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PubMed2005

Prediction of individual clinical outcome in MCI by means of genetic assessment and (18)F-FDG PET.

UNLABELLED: Patients with mild cognitive impairment (MCI) represent a risk population for progressing to dementia of the Alzheimer type (DAT). However, clinical criteria do not ensure reliable individual prognosis in these patients. The objective of this longitudinal, prospective study was to examine the value of (18)F-FDG PET of cerebral glucose metabolism and of genetic susceptibility, as defined by an APOEepsilon4-positive genotype, with regard to the early diagnosis of DAT in patients with MCI. METHODS: In 30 patients with the diagnosis of MCI (16 female, 14 male; age, 70 +/- 8 y), baseline and follow-up examinations (mean observation period, 16 mo) were performed. In all patients, the APOE genotype was assessed and cerebral glucose metabolism was evaluated at baseline using cranial (18)F-FDG PET. Individual PET data were screened for findings suggestive of Alzheimer's disease (AD), with the help of an automated computer program. After stereotactical normalization of the PET images, this program performs an observer-independent statistical comparison with an age-matched reference database (n = 22). RESULTS: In 43% of all MCI subjects, a PET scan suggestive of AD pathology according to our predefined criteria was observed at baseline (PET+); 57% of all MCI patients were carriers of the APOE epsilon4 allele (e4+). In 40% of all patients, progression of symptoms within the observation period justified the clinical diagnosis of probable DAT at the time of follow-up reevaluation. Statistical evaluation revealed the best results for PET with regard to early diagnosis of DAT in MCI patients (sensitivity, 92%; specificity, 89%). Classification according to the APOE genotype was significantly less successful (sensitivity, 75%; specificity, 56%). However, a combination of both diagnostic tests allowed early diagnosis with either very high specificity (PET+ AND e4+: sensitivity, 67%; specificity, 100%) or very high sensitivity (PET+ OR e4+: sensitivity, 100%; specificity, 44%). CONCLUSION: (18)F-FDG PET of cerebral glucose metabolism is a valuable diagnostic tool for the prediction of clinical outcome in individual MCI patients. Results are superior to the exclusive assessment of the APOE genotype. A combination of both functional imaging and genotyping may allow an early high-risk or low-risk stratification of patients with either very high sensitivity or very high specificity. This may be valuable, for example, for patient selection in scientific studies.

Aged↗

PubMed2005

The effects of prescription drug cost sharing: a review of the evidence.

OBJECTIVES: To determine whether patients respond to increased cost sharing by substituting less expensive alternatives for medications with higher levels of copayments or coinsurance, and to examine the body of evidence on the relationships between cost sharing and use of essential or maintenance medications, health outcomes, process-of-care measures (such as medication adherence and discontinuation), and costs. STUDY DESIGN: Literature review. METHODS: Healthcare reference databases and key journals were searched to identify peer-reviewed empirical studies that examined the effects of variation in the amount of prescription drug copayments or coinsurance on healthcare utilization patterns. Thirty studies met our search criteria. RESULTS: Higher levels of prescription drug cost sharing generally produce intended effects, namely, decreasing the consumption of prescription drugs and steering patients away from nonpreferred to preferred brand-name drugs. However, patients do not always switch to generic drugs. Although not consistently reported, the most troublesome effects associated with higher levels of cost sharing are treatment disruptions (such as lower levels of treatment adherence, continuation, and initiation) for chronically ill patients. At times, higher levels of cost sharing can affect the use of essential medications and outcomes of care. CONCLUSIONS: Cost sharing reduces the consumption of prescription drugs but may have unintended effects on the process and outcomes of therapy. Further research is warranted in this area. The central question for health plan managers and policy makers is whether we will continue to use cost sharing as is or make modifications to reduce unintended effects.

Choice Behavior↗

PubMed2005

Optimisation of statistical methodologies for a better diagnosis of neurological and psychiatric disorders by means of SPECT.

In the last years there has been a wide consensus on the importance of brain imaging in assessing neurodegenerative and psychiatric disorders. Different techniques for functional and anatomical examination are currently clinically implemented in neurology and psychiatry to improve sensitivity, specificity and accuracy of the diagnosis of various diseases. In addition, the increasing life expectancy in the Western world raises the social importance and the economical impact of age-related neurodegenerative disorders since the incidence of Alzheimer disease and Parkinson disease is higher in the elderly. An early diagnosis of neuro-psychiatric diseases and the assessment of "natural" changes of regional cerebral blood flow (rCBF) distribution during normal aging are hence of utmost importance. In the recent past brain disorders have extensively been investigated by means of optimised nuclear medicine techniques, instruments and algorithms. Diagnosis can be better achieved by identifying those structures in which CBF or metabolism deviate from normality resulting in significant changes as compared to a reference database. In the present paper we present some studies investigating, by means of recently implemented diagnostic tools, patients bearer of various neuro-psychiatric disorders. The improved nuclear medicine techniques and instrumentation, the state-of-the-art software for brain imaging standardisation and the use of sophisticated multivariate data analysis are extensively reviewed.

Algorithms↗

PubMed2005

Quantitative morphometric analysis of vertebral fracture severity in healthy Thai (women and men).

The vertebral morphometry and severity of fracture were studied in normal healthy Thais (602 women and 74 men) Their mean (+/-SD) age was 41.4 (+/- 8.7) years, ranging from 20-81 years. A standard lateral thoraco-lumbar (T-L) spine radiograph was done by centering the X-ray at L1. Vertebral heights (anterior: Ha, middle: Hm and posterior: Hp), disc height (Hd) and 4 vertebral ratios (anterior wedging: Ha/Hp, central wedging: Hm/Hp, vertebral body index: Hm/Hd and spine score: Hm/Ha) of T10-L3 were assessed. Degree of severity of anterior and central wedging fracture was derived to mild, moderate and severe fracture ratios (0.80-0.89, 0.70-0.79 and < 0.70, respectively). In Thai females, anterior and central wedging significantly changed at T11 after the 40-49 age group, while spine score markedly declined at L2-L3 after the 30-39 age group. The change of vertebral body index was not seen. The overall (T10-L3) mean of all ratios of women aged <50 years were more than that of those aged > or = 50 years (p < 0.05). No statistical change of the above ratios was seen at any levels of the spine in males (p > 0.05). The prevalence of mild and moderate degree of anterior vertebral fracture was 22.76% and 0.50% in females and 25.68 and 0% in males. Percentage of mild and moderate degree of central vertebral fracture was 66.61 and 1.00 in females and 68.92 and 1.35 in males. The prevalence of anterior and central compression fracture in females and males who were aged > or = 50 years were higher than those aged <50 years. No severe degree of anterior and central vertebral fracture was detected in both sexes. 407 young adults mean (20-40 years) of the 4 ratios at T10-L3 were also surveyed and calculated for Thai reference databases. The prevalence of the 4 ratios below young adult mean 1, 1.5, 2, 2.5 and 3 SDs in males were greater than in females. In the older age groups, the percentage of females and males who had a mean ratio below young adult mean was much more than that in the younger age groups. In screening of spinal osteoporosis, the authors suggested that the age after 40 years of populations should be x-rayed and spinal radiograph should have an observed focus at T11, L2 and L3.

Absorptiometry, Photon↗

PubMed2006

Pharmacotherapy for post-traumatic stress disorder - a systematic review and meta-analysis.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a prevalent and disabling condition. Evidence that PTSD is characterized by specific psychobiological dysfunctions has contributed to a growing interest in use of medication in its treatment. OBJECTIVES: To assess the effects of medication in the treatment of PTSD. DESIGN: Systematic review of randomised controlled trials (RCTs) following the Cochrane Collaboration guidelines. A more detailed version of the review is published in the Cochrane Database of Systematic Reviews. METHODS: We searched the Cochrane Depression, Anxiety and Neurosis Group specialised register, the Cochrane Central Register of Controlled Trials (Cochrane Library issue 4, 2004), MEDLINE (January 1966 - December 2004), PsycINFO (1966 - 2004), the National PTSD Center Pilots database, and the meta register module of the Controlled Trials database. Reference lists of retrieved articles were searched for additional studies. Two raters independently assessed RCTs for inclusion in the review, collated trial data, and assessed trial quality. Investigators were contacted to obtain missing data. Summary statistics were stratified by medication class, and by medication agent for the selective serotonin re-uptake inhibitors (SSRIs). Dichotomous and continuous measures were calculated using a random effects model, heterogeneity was assessed, and subgroup/sensitivity analyses were done. MAIN RESULTS: Thirty-five short-term (14 weeks or less) RCTs were included in the analysis (4 597 participants). Symptom severity for 17 trials was significantly reduced in the medication groups, relative to placebo (weighted mean difference (WMD) = -5.76, 95% confidence interval (CI)-8.16 - -3.36, N = 2 507). Similarly, summary statistics for responder status from 13 trials demonstrated overall superiority of a variety of medication agents compared with placebo (relative risk (RR) = 1.49, 95% CI: 1.28, 1.73, number needed to treat (NNT) = 4.85, N = 1 272). Medication and placebo response occurred in 59.1% (N = 644) and 38.5% (N = 628) of patients, respectively. Of the medication classes, evidence of treatment efficacy was most convincing for the SSRIs. Medication was also effective in reducing the severity of the PTSD re-experiencing/intrusion, avoidance/numbing, and hyperarousal symptom clusters in 9 trials (N = 1 304). In addition, medication was superior to placebo in reducing comorbid depression and disability. Medication was also less well tolerated than placebo. A narrative review of the 3 maintenance trials suggested that long-term medication may be required in treating PTSD. CONCLUSION: Medication treatments can be effective in treating PTSD, acting to reduce its core symptoms, as well as associated depression and disability, and should be considered as part of the treatment of this disorder. The findings of this review support the status of SSRIs as first-line agents in the pharmacotherapy of PTSD, as well as their value in longterm treatment. However, there remain important gaps in the evidence base, and there is a continued need for more effective agents in the management of PTSD.

Clinical Trials as Topic↗

PubMedDate not supplied

Ultrastructural morphometric data of human spermatozoa.

A morphometric study of the volumetric parameters of human spermatozoa has been carried out, volume densities being obtained by point counting and converted to absolute volumes by employing the point-sampled intercept method. Data for the Spermatozoa from the semen of 15 recently fertile men are presented. The significance of the results is discussed in relation to results obtained by other methods and in relation to the building of a diagnostic reference database.

Humans↗

PubMed1994

On-line information sources on chemical substances.

Information technology has brought about changes in the work patterns of researchers and scientists. After some hints on the on-line facilities needed to be connected to the international host computers, an analysis is made of some of the main automated sources available to retrieve information on chemical substances. Special emphasis is given to textual-numeric data banks, first reviewing the main chemical dictionaries, like Registry and Chemline, and then focusing on those sources that offer immediate information in case of emergency. Among the Toxnet files, produced and managed within the US National Library of Medicine Toxicology Information Program, play a very important role in offering publicly available data on toxicology and on hazardous chemicals. Therefore, the Hazardous Substances Data Bank (HSDB) and the Registry of Toxic Effects of Chemical Substances (RTECS) are described for their relevance thereon. Other data banks produced in Europe, like the Environmental Chemicals Data Information Network (ECDIN) and the very specialized Major Hazard Incident Data Service (MHIDAS) are also briefly outlined. To integrate this overview on online information, the attention is then shifted on sources having the characteristic of reference databases: prestigious files covering the international scientific literature, as CA/Chemabs, Toxline/Toxlit, Embase, Medline are introduced. Implications of on-line technology in enhancing information access in the next future are discussed, pointing out the new tools created to meet the information needs of end-users.

Databases, Bibliographic↗

PubMed1994

Medical data capture and display: the importance of clinicians' workstation design.

The Department of Veterans Affairs is developing, testing and evaluating the benefits of physicians' workstations as an aid to medical data capture in an outpatient clinic setting. The physician's workstation uses a graphical user interface to aid the clinician in recording encounter data. Various input devices including keyboard, mouse, pen, voice, barcode reader, and tablet are available on the workstations, and user preferences will be examined. Access to general services such as electronic mail and reference databases is also available. The workstation provides a wide variety of patient specific data from the hospital information system, including image data. The single data collection process by the clinician will also provide data for the cost recovery process.

Computer Peripherals↗

PubMed1993

Refractive error distribution and incidence among U.S. Army aviators.

Spectacle incompatibility has been a major problem in the fielding of advanced Army avionic and electro-optical systems. As a result, routine contact lens wear may be instituted as an option to spectacles. Refractive error data were extracted from the Aviation Epidemiological Data Registry, a computer-accessible repository of flight physical medical information on the entire Army aviation population. Refractive error distribution patterns in the class 1 and class 2 flight physical populations were analyzed in order to provide a contact lens supply reference database, estimate the annual incidence of refractive error development, and estimate costs of possible spectacle-wearer flight-duty deselection. Contact lens wear appears to be a more cost-effective alternative than deselection.

Aerospace Medicine↗

PubMed1996

Quality assurance of autopsy permit form information, timeliness of performance, and issuance of preliminary report. A College of American Pathologists Q-Probes study of 5434 autopsies from 452 institutions.

OBJECTIVE: To develop a multi-institutional reference database of autopsy practices and performance for quality improvement purposes. DESIGN: In 1992, participants in the Q-Probes quality improvement program of the College of American Pathologists each prospectively evaluated consecutive autopsies performed over a 6-month period, up to a maximum of 20 autopsies per institution. SETTING: Hospital-based autopsies, excluding forensic cases and stillborn infants. PARTICIPANTS: Four hundred forty-nine North American institutions and three Australian laboratories. MAIN OUTCOME MEASURES: Completeness of information contained on autopsy permit forms, timeliness of autopsy performance between patients' deaths and autopsy prosections, and turnaround time of preliminary autopsy reports. RESULTS: In the aggregate database of 5434 autopsy cases, 7 of 11 selected data items were consistently present on autopsy permit forms in 80% of the participating institutions. The median percentage of autopsies in which permission was given for an unrestricted (complete) autopsy was 71%. The following median time intervals were obtained: time of the patient's death to time the autopsy permission was received, 5 hours, 23 minutes; time the autopsy permission was received to time the prosection was started, 3 hours, 30 minutes; and time of the patient's death to time the prosection was started, 14 hours, 52 minutes. Differences were observed in some time intervals when the participating institutions were grouped by reported demographic characteristics. Preliminary reports were completed in 2 days or less in 80.9% of the autopsies. CONCLUSIONS: Through this multi-institutional study, we have documented a consistent core of autopsy permit form information requested and a wide range of time intervals elapsed between the patients' deaths and autopsy performance. We have also established that the majority of participating institutions meet the College of American Pathologists' laboratory accreditation standard of providing a documented preliminary report of the gross pathologic diagnoses submitted to the attending physicians and institutional record within 2 working days following autopsy completion.

Autopsy↗

PubMedDate not supplied

Upper urinary tract stone analysis using X-ray diffraction: results from a tertiary referral centre in northern India.

BACKGROUND: The spectrum of urinary stone disease has changed considerably in India from the common childhood bladder stone to the more frequent upper tract calculi. We analysed the gravel retrieved from the upper urinary tract using X-ray diffraction analysis in an attempt to evaluate the composition of the stones. METHODS: We analysed 434 upper urinary tract calculi from May 1993 to June 1994 obtained endourologically, as well as by extracorporeal shock wave lithotripsy and open surgery. The stones were analysed using a Phillips compact X-ray diffractometer (PW1840). The PC-APD software was used for data collection and peak search. The phase matching was done by the software using the JCPDS reference database. RESULTS: Oxalate stones comprised 97% of the total stones with calcium oxalate monohydrate forming 90% and calcium oxalate dihydrate and mixed stones forming the remainder. Struvite stones were found in 1.4%, while uric acid and apatite stones were less than 1%. There were no cystine calculi. Seventy per cent of calcium oxalate monohydrate and 40% of calcium oxalate dihydrate stones were pure. All the struvite and apatite calculi were almost pure. Only 15% of staghorns did not consist of oxalate. Nine of the ten stones in children were of the calcium oxalate monohydrate variety. The stone composition in females was similar to that in males. CONCLUSIONS: X-ray diffraction data indicate that urinary stone disease in north India is different from that in the western world. Calcium oxalate monohydrate stones predominate. These stones are hard to break and have a different metabolic origin from those consisting of calcium oxalate dihydrate. These findings might help in selecting the most appropriate method of treatment in north India and they indicate directions in which further metabolic studies might be planned.

Adolescent↗

PubMed1986

Microcomputers and biologists.

Microcomputers have now become a working tool of the biologist. This article explores some of the consequences of this revolution both in terms of the skills and working habits needed and of the range of uses which have been found. The primary consequence is that biologists must learn how to become computer managers. This does not mean learning BASIC and computer architecture, though this will usually prove valuable, but that we must be able to grasp from the flood of sales literature and computer specialists what tasks can or should be undertaken with the aid of microcomputers. Secondly it means being able to choose and maintain the right machinery for the tasks needed. An overview of applications shows four main areas of use. 1) The standard packages where one can expect the computer manufacturer to provide a complete working system. These are word-processing, database reference systems, spreadsheet calculations, graphics production and communications. 2) Specialist scientific programs such as statistics, data processing and model making. 3) The use of the microcomputer as a laboratory instrument for control or measurement. 4) Educational applications. Each of these areas has separate, often conflicting, requirements which can only be balanced by the user.

Audiovisual Aids↗

PubMed1996

Quality assessment in anatomic pathology in the cost-conscious era.

In this cost-conscious era, quality assessment activities in anatomic pathology are required not only to assure that quality practices result in satisfaction of accreditation standards but also to focus quality management to improve services in an economically competitive manner. Selected high yield monitoring activities that provide comparison to reference databases for benchmarking performance and adoption of practice variables effective in the best laboratories are recommended.

Autopsy↗

PubMed1996

Conservative management of mechanical neck pain: systematic overview and meta-analysis.

OBJECTIVE: To review the efficacy of conservative management of mechanical neck disorders. METHODS: Published and unpublished reports were identified through computerised and manual searches of bibliographical databases, reference lists from primary articles, and letters to authors, agencies, foundations, and content experts. Selection criteria were applied to blinded articles, and selected articles were scored for methodological quality. Effect sizes were calculated from raw pain scores and combined by using meta-analytic techniques when appropriate. RESULTS: Twenty four randomised clinical trials met the selection criteria and were categorised by type of intervention: nine used manual treatments; 12 physical medicine methods; four drug treatment; and three education of patients (four trials investigated more than one form of intervention). The intervention strategies were summarised separately. Pooling of studies was considered only within each category. Five of the nine trials that used manual treatment in combination with other treatments were combined. One to four weeks after treatment the pooled effect size was -0.6 (95% confidence interval -0.9 to -0.4), equivalent to an improvement of 16 (6.9 to 23.1) points on a 100 point scale. Sensitivity analyses on study quality, chronicity, and data imputation did not alter this estimate. For other interventions, studies could not be combined to arrive at pooled estimates of effect. CONCLUSIONS: There is little information available from clinical trials to support many of the treatments for mechanical neck pain. In general, conservative interventions have not been studied in enough detail to assess efficacy or effectiveness adequately.

Anti-Inflammatory Agents↗

PubMed1997

Long-term survival after hepatic cryosurgery versus surgical resection for metastatic colorectal carcinoma: a critical review of the literature.

OBJECTIVE: To critically assess the evidence for long-term survival after hepatic resection and hepatic cryosurgery for metastatic colorectal cancer. The purpose of this review is to determine if a randomized controlled trial comparing these two treatment modalities is justified. DATA SOURCES: A review of the medical literature from 1973 to 1995 using the MEDLINE and CANCERLIT databases. References were also retrieved from the bibliographies of identified articles and from experts in the field of hepatobiliary and pancreatic surgery. STUDY SELECTION: One hundred and seventy-eight studies were reviewed. Studies presenting original data on the results of hepatic resection or cryotherapy for colorectal liver metastases were selected. Studies were excluded if they did not present survival data longer than 2 years. Studies pertaining to resection for fewer than 60 patients with colorectal metastases to the liver were excluded. DATA EXTRACTION: Data forms were designed before studies were examined in detail. All studies that met the inclusion and exclusion criteria were reviewed and the identified data extracted and tabulated. DATA SYNTHESIS: No controlled studies were identified, only case series. Four reports on hepatic cryosurgery and 9 on hepatic resection met the study criteria. The cryosurgery studies were methodologically poor; the resection studies were larger and more methodologically sound. The median follow-up for cryosurgery ranged from 12 to 28.8 months, that for resection 21 to 69 months. There is clear evidence that hepatic cryosurgery has a role in the management of selected patients with colorectal metastases to the liver. However, valid conclusions cannot be made about the 5-year survival rate. The results of the studies on hepatic resection in patients with colorectal metastases to the liver have greater validity and consistency, with 5-year survival rates of 20% to 40%. CONCLUSIONS: Although hepatic cryosurgery offers some unequivocal and other potential advantages over surgical resection for colorectal metastases to the liver, the published data do not support its use in patients with resectable disease outside a clinical trial, and do not yet justify a randomized trial. A study that collects prospective data on 2 groups of patients (resectable v. unresectable) who differ only in the anatomic location of their metastases within the liver is needed.

Carcinoma↗

PubMed1997

Quantitative assessment of cerebral blood flow in patients with Alzheimer's disease by SPECT.

UNLABELLED: This study evaluated an automated analysis of SPECT brain imaging in patients with Alzheimer's disease (AD). METHODS: Patients [n = 81; mean age, 69.9 +/- 10.6 yr (mean +/- s.d.)] with a clinical diagnosis of probable AD (NINCDS-Alzheimer's Disease and Related Disorders Association criteria) underwent 99mTc-ethyl cysteine dimer SPECT imaging. After imaging registration and data extraction using three-dimensional stereotactic surface projections, a pixel-wise comparison of ethyl cysteine dimer uptake was performed using a reference database of 10 cognitive intact controls of comparable age. RESULTS: When individual cases were compared to the normal database, temporo-parietal regional cerebral blood flow (rCBF) abnormalities across different levels of dementia severity were clearly depicted on pixel-wise Z-score images. The rCBF reduction in cortical association areas showed a significant correlation with an overall level of cognitive decline, as assessed by the Mini Mental State Examination and by the cognitive section of the Cambridge Mental Disorders of the Elderly Examination. In addition, there were significant region-specific correlations between left temporo perfusion deficit and language performance and between right parietal rCBF reduction and praxis. CONCLUSION: These results indicate that this observer-independent analysis of SPECT data enables objective and semiquantitative assessment of the magnitude and extent of cortical perfusion abnormalities in patients with AD.

Alzheimer Disease↗

PubMed1997

Genomic structure and genetic mapping of the human neutral cysteine protease bleomycin hydrolase.

Bleomycin hydrolase (BH) is the only known eukaryotic enzyme that inactivates the widely used antineoplastic agent bleomycin (BLM) and is a primary candidate gene for protection against lethal BLM-induced pulmonary fibrosis and for BLM resistance in tumors. Human BH was found to exist as a single gene that was mapped to chromosome 17 using National Institute of General Medical Sciences human/rodent hybrid mapping panels and localized to 17q11.1-11.2 by linkage analysis using the Centre d'Etude du Polymorphisme Humain reference database. The human BH gene consisted of 11 exons ranging in size from 69-198 bp separated by introns of approximately 1 kb, reflecting the archetypal genomic structure of the cysteine protease family. A polymorphic site was identified in the eleventh exon at bp 1450 encoding either valine or isoleucine. These findings provide essential tools required to define the role of BH in BLM-induced pulmonary fibrosis and BLM resistance in tumors.

Animals↗

PubMed1997

Screening for fragile X syndrome.

BACKGROUND AND AIM OF REVIEW. In 1991, the gene responsible for fragile X syndrome, a common cause of learning disability, was discovered. As a result, diagnosis of the disorder has improved and its molecular genetics are now understood. This report seems to provide the information needed to decide whether to use DNA testing to screen for the disorder. HOW THE RESEARCH WAS CONDUCTED. A literature search of electronic reference databases of published and 'grey' literature was undertaken together with hand searching of the most recent publications. RESEARCH FINDINGS. NATURAL HISTORY. Physical characteristics of fragile X syndrome include facial atypia, joint laxity and, in boys, macro-orchidism. Most affected males have moderate-to-severe learning disabilities with IQs under 50 whereas most females have borderline IQs of 70-85. Behavioural problems are similar to those seen with autism and attention-deficit disorders. Although fragile X syndrome is not curable there are a number of medical, educational, psychological and social interventions that can improve the symptoms. About 6% of those with learning disabilities tested in institutions have fragile X syndrome. Population prevalence figures are 1 in 4000 in males and 1 in 8000 in females. GENETICS. The disorder is caused by a mutation in a gene on the X chromosome which includes a trinucleotide repeat sequence. The mutation is characterized by hyper-expansion of the repeat sequence leading to down-regulation of the gene. In males an allele with repeat size in excess of 200, termed a full mutation (FM), is always associated with the affected phenotype, whereas in females only half are affected. Individuals with alleles having repeat size in the range 55-199 are unaffected but in females the sequence is heritably unstable so that it is at high risk of expansion to an FM in her offspring. This allele is known as a pre-mutation (PM) to contrast it with the FM found in the affected individual. No spontaneous expansions directly from a normal allele to an FM have been observed. SCREENING STRATEGIES. The principal aims of screenng for fragile X syndrome is to reduce the birth prevalence of the disorder, by prenatal diagnosis and selective termination of pregnancy, or by reducing the number of pregnancies in women who have the FM or PM alleles. Possible screening strategies are: routine antenatal testing of apparently low risk pregnancies, preconceptual testing of young women, and systematic testing in affected families ('cascade' screening). A secondary aim is to bring forward the diagnosis of affected individuals so that they might benefit from early treatment. Active paediatric screening and neonatal screening could achieve this but there is no direct evidence of any great benefit from early diagnosis. SCREENING TESTS. Cytogenetic methods are unsuitable for screening purposes. Southern blotting of genomic DNA can be used but is inaccurate in measuring the size of small PMs, there is a long laboratory turnaround time, and it is relatively expensive. The best protocol is to amplify the DNA using polymerase chain reaction on all samples, and when there is a possible failure to amplify, a Southern blot.(ABSTRACT TRUNCATED)

Costs and Cost Analysis↗