI 1.94-4.77);基因型ALDH-2*1/*2和ALDH-2*2/*2的OR值分别为1.6(95%CI 1.01-2.03)和0.77(95%CI 0.28-2.09)。在饮酒人群中,与基因型ADH1B*2/*2相比,ADH1B*1/*2+*2/*2的OR=3.13(95%CI 2.17-4.51);与基因型ALDH-2*1/*1相比,ALDH-2*1/*2+*2/*2的OR=4.12(95%CI 1.98-8.56)。结论在中国人群中,等位基因ADH1B*1和ALDH-2*2均能增加食管癌患病的风险,且饮酒可以增加这一风险。     

Major histocompatibility complex class II polymorphisms and risk of cervical cancer in Puerto Rican women

Association between HLA antigens and cervical squamous cell carcinoma has been described in several populations. To verify whether HLA-DRB1 and DQB1 diversity is related to cervical cancer in Puerto Rican women, 40 cases and 50 controls were HLA typed. DRB1*16 (POR=2.89) and DRB1*11 (POR=1.74) were positively associated with cervical cancer. A negative association was found with DRB1*01 (POR=0.52), DRB1*04 (POR=0.60), DRB1*14 (POR=0.33), DRB1*15 (POR=0.65), DQB1*04 (POR=0.33), DQB1*05 (POR=0.64) and DQB1*06 (POR=0.65). We suggest that HLA Class H polymorphisms are involved in genetic susceptibility to cervical cancer in Puerto Rican women. These results should be confirmed in studies with larger sample size to preclude the possibility of false positive observations.     

Use proven strategies for error disclosure to patients

* Workforce needs to be prepared and to deliver effective error disclosure. * At Baylor, quality, safety, and risk management are involved in error disclosure. * Quality professionals should get to the bottom of the problem.