Prevention of postoperative delirium in elderly patients planned for elective surgery: systematic review and meta-analysis.

Introduction: Vulnerable or "frail" patients are susceptible to the development of delirium when exposed to triggers such as surgical procedures. Once delirium occurs, interventions have little effect on severity or duration, emphasizing the importance of primary prevention. This review provides an overview of interventions to prevent postoperative delirium in elderly patients undergoing elective surgery. Methods: A literature search was conducted in March 2018. Randomized controlled trials (RCTs) and before-and-after studies on interventions with potential effects on postoperative delirium in elderly surgical patients were included. Acute admission, planned ICU admission, and cardiac patients were excluded. Full texts were reviewed, and quality was assessed by two independent reviewers. Primary outcome was the incidence of delirium. Secondary outcomes were severity and duration of delirium. Pooled risk ratios (RRs) were calculated for incidences of delirium where similar intervention techniques were used. Results: Thirty-one RCTs and four before-and-after studies were included for analysis. In 19 studies, intervention decreased the incidences of postoperative delirium. Severity was reduced in three out of nine studies which reported severity of delirium. Duration was reduced in three out of six studies. Pooled analysis showed a significant reduction in delirium incidence for dexmedetomidine treatment, and bispectral index (BIS)-guided anaesthesia. Based on sensitivity analyses, by leaving out studies with a high risk of bias, multicomponent interventions and antipsychotics can also significantly reduce the incidence of delirium. Conclusion: Multicomponent interventions, the use of antipsychotics, BIS-guidance, and dexmedetomidine treatment can successfully reduce the incidence of postoperative delirium in elderly patients undergoing elective, non-cardiac surgery. However, present studies are heterogeneous, and high-quality studies are scarce. Future studies should add these preventive methods to already existing multimodal and multidisciplinary interventions to tackle as many precipitating factors as possible, starting in the pre-admission period.

Validation of maternal cardiac output assessed by transthoracic echocardiography against pulmonary artery catheterization in severely ill pregnant women: prospective comparative study and systematic review.

OBJECTIVE: Most severe pregnancy complications are characterized by profound hemodynamic disturbances, thus there is a need for validated hemodynamic monitoring systems for pregnant women. Pulmonary artery catheterization (PAC) using thermodilution is the clinical gold standard for the measurement of cardiac output (CO), however this reference method is rarely performed owing to its invasive nature. Transthoracic echocardiography (TTE) allows non-invasive determination of CO. We aimed to validate TTE against PAC for the determination of CO in severely ill pregnant women. METHODS: This study consisted of a meta-analysis combining data from a prospective study and a systematic review. The prospective arm was conducted in Pretoria, South Africa, in 2003. Women with severe pregnancy complications requiring invasive monitoring with PAC according to contemporary guidelines were included. TTE was performed within 15 min of PAC and the investigator was blinded to the PAC measurements. Comparative measurements were extracted from similar studies retrieved from a systematic review of the literature and added to a database. Simultaneous CO measurements by TTE and PAC were compared. Agreement between methods was assessed using Bland-Altman statistics and intraclass correlation coefficients (ICC). RESULTS: Thirty-four comparative measurements were included in the meta-analysis. Mean CO values obtained by PAC and TTE were 7.39 L/min and 7.18 L/min, respectively. The bias was 0.21 L/min with lower and upper limits of agreement of -1.18 L/min and 1.60 L/min, percentage error was 19.1%, and ICC between the two methods was 0.94. CONCLUSIONS: CO measurements by TTE show excellent agreement with those obtained by PAC in pregnant women. Given its non-invasive nature and availability, TTE could be considered as a reference for the validation of other CO techniques in pregnant women. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. RESUMEN OBJETIVO: Las complicaciones del embarazo más graves se caracterizan por trastornos hemodinámicos serios, debido a los cuales existe la necesidad de sistemas validados de monitorización hemodinámica para mujeres embarazadas. Aunque la cateterización de la arteria pulmonar (CAP) mediante termodilución es el patrón de referencia clínico para la medición del gasto cardíaco (GC), este método se usa con poca frecuencia debido a su naturaleza invasiva. La ecocardiografía transtorácica (ETT) permite la determinación no invasiva del GC. El objetivo de este estudio fue validar la ETT frente al CAP para determinar el GC en mujeres embarazadas gravemente enfermas. MÉTODOS: Este estudio consistió en un metaanálisis que combinó datos de un estudio prospectivo y una revisión sistemática. El estudio prospectivo se llevó a cabo en Pretoria (Sudáfrica) en 2003. Se incluyeron mujeres con complicaciones graves en el embarazo que requerían una monitorización invasiva mediante CAP según las directrices de ese momento. Se realizó una ETT en un plazo de 15 minutos de haber realizado el CAP y el investigador no tuvo acceso a las mediciones del CAP. Las mediciones comparativas se extrajeron de estudios similares obtenidos a partir de una revisión sistemática de la literatura y se añadieron a una base de datos. Se compararon las mediciones simultáneas del GC mediante ETT y CAP. La concordancia entre métodos se evaluó a través del método estadístico de Bland-Altman y de coeficientes de correlación intraclase (CCI). RESULTADOS: Se incluyeron treinta y cuatro mediciones comparativas en el metaanálisis. Los valores medios del GC obtenidos mediante CAP y ETT fueron de 7,39 l/min y 7.18 l/min, respectivamente. El sesgo fue de 0,21 l/min, siendo los límites inferior y superior de la concordancia de -1,18 l/min y 1.60 l/min; el error porcentual fue del 19,1%, y el CCI entre ambos métodos fue de 0,94. CONCLUSIONES: Las mediciones del GC en mujeres embarazadas mediante ETT muestran una excelente concordancia con las obtenidas mediante CAP. Dada su naturaleza no invasiva y su disponibilidad, la ETT podría considerarse como referencia para la validación de otras técnicas relacionadas con el GC en mujeres embarazadas. : ,。(pulmonary artery catheterization,PAC)(cardiac output,CO),,。(transthoracic echocardiography,TTE)CO。PACTTECO。 : meta。2003。PAC。PAC 15 minTTE,PAC。,。TTEPACCO。Bland-Altman(intraclass correlation coefficients,ICC)。 : meta34。PACTTECO7.39 L/min7.18 L/min。-1.18 L/min、1.60 L/min0.21 L/min,19.1%,ICC0.94。 : TTECOPACCO。,TTECO。.

Defining functional interactions during biogenesis of epithelial junctions.

In spite of extensive recent progress, a comprehensive understanding of how actin cytoskeleton remodelling supports stable junctions remains to be established. Here we design a platform that integrates actin functions with optimized phenotypic clustering and identify new cytoskeletal proteins, their functional hierarchy and pathways that modulate E-cadherin adhesion. Depletion of EEF1A, an actin bundling protein, increases E-cadherin levels at junctions without a corresponding reinforcement of cell-cell contacts. This unexpected result reflects a more dynamic and mobile junctional actin in EEF1A-depleted cells. A partner for EEF1A in cadherin contact maintenance is the formin DIAPH2, which interacts with EEF1A. In contrast, depletion of either the endocytic regulator TRIP10 or the Rho GTPase activator VAV2 reduces E-cadherin levels at junctions. TRIP10 binds to and requires VAV2 function for its junctional localization. Overall, we present new conceptual insights on junction stabilization, which integrate known and novel pathways with impact for epithelial morphogenesis, homeostasis and diseases.

Lung function in African infants: a pilot study.

BACKGROUND: The burden of childhood respiratory illness is large in low and middle income countries (LMICs). Infant lung function (ILF) testing may provide useful information about lung growth and susceptibility to respiratory disease. However, ILF has not been widely available in LMICs settings where the greatest burden of childhood respiratory disease occurs. AIM: To implement and evaluate a pilot study of ILF testing in a semi-rural setting in South Africa. METHOD: Infant lung function testing was established at a community hospital in South Africa. All measures were done in unsedated infants during sleep. Measurements, made with the infant quietly breathing through a face mask and bacterial filter, included tidal breathing (TBFVL), exhaled nitric oxide (eNO), and sulphur hexafluoride multiple breath washout (MBW) measures using an ultrasonic flow meter and chemoluminescent NO analyzer. RESULTS: Twenty infants, mean age of 7.7 (SD 2.9) weeks were tested; 8 (40%) were Black African and 12 (60%) were mixed race. Five (25%) infants were preterm. There were 19 (95%) successful TBFVL and NO tests and 18 (90%) successful MBW tests. The mean tidal volume was 30.5 ml (SD 5.9), respiratory rate 50.2 breaths per minute (SD 8.7), and eNO 10.4 ppb (SD 7.3). The mean MBW measures were: functional residual capacity 71 ml (SD 13) and the lung clearance index 7.6 (SD 0.5). The intra-subject coefficient of variations (CV) of lung function measures were similar to published normative data for Caucasian European infants. CONCLUSION: In this study we demonstrate that unsedated infant lung function measures of tidal breathing, MBW, and eNO are feasible in a semi-rural African setting with rates comparable to those reported from high income countries.

Phase II study of pegylated liposomal doxorubicin and carboplatin in patients with platinum-sensitive and partially platinum-sensitive metastatic ovarian cancer.

OBJECTIVE: This phase II study assessed the activity and safety of pegylated liposomal doxorubicin (PLD) plus carboplatin in relapsed ovarian cancer (ROC). METHOD: Forty women with platinum-sensitive and partially platinum-sensitive ROC were treated with PLD 50 mg/m2 plus carboplatin area under the curve 5 every 28 days in this South African multicenter study. All patients who completed 3 cycles of chemotherapy were evaluated for response. Primary outcome was response in the intent-to-treat population. RESULTS: Complete response was 35%, and partial response was 32.5% (overall response, 67.5%). Median time-to-progression was 11.9 months, and median survival was 30.0 months. Overall response was higher in platinum-sensitive (81%) versus partially platinum-sensitive patients (53%), as were median duration of response, median time-to-progression, and median survival. Treatment was well tolerated, with no grade 4 nonhematologic toxicities. Grade 3/4 hematologic toxicities included leukopenia (58%), neutropenia (55%), and thrombocytopenia (43%). CONCLUSION: Pegylated liposomal doxorubicin plus carboplatin is well tolerated and active in the treatment of platinum-sensitive and partially platinum-sensitive ROC.

5q- myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics.

Complete loss or interstitial deletions of chromosome 5 are the most common karyotypic abnormality in myelodysplastic syndromes (MDSs). Isolated del(5q)/5q- MDS patients have a more favorable prognosis than those with additional karyotypic defects, who tend to develop myeloproliferative neoplasms (MPNs) and acute myeloid leukemia. The frequency of unbalanced chromosome 5 deletions has led to the idea that 5q harbors one or more tumor-suppressor genes that have fundamental roles in the growth control of hematopoietic stem/progenitor cells (HSCs/HPCs). Cytogenetic mapping of commonly deleted regions (CDRs) centered on 5q31 and 5q32 identified candidate tumor-suppressor genes, including the ribosomal subunit RPS14, the transcription factor Egr1/Krox20 and the cytoskeletal remodeling protein, alpha-catenin. Although each acts as a tumor suppressor, alone or in combination, no molecular mechanism accounts for how defects in individual 5q candidates may act as a lesion driving MDS or contributing to malignant progression in MPN. One candidate gene that resides between the conventional del(5q)/5q- MDS-associated CDRs is DIAPH1 (5q31.3). DIAPH1 encodes the mammalian Diaphanous-related formin, mDia1. mDia1 has critical roles in actin remodeling in cell division and in response to adhesive and migratory stimuli. This review examines evidence, with a focus on mouse gene-targeting experiments, that mDia1 acts as a node in a tumor-suppressor network that involves multiple 5q gene products. The network has the potential to sense dynamic changes in actin assembly. At the root of the network is a transcriptional response mechanism mediated by the MADS-box transcription factor, serum response factor (SRF), its actin-binding myocardin family coactivator, MAL, and the SRF-target 5q gene, EGR1, which regulate the expression of PTEN and p53-family tumor-suppressor proteins. We hypothesize that the network provides a homeostatic mechanism balancing HPC/HSC growth control and differentiation decisions in response to microenvironment and other external stimuli.

Resorbable cement for the augmentation of internally-fixed unstable trochanteric fractures. A prospective, randomised multicentre study.

We undertook a multicentre, prospective study of a series of 112 unstable trochanteric fractures in order to evaluate if internal fixation with a sliding screw device combined with augmentation using a calcium phosphate degradable cement (Norian SRS) could improve the clinical, functional and radiological outcome when compared with fractures treated with a sliding screw device alone. Pain, activities of daily living, health status (SF-36), the strength of the hip abductor muscles and radiological outcome were analysed. Six weeks after surgery, the patients in the augmented group had significantly lower global and functional pain scores (p < 0.003), less pain after walking 50 feet (p < 0.01), and a better return to the activities of daily living (p < 0.05). At follow-up at six weeks and six months, those in the augmented group showed a significant improvement compared with the control group in the SF-36 score. No other significant differences were found between the groups. We conclude that augmentation with calcium phosphate cement in unstable trochanteric fractures provides a modest reduction in pain and a slight improvement in the quality of life during the course of healing when compared with conventional fixation with a sliding screw device alone.

Cdc42, dynein, and dynactin regulate MTOC reorientation independent of Rho-regulated microtubule stabilization.

In migrating adherent cells such as fibroblasts and endothelial cells, the microtubule-organizing center (MTOC) reorients toward the leading edge [1-3]. MTOC reorientation repositions the Golgi toward the front of the cell [1] and contributes to directional migration [4]. The mechanism of MTOC reorientation and its relation to the formation of stabilized microtubules (MTs) in the leading edge, which occurs concomitantly with MTOC reorientation [3], is unknown. We show that serum and the serum lipid, lysophosphatidic acid (LPA), increased Cdc42 GTP levels and triggered MTOC reorientation in serum-starved wounded monolayers of 3T3 fibroblasts. Cdc42, but not Rho or Rac, was both sufficient and necessary for LPA-stimulated MTOC reorientation. MTOC reorientation was independent of Cdc42-induced changes in actin and was not blocked by cytochalasin D. Inhibition of dynein or dynactin blocked LPA- and Cdc42-stimulated MTOC reorientation. LPA also stimulates a Rho/mDia pathway that selectively stabilizes MTs in the leading edge [5, 6]; however, activators and inhibitors of MTOC reorientation and MT stabilization showed that each response was regulated independently. These results establish an LPA/Cdc42 signaling pathway that regulates MTOC reorientation in a dynein-dependent manner. MTOC reorientation and MT stabilization both act to polarize the MT array in migrating cells, yet these processes act independently and are regulated by separate Rho family GTPase-signaling pathways.

mDia mediates Rho-regulated formation and orientation of stable microtubules.

Rho-GTPase stabilizes microtubules that are oriented towards the leading edge in serum-starved 3T3 fibroblasts through an unknown mechanism. We used a Rho-effector domain screen to identify mDia as a downstream Rho effector involved in microtubule stabilization. Constitutively active mDia or activation of endogenous mDia with the mDia-autoinhibitory domain stimulated the formation of stable microtubules that were capped and oriented towards the wound edge. mDia co-localized with stable microtubules when overexpressed and associated with microtubules in vitro. Rho kinase was not necessary for the formation of stable microtubules. Our results show that mDia is sufficient to generate and orient stable microtubules, and indicate that Dia-related formins are part of a conserved pathway that regulates the dynamics of microtubule ends.

Comprehensive genome sequence analysis of a breast cancer amplicon.

Gene amplification occurs in most solid tumors and is associated with poor prognosis. Amplification of 20q13.2 is common to several tumor types including breast cancer. The 1 Mb of sequence spanning the 20q13.2 breast cancer amplicon is one of the most exhaustively studied segments of the human genome. These studies have included amplicon mapping by comparative genomic hybridization (CGH), fluorescent in-situ hybridization (FISH), array-CGH, quantitative microsatellite analysis (QUMA), and functional genomic studies. Together these studies revealed a complex amplicon structure suggesting the presence of at least two driver genes in some tumors. One of these, ZNF217, is capable of immortalizing human mammary epithelial cells (HMEC) when overexpressed. In addition, we now report the sequencing of this region in human and mouse, and on quantitative expression studies in tumors. Amplicon localization now is straightforward and the availability of human and mouse genomic sequence facilitates their functional analysis. However, comprehensive annotation of megabase-scale regions requires integration of vast amounts of information. We present a system for integrative analysis and demonstrate its utility on 1.2 Mb of sequence spanning the 20q13.2 breast cancer amplicon and 865 kb of syntenic murine sequence. We integrate tumor genome copy number measurements with exhaustive genome landscape mapping, showing that amplicon boundaries are associated with maxima in repetitive element density and a region of evolutionary instability. This integration of comprehensive sequence annotation, quantitative expression analysis, and tumor amplicon boundaries provide evidence for an additional driver gene prefoldin 4 (PFDN4), coregulated genes, conserved noncoding regions, and associate repetitive elements with regions of genomic instability at this locus.

Cigarette smoking, alcohol consumption, and risk of hip fracture in women.

BACKGROUND: Previous studies regarding the impact of cigarette smoking on the risk of hip fracture in postmenopausal women have been inconsistent, suggesting different effects in different groups. The effect of alcohol intake on fracture risk is puzzling: moderate alcohol intake appears to increase bone density, and its association with hip fracture is not clear. METHODS: To assess the associations of cigarette smoking and alcohol consumption with hip fracture risk among postmenopausal women, we conducted an analysis of a population-based case-control study from Sweden. Cases were postmenopausal women, aged 50 to 81 years, who sustained a hip fracture after minor trauma between October 1, 1993, and February 28, 1995; controls were randomly selected from a population-based register during the same period. A mailed questionnaire requesting information on lifestyle habits and medical history was used 3 months after the hip fracture for cases and simultaneously for controls. Age-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed by means of logistic regression. RESULTS: Of those eligible, 1328 cases (82.5%) and 3312 controls (81.6%) responded. Compared with never smokers, current smokers had an increased risk of hip fracture (age-adjusted OR, 1.66; 95% CI, 1.41-1.95). Duration of smoking-particularly postmenopausal smoking-was more important than the amount smoked. Former smokers had a small increase in risk (age-adjusted OR, 1.15; 95% CI, 0.97-1.37) that decreased with the duration of cessation. The age-adjusted OR for women consuming alcohol was 0.80 (95% CI, 0.69-0.93). CONCLUSIONS: Cigarette smoking is a risk factor for hip fracture among postmenopausal women; risk decreases after cessation. Alcohol consumption has a weak inverse association with risk.

Identification of a carboxyl-terminal diaphanous-related formin homology protein autoregulatory domain.

Mammalian and fungal Diaphanous-related formin homology (DRF) proteins contain several regions of conserved sequence homology. These include an amino-terminal GTPase binding domain (GBD) that interacts with activated Rho family members and formin homology domains that mediate targeting or interactions with signaling kinases and actin-binding proteins. DRFs also contain a conserved Dia-autoregulatory domain (DAD) in their carboxyl termini that binds the GBD. The GBD is a bifunctional autoinhibitory domain that is regulated by activated Rho. Expression of the isolated DAD in cells causes actin fiber formation and stimulates serum response factor-regulated gene expression. Inhibitor experiments show that the effects of exogenous DAD expression are dependent upon cellular Dia proteins. Alanine substitution of DAD consensus residues that disrupt GBD binding also eliminate DAD biological activity. Thus, DAD expression activates nuclear signaling and actin remodeling by mimicking activated Rho and unlatching the autoinhibited state of the cellular complement of Dia proteins.

Physical activity and hip fracture: a population-based case-control study. Swedish Hip Fracture Study Group.

BACKGROUND: A growing body of literature suggests that physical activity may be a protective factor against hip fracture. METHODS: To study the association between hip fracture risk and recreational physical activity at various ages, changes in activity during adult life, occupational physical activity and how risks vary by adult weight change, we performed a population-based case-control study among postmenopausal women aged 50-81 years residing in six counties in Sweden in 1993-1995. The analysis consisted of 1327 women with hip fracture and 3262 randomly selected controls. Information on leisure physical activity before age 18, at 18-30 years and during recent years was based on a questionnaire. Data on occupational physical activity were collected through an independent classification of job titles obtained from record linkage with census data from 1960, 1970 and 1980. RESULTS: There was a protective effect of recent leisure physical activity. Compared to women who reported no leisure activity, the odds ratios (OR) were 0.79 (95% CI: 0.62-1.00), 0.67 (95% CI: 0.54-0.84) and 0.48 (95% CI: 0.39-0.60) for women who exercised <1 h per week, 1-2 h per week, and 3+ h per week, respectively. These decreased OR were more pronounced in women who had lost weight after 18 years of age than in those who had gained weight. Women with high physical activity at both 18-30 years and during recent years did not have a stronger protection than those with isolated high activity late in life, after accounting for recent activity. Occupational physical activity was not associated with hip fracture risk in this study. CONCLUSIONS: Recent physical activity is protective against hip fracture. The protective effect is most pronounced in women who had lost weight after age 18.

Diaphanous-related formins bridge Rho GTPase and Src tyrosine kinase signaling.

We have examined the role of the mouse Diaphanous-related formin (DRF) Rho GTPase binding proteins, mDia1 and mDia2, in cell regulation. The DRFs are required for cytokinesis, stress fiber formation, and transcriptional activation of the serum response factor (SRF). 'Activated' mDia1 and mDia2 variants, lacking their GTPase binding domains, cooperated with Rho-kinase or ROCK to form stress fibers but independently activated SRF. Src tyrosine kinase associated and co-localized with the DRFs in endosomes and in mid-bodies of dividing cells. Inhibition of Src also blocked cytokinesis, SRF induction by activated DRFs, and cooperative stress fiber formation with active ROCK. Our results show that the DRF proteins couple Rho and Src during signaling and the regulation of actin dynamics.

p21-activated kinase 1 plays a critical role in cellular activation by Nef.

The activation of Nef-associated kinase (NAK) by Nef from human and simian immunodeficiency viruses is critical for efficient viral replication and pathogenesis. This induction occurs via the guanine nucleotide exchange factor Vav and the small GTPases Rac1 and Cdc42. In this study, we identified NAK as p21-activated kinase 1 (PAK1). PAK1 bound to Nef in vitro and in vivo. Moreover, the induction of cytoskeletal rearrangements such as the formation of trichopodia, the activation of Jun N-terminal kinase, and the increase of viral production were blocked by an inhibitory peptide that targets the kinase activity of PAK1 (PAK1 83-149). These results identify NAK as PAK1 and emphasize the central role its kinase activity plays in cytoskeletal rearrangements and cellular signaling by Nef.

Use of archival fine-needle aspirates for the allelotyping of tumors.

BACKGROUND: Loss of heterozygosity (LOH) analysis (allelotyping) based on polymorphic microsatellite DNA is one of the most powerful molecular tools currently available for studying carcinogenesis. However, allelotyping studies that require archival paraffin embedded tissues are often hampered by technical difficulties related to microdissection and poor DNA quality. METHODS: The authors compared allelotyping results from 12 paraffin embedded breast carcinoma cases with those from matching alcohol fixed fine-needle aspiration (FNA) cytology slides obtained for routine diagnostic purposes, using 30 polymorphic microsatellite markers at chromosomes 3p, 4p, 4q, 5q, 6p, 8p, 9p, 11q, 17p, and 17q. Cells from the alcohol fixed FNA slides were dissected and processed in three different ways, and DNA dilution experiments were performed to determine the minimum number of cells required for accurate allelotyping. RESULTS: LOH results were identical for paraffin embedded and alcohol fixed tumors for 97% of 114 polymerase chain reactions (PCR) when 1000-2000 cells were dissected from each FNA slide and DNA from 100 cells was used for each multiplex PCR. However, with lower cell numbers, the discordance rate increased and artifactual LOH was observed. Intratumor allelotype heterogeneity could not be documented. CONCLUSIONS: The use of alcohol fixed cytology preparations improves the ease of PCR-based allelotyping and greatly expands the range of archival materials available for study. The allelotyping is accurate and reproducible when DNA from >/=25 cells is used in the initial multiplex PCR. Cancer (Cancer Cytopathol)

A role for the polymorphism at position 247 of the beta2-glycoprotein I gene in the generation of anti-beta2-glycoprotein I antibodies in the antiphospholipid syndrome.

OBJECTIVE: To determine the frequencies at which either a valine or leucine occurs at position 247 in the beta2-glycoprotein I (beta2GPI) gene of normal individuals of the Caucasian, African American, and Asian ethnic groups and to compare these data with those in patients with the antiphospholipid syndrome (APS), with and without anti-beta2GPI antibodies. METHODS: The DNA segment containing the position-247 polymorphism was amplified by seminested polymerase chain reaction, and the polymorphism was detected by restriction endonuclease digestion. DNA samples from 370 healthy controls of different racial backgrounds were analyzed, and the results were compared with those from 149 APS patients (66 primary; 83 secondary). Allele and genotype frequencies were compared using Fisher's exact test. When significant differences were detected, pairwise comparisons were made using Fisher's exact test with a Bonferroni adjustment. RESULTS: Allele and genotype expression was significantly different (P < 0.0001 for both) among the 3 races, with the V allele and the VV genotype occurring most often among Caucasians, less among African Americans, and least among Asians. Conversely, the V allele and the VV genotype were found more frequently among Asian APS patients than among controls (P = 0.0028 and P = 0.0023, respectively). No significant differences in allele or genotype frequencies were seen in comparisons of the Caucasian or the African American patients with appropriate controls. The differences in allele and genotype frequencies seen in the Asian APS patients were restricted to the anti-beta2GPI-positive patients (P = 0.0018 and P = 0.0005, respectively). CONCLUSION: In Asian patients with APS, expression of a V at position 247, especially in the homozygous state, is significantly associated with the presence of anti-beta2GPI antibodies and, therefore, can be viewed as a major risk factor in this ethnic group (odds ratio 9.19 and 16.33, respectively).