Biomedical subjects

S John

Publications and source records attributed to S John.

At least 37 records · Page 2Linked to original sources

PubMed2001

High resolution linkage and association mapping identifies a novel rheumatoid arthritis susceptibility locus homologous to one linked to two rat models of inflammatory arthritis.

Rheumatoid arthritis (RA) is an oligogenic autoimmune disease but, to date, linkage and association to major histocompatibility complex (MHC) has been the only consistent finding in genetic studies. However, MHC is estimated to contribute only 30-40% of the total genetic component to disease susceptibility. Studies in animal models of inflammatory arthritis have identified a number of putative vulnerability loci but the homologous regions in the human genome have not previously been investigated as candidate RA susceptibility loci. We have investigated linkage to five regions homologous to those identified in animal models of inflammatory arthritis in RA affected sibling pair (ASP) families. Linkage to 17q22 syntenic to a susceptibility locus common to two experimental rat models was detected in 200 RA ASP families and replicated in a further 100 RA ASP families. Linkage to additional markers mapping to the area has refined the extent of linkage to a 4 cM region. Association to one of the markers (D17S807) was demonstrated in this cohort using extensions of the transmission disequilibrium test. Association to two 2-marker haplotypes including this marker was detected in an independent cohort of single-case RA families, thus narrowing the region harbouring the aetiological mutation to approximately 1 cM. This is the first time that an arthritis susceptibility locus mapped in experimental animal models of disease has been used to identify a novel RA susceptibility locus in humans. The difficult task of identifying a disease mutation from a linkage result should, in this case at least, be facilitated by the combined use of animal and human based investigations.

Animals↗

PubMed2001

Proposed square spiral microfabrication architecture for large three-dimensional photonic band gap crystals.

We present a blueprint for a three-dimensional photonic band gap (PBG) material that is amenable to large-scale microfabrication on the optical scale using glancing angle deposition methods. The proposed chiral crystal consists of square spiral posts on a tetragonal lattice. In the case of silicon posts in air (direct structure), the full PBG can be as large as 15% of the gap center frequency, whereas for air posts in a silicon background (inverted structure) the maximum PBG is 24% of the center frequency. This PBG occurs between the fourth and fifth bands of the photon dispersion relation and is very robust to variations (disorder) in the geometrical parameters of the crystal.

Journal Article↗

PubMed2001

Split Na+-Ca2+ exchangers. Implications for function and expression.

The Na(+)-Ca(2+) exchanger has nine transmembrane segments, with a large cytoplasmic loop between the fifth and sixth transmembrane segments. The protein was split within the cytoplasmic loop into two domains consisting of the first five transmembrane segments and the last four transmembrane segments, respectively. The two domains were either expressed individually or coexpressed. Each of the two domains with different lengths of the cytoplasmic loop was fused to green fluorescent protein. We show that coexpression of both domains is required for proper membrane targeting and for expression of functional exchange activity. Fusion to green fluorescent protein does not alter biophysical properties of the exchange process. In addition, truncation of a large portion of the cytoplasmic loop does not alter important properties of the exchanger such as Na(+)-dependent inactivation, activation by chymotrypsin, or exchanger inhibitory peptide (XIP) sensitivity.

Animals↗

PubMed2001

Genetic epidemiology. Approaches to the genetic analysis of rheumatoid arthritis.

The basis of susceptibility to rheumatoid arthritis (RA) is complex, comprising genetic and environmental susceptibility factors. We have reviewed the available approaches to the investigation of the genetic basis of complex diseases and how these are being applied to RA. Affected-sibling-pair methods for nonparametric linkage analysis, linkage-disequilibrium-based approaches, transmission disequilibrium testing, and disease-association studies are discussed. The pros, cons, and limitations of the approaches are considered and are illustrated by examples from the literature about rheumatoid arthritis.

Arthritis, Rheumatoid↗

PubMed2001

Association between rheumatoid arthritis and polymorphism of tumor necrosis factor receptor II, but not tumor necrosis factor receptor I, in Caucasians.

OBJECTIVE: Tumor necrosis factor (TNF) is a powerful mediator of inflammation in rheumatoid arthritis (RA). In vivo, its acute effects are limited by binding to soluble receptors (TNFR), suggesting that TNFR genes could be important candidate risk factors. The present study was undertaken to investigate association of polymorphisms of TNFRI and TNFRII with RA in subjects in the UK. METHODS: Unrelated Caucasian RA patients (n = 291) and healthy Caucasian controls (n = 143) were genotyped for A/G polymorphism in exon 1 of TNFRI. From this sample, 240 of the patients and 137 controls were also typed for a single-nucleotide polymorphism (SNP) in exon 6 of the TNFRII gene. In followup studies, DNA samples from UK Caucasian RA patients with a positive family history (n = 149) and UK Caucasian patients with sporadic RA (n = 208) were also typed for the exon 6 TNFRII polymorphism. RESULTS: TNFRI polymorphism was not associated with RA (odds ratio [OR] for GG genotype 0.93, 95% confidence interval [95% CI] 0.54-1.60). For TNFRII, in the initial study group, patients with RA were significantly more likely to be positive for both the G allele and GG genotype than were controls (OR for GG genotype 2.55, 95% CI 1.11-5.86). The association appeared to be confined to those with a family history of RA. This finding was replicated in an independent cohort of patients with familial RA. CONCLUSION: The results of this study provide evidence of association between an SNP in the TNFRII gene and RA, the strongest association being observed in patients with a family history. No evidence of association between RA and TNFRI was demonstrated.

Arthritis, Rheumatoid↗

PubMed2001

The single-nucleotide polymorphism lottery: how useful are a few common SNPs in identifying disease-associated alleles?

It has been proposed that using association analysis of single nucleotide polymorphism (SNP) markers in candidate genes may be more successful in identifying disease susceptibility genes for complex diseases. Finding all the SNPs within a candidate gene and genotyping a large case-control cohort is a resource-intensive process. As linkage disequilibrium extends across small regions of the genome, the expectation is that a few common anonymous SNPs will be sufficient to detect functional disease-associated alleles. The aim of this investigation was to compare the ability of a number of family- and population-based association methods to identify known susceptibility loci using the Genetic Analysis Workshop 12 simulated data set. As expected, case-control methods were more likely to detect association with individual SNPs but family-based haplotyping methods appeared better able to localize the position of functional polymorphism.

Adult↗

PubMed2001

Rapid improvement of nitric oxide bioavailability after lipid-lowering therapy with cerivastatin within two weeks.

OBJECTIVES: We investigated whether improvement of endothelial dysfunction in hypercholesterolemia can be achieved with short-term lipid-lowering therapy. BACKGROUND: Impaired endothelium-dependent vasodilation plays a pivotal role in the pathogenesis of atherosclerosis and acute coronary syndromes. METHODS: In a randomized, double-blind, placebo-controlled trial, we studied 37 patients (52 +/- 11 yrs) with low density lipoprotein cholesterol > or = 160 mg/dl (196 +/- 44 mg/dl) randomly assigned to either cerivastatin (0.4 mg/d) or placebo. Endothelium-dependent vasodilation of the forearm vasculature was measured by plethysmography and intra-arterial infusion of acetylcholine (ACh 12, 48 microg/min) and endothelium-independent vasodilation by intra-arterial infusion of nitroprusside (3.2, 12.8 microg/min). RESULTS: Low density lipoprotein cholesterol decreased after two weeks of treatment (cerivastatin -33 +/- 4% vs. placebo + 2 +/- 4%, x +/- SEM, p < 0.001). Endothelium-dependent vasodilation improved after two weeks of therapy with cerivastatin compared with baseline (ACh 12 microg/min: + 22.3 +/- 5.2 vs. + 11.2 +/- 1.9 ml/min/100 ml, p < 0.01; ACh 48 microg/min: +31.2 +/- 6.3 vs. +19.1 +/- 3.1 ml/min/100 ml, p < 0.05). In contrast, changes in forearm blood flow to ACh were similar before and after therapy in the placebo group (ACh 12 microg/min: + 12.9 +/- 3.6 vs. + 9.0 +/- 1.9 ml/min/100 ml, NS; ACh 48 microg/min: +20.7 +/- 3.7 vs. 19.4 +/- 2.9 ml/min/100 ml, NS). Endothelium-dependent vasodilation improved in comparison with placebo (ACh 48 microg/min: +203 +/- 85% [cerivastatin] vs. -26 +/- 71% [placebo], p < 0.05). This improvement in endothelium-dependent vasodilation was no longer observed when the nitric oxide-synthase inhibitor N(G)-monomethyl-L-arginine was coinfused (ACh 48 microg/min + N(G)-monomethyl-L-arginine 4 micromol/min -48 +/- 85% [cerivastatin]). CONCLUSIONS: Short-term lipid-lowering therapy with cerivastatin can improve endothelial function and NO bioavailability after two weeks in patients with hypercholesterolemia.

Adult↗

PubMed2001

Protective effect of vitamin E in dimethoate and malathion induced oxidative stress in rat erythrocytes.

Organophosphate (OP) pesticides such as dimethoate and malathion intoxication has been shown to produce oxidative stress due to the generation of free radicals and alter the antioxidant defense system in erythrocytes. It is possible that vitamin E being present at the cell membrane site may prevent OP-induced oxidative damage. In the present study, rats were pretreated orally with vitamin E (250 mg/kg body wt, twice a week for 6 weeks) prior to oral administration of a single low dose of dimethoate and/or malathion (0.01% LD(50)). The result showed that treatment with OP increased lipid peroxidation (LPO) in erythrocytes, however, vitamin E pretreated rats administered OP's showed decreased LPO in erythrocytes. The increase in the activities of superoxide dismutase (SOD) and catalase (CAT) and total-SH content in erythrocytes from dimethoate and/or malathion treated rats as compared to control appears to be a response towards increased oxidative stress. Vitamin E pretreated animals administered OP's showed a lowering in these parameters as compared to OP treated rats which indicates that vitamin E provide protection against OP-induced oxidative stress. The glutathione-S-transferase (GST) activity in erythrocytes was inhibited in OP intoxicated rats which partially recovered in vitamin E pretreated animals administered OP's. Inhibition in erythrocyte and serum acetylcholinesterase (AChE) activity was not relieved in vitamin E pretreated rats administered OP's probably due to the competitive nature of enzyme inhibition by OP's. The results show that vitamin E may amelierate OP-induced oxidative stress by decreasing LPO and altering antioxidant defense system in erthrocytes.

Journal Article↗

PubMed2001

Effects of continuous haemofiltration vs intermittent haemodialysis on systemic haemodynamics and splanchnic regional perfusion in septic shock patients: a prospective, randomized clinical trial.

BACKGROUND: Parameters of splanchnic regional perfusion, like intramucosal pH (pHi) and pCO(2) (pCO(2)i), may predict outcome in septic shock patients. Continuous venovenous haemofiltration (CVVH) has been considered beneficial in haemodynamically unstable septic shock patients. In a prospective, randomized, clinical study, we investigated whether CVVH, in comparison to intermittent haemodialysis (IHD), is able to improve splanchnic regional perfusion in critically ill patients. METHODS: Thirty septic shock patients with acute renal failure were randomized to either CVVH (n=20) or IHD (n=10) groups for renal replacement therapy. Patient characteristics at baseline were not different in terms of severity of illness (APACHE II scores), haemodynamics, and pHi/pCO(2)i values. Systemic haemodynamics, oxygen transport variables, and splanchnic regional perfusion parameters were measured at 0.5, 2, 4 and 24 h after initiation of renal replacement therapy. There were no major changes in vasopressor support throughout the 24-h study period. RESULTS: In contrast to IHD, CVVH caused a decrease in heart rate (-3+/-11 vs +9+/-8/min, P<0.01) and an increase in systolic blood pressure (+12+/-1 vs -5+/-17 mmHg, P<0.05) after 2 h. After 24 h, increased systemic vascular resistance was found in the CVVH group in comparison with the IHD group (+312+/-755 vs -29+/-89 dyne/cm(5), P<0.05) and was accompanied by a decrease in cardiac output (-1.54+/-1.4 vs -0.25+/-0.9 l/min, P<0.01). However pHi values remained constant throughout the 24-h study period in both groups and were not different between the groups (CVVH 7.19+/-0.1 vs IHD 7.19+/-0.1, n.s.) as did the pCO(2)i values (CVVH +7+/-17 vs IHD 0+/-15 mmHg, n.s.) and pCO(2) gap values (CVVH +6+/-15 vs IHD +5+/-12 mmHg, n.s.). CONCLUSIONS: Despite different changes of systemic haemodynamics between CVVH and IHD, CVVH did not improve parameters of splanchnic regional perfusion like pHi, pCO(2)i or pCO(2) gap in septic shock patients.

Acid-Base Equilibrium↗

PubMed2001

Linkage and association analysis of candidate genes in rheumatoid arthritis.

OBJECTIVES: To test for linkage and association to rheumatoid arthritis (RA) in multiplex families for polymorphic markers in candidate gene loci. Loci including the cytokine cluster on 5q31.1 and IL10, both previously investigated in RA, were included along with several other genes including ICAM-1, cMYC, the cytokine cluster on 17q11.2 and IL1RA. METHODS: One hundred eighty-five multiplex RA families were genotyped for 11 microsatellite markers close to candidate genes. Markers showing evidence of linkage and/or association to RA were tested in a further cohort of families (n = 99). RESULTS: A single microsatellite marker in the GSTM4 gene showed some evidence of linkage, LOD 1.6 (p = 0.006). However, there was no evidence of excess allele sharing in the second cohort of families tested. There was also evidence of association to RA, using the transmission disequilibrium test for a dinucleotide repeat in the IRF gene in the cytokine cluster on 5q31.1; this was not replicated in a second cohort of families. CONCLUSION: Our results do not provide evidence of a role for these genes in RA susceptibility.

Arthritis, Rheumatoid↗

PubMed2001

Chromium removal and reduction in COD of tannery effluents by actinomycetes.

Tannery effluents are highly polluting and contain chroomium and high Cod and Bod. Alkalotolerant/alkalophilic actinomycetes NCIM 5080 and NCIM 5142 have been shown earlier to tolerate and accumulate chromium during growth also produce alkaline protease in presence of chromium ions, these properties of the isolates are suitable for treatment of tannery effluents which are alkaline and contain chromium and proteinaceous matter, both the actinomycetes are able to grow in undiluted tannery effluents and remove chromium almost completely and reduce the COD by 70%-80% during growth as well as by pregrown biomass.

Actinobacteria↗

PubMed2000

Prospective analysis of the value of 24-hour ambulatory blood pressure on renal function after kidney transplantation.

BACKGROUND: No prospective study has been performed to determine the prognostic value of 24-hr ambulatory blood pressure (24-hr ABP) versus casual blood pressure (CBP) in patients after kidney transplantation. We have addressed this issue by analyzing renal graft function in patients for the first 5 years after transplantation. METHODS: The 24-hr ABP (SpaceLabs 90207) was monitored 6 and 18 months after transplantation in 46 renal transplant recipients without any acute episodes of rejection. Combined study endpoints were death of patients, need for dialysis, second transplantation, and doubling of serum creatinine. RESULTS: Six months after transplantation systolic and diastolic 24-hr ABP correlated with serum creatinine (r=0.41, P=0.005 and r=0.37, P<0.01, respectively) although CBP did not. Divided into tertiles according to average 24-hr ABP (lower tertile: < or =91 mmHg; middle tertile: 92-97 mmHg; upper tertile: > or =98 mmHg) serum creatinine significantly differed between the three groups (1.26 +/- 0.38 vs. 1.32 +/- 0.25 vs. 1.65 +/- 0.39 mg/dl, respectively; analysis of variance, P< 0.01). Confounding factors of renal function such as age, body weight, cold and warm ischemic time, cytomegaly virus status, methylprednisone and cyclosporine dosages, cyclosporine concentrations, as well as concomitant antihypertensive medication did not differ among the three groups. In the long-term follow-up (5 years), combined endpoints were reached in 3 of 15 of the lower tertile group, in 3 of 15 of the median tertile group, and in 8 of 16 of the upper tertile group (log-rank test, P<0.01). No relation to long-term out come was found when patients were stratified according to their CBP. CONCLUSION: In our small but homogenous study cohort 24-hr ABP was more closely related to renal function in patients after transplantation than CBP suggesting that 24-hr ABP is superior for evaluation of hypertension-related renal graft dysfunction.

Adult↗

PubMed2000

Large-scale synthesis of a silicon photonic crystal with a complete three-dimensional bandgap near 1.5 micrometres

Photonic technology, using light instead of electrons as the information carrier, is increasingly replacing electronics in communication and information management systems. Microscopic light manipulation, for this purpose, is achievable through photonic bandgap materials, a special class of photonic crystals in which three-dimensional, periodic dielectric constant variations controllably prohibit electromagnetic propagation throughout a specified frequency band. This can result in the localization of photons, thus providing a mechanism for controlling and inhibiting spontaneous light emission that can be exploited for photonic device fabrication. In fact, carefully engineered line defects could act as waveguides connecting photonic devices in all-optical microchips, and infiltration of the photonic material with suitable liquid crystals might produce photonic bandgap structures (and hence light-flow patterns) fully tunable by an externally applied voltage. However, the realization of this technology requires a strategy for the efficient synthesis of high-quality, large-scale photonic crystals with photonic bandgaps at micrometre and sub-micrometre wavelengths, and with rationally designed line and point defects for optical circuitry. Here we describe single crystals of silicon inverse opal with a complete three-dimensional photonic bandgap centred on 1.46 microm, produced by growing silicon inside the voids of an opal template of dose-packed silica spheres that are connected by small 'necks' formed during sintering, followed by removal of the silica template. The synthesis method is simple and inexpensive, yielding photonic crystals of pure silicon that are easily integrated with existing silicon-based microelectronics.

Journal Article↗

PubMed2000

The something about silencing protein, Sas3, is the catalytic subunit of NuA3, a yTAF(II)30-containing HAT complex that interacts with the Spt16 subunit of the yeast CP (Cdc68/Pob3)-FACT complex.

We have purified and characterized a Gcn5-independent nucleosomal histone H3 HAT complex, NuA3 (Nucleosomal Acetyltransferase of histone H3). Peptide sequencing of proteins from the purified NuA3 complex identified Sas3 as the catalytic HAT subunit of the complex. Sas3 is the yeast homolog of the human MOZ oncogene. Sas3 is required for both the HAT activity and the integrity of the NuA3 complex. In addition, NuA3 contains the TBP- associated factor, yTAF(II)30, which is also a component of the TFIID, TFIIF, and SWI/SNF complexes. Sas3 mediates interaction of the NuA3 complex with Spt16 both in vivo and in vitro. Spt16 functions as a component of the yeast CP (Cdc68/Pob3) and mammalian FACT (facilitates chromatin transcription) complexes, which are involved in transcription elongation and DNA replication. This interaction suggests that the NuA3 complex might function in concert with FACT-CP to stimulate transcription or replication elongation through nucleosomes by providing a coupled acetyltransferase activity.

Acetyltransferases↗

PubMed2000

A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration.

The disks of vertebrate photoreceptors are produced by outgrowths of the plasma membrane. Hence genes that encode retinal proteins targeted to plasma membrane protrusions represent candidates for inherited retinal degenerations. One such candidate is the gene encoding human prominin (mouse)-like 1 (PROML1, previously known as AC133 antigen) which belongs to the prominin family of 5-transmembrane domain proteins. Murine prominin (prom) shows a strong preference for plasma membrane protrusions in a variety of epithelial cells whereas PROML1 is expressed in retinoblastoma cell lines and adult retina. In the present study, molecular genetic analyses of a pedigree segregating for autosomal recessive retinal degeneration indicated that the affected individuals were homozygous for a nucleotide 1878 deletion in PROML1. This alteration is predicted to result in a frameshift at codon 614 with premature termination of translation. Expression of a similar prom deletion mutant in CHO cells indicated that the truncated protein does not reach the cell surface. Immunocytochemistry revealed that prom is concentrated in the plasma membrane evaginations at the base of the outer segments of rod photoreceptors. These findings suggest that loss of prominin causes retinal degeneration, possibly because of impaired generation of the evaginations and/or impaired conversion of the evaginations to disks.

AC133 Antigen↗

PubMed2000

Multipoint linkage analysis of a candidate gene locus in rheumatoid arthritis demonstrates significant evidence of linkage and association with the corticotropin-releasing hormone genomic region.

OBJECTIVE: Rheumatoid arthritis (RA) is the most common disabling autoimmune disease, affecting approximately 1% of the population. The disease etiology is unknown, but it involves inflammation and immune dysregulation and is influenced by genetic variation at both HLA and other, as-yet-unidentified genetic loci. Corticotropin-releasing hormone (CRH; or corticotropin-releasing factor), a primary regulator of the hypothalamic-pituitary-adrenal axis and a key element in the response to stress and inflammation, is a strong candidate gene for RA. We examined the role of DNA variation across the region containing this gene in multicase families with RA. METHODS: We genotyped fluorescently labeled simple tandem repeat genetic markers from chromosome 8q13 in 295 families with multiple cases of RA. Singlepoint and multipoint nonparametric linkage analysis and association analysis using transmission disequilibrium testing (TDT) were also used. RESULTS: Single-point linkage analysis using a microsatellite within 30 kb of the CRH locus (CRH.PCR at position 8q13) showed a significant excess of allele sharing in 295 United Kingdom RA families with at least 2 affected members (MapMaker/Sibs logarithm of odds [LOD] 1.4; P = 5.5x10(-3); mean identity by descent [ibd] sharing 55.9%). To provide a more detailed linkage map, a multipoint analysis was conducted with an additional 7 dinucleotide microsatellite markers (average heterozygosity 0.75) flanking the CRH locus. Significant linkage was detected over a 22-cM region between D8S285 and D8S530, with the maximum singlepoint LOD score of 1.77 at D8S1723 (MapMaker/Sibs P = 2.2x10(-3); mean ibd sharing 59.3%). Multipoint analysis showed strongest evidence for linkage at the same marker (multipoint LOD 1.78, P = 2.1x10(-3), mean ibd sharing 55.8%). TDT analysis showed significant association at the CRH locus (P = 2.6x10(-3)). CRH has a sibling relative risk of 1.14, and contributes <10% to the sibling relative risk of RA. CONCLUSION: With the exception of HLA, this is the strongest evidence yet of a genetic locus that is both linked to and associated with RA, and provides an avenue for further genetic characterization and potentially novel therapeutic intervention.

Adult↗

PubMed2000

Linkage of rheumatoid arthritis to insulin-dependent diabetes mellitus loci: evidence supporting a hypothesis for the existence of common autoimmune susceptibility loci.

OBJECTIVE: To seek potential autoimmune disease susceptibility loci by testing for linkage and linkage disequilibrium between insulin-dependent diabetes mellitus (IDDM) susceptibility loci and rheumatoid arthritis (RA). METHODS: Five IDDM susceptibility loci map to 2 chromosomal regions, chromosome 2q31-34 (IDDM7, 12, and 13) and chromosome 6q25-27 (IDDM5 and 8). Microsatellite markers within these regions were genotyped in 255 RA families, by fluorescence-based genotyping technology. Evidence for linkage disequilibrium was assessed using the extended transmission disequilibrium test (ETDT) program. RESULTS: With the ETDT, we found evidence for linkage disequilibrium of the marker D6S446, at IDDM8, with RA (P < 0.0001). There was additional evidence for linkage disequilibrium with 2 markers at IDDMS (D6S311 and D6S440) (P = 0.016 and P = 0.017, respectively). There was no evidence for significant linkage disequilibrium of RA with any markers at IDDM7, 12, or 13. CONCLUSION: These results support the hypothesis that there are autoimmune disease genes at IDDM5 and IDDM8.

Alleles↗

PubMed2000

25-year experience with 456 combined mitral and aortic valve replacement for rheumatic heart disease.

BACKGROUND: Valvular heart disease in developing countries resulting from rheumatic fever is disabling and if untreated leads to congestive heart failure and death. Valve replacement has remained the procedure of choice for advanced valve disease. METHODS: Between 1973 and 1997, 456 patients underwent combined mitral and aortic valve replacement. In light of our favorable earlier experience the Starr-Edwards ball valve prostheses were implanted in 90% and 72.8% of mitral and aortic positions, respectively. Follow-up ranged from 1 to 24 years with a median of 8.5 years. RESULTS: The 30-day hospital death rate was 9.2% and late death occurred in 10.1%. A low-intensity anticoagulant regimen was followed to maintain the target prothrombin time at 1.5 times the control value. The actuarial survival at 5, 10, 20, and 24 years was 90.4%, 85.6%, 84.4%, and 82.4% per year, respectively. CONCLUSIONS: In view of the acknowledged advantage of superior durability, increased thromboresistance in our patient population, and its cost effectiveness the Starr-Edwards ball valve is the mechanical prosthesis of choice for advanced combined valvular disease. The low-intensity anticoagulant regimen has offered sufficient protection against thromboembolism as well as hemorrhage.

Adult↗