Incidence of donor and recipient toll-like receptor-4 polymorphisms in kidney transplantation

Toll-like receptors (TLR) comprise an emerging family that recognize pathogen-associated molecular patterns and promote the activation of leukocytes. Recently, TLR has been demonstrated to play a role in experimental allograft rejection. However, the TLR-4 gene has a polymorphism that can be associated with a blunted immune response, especially to microbial pathogens. We sought to study the incidence of TLR 4 gene variants among renal transplant donors and recipients from living and deceased organs and then to correlate them with short-term and long-term outcomes. METHODS: Analysis of TLR4 polymorphisms at Asp299Gly and Thr399Ile codons were performed using restriction fragment length polymorphism. Demographic data was obtained from patient records. RESULTS: Among 201 patients, 141 were recipients from related donors (group 1) and 60 recipients from 45 deceased donors (group 2). Patients were followed for 108 +/- 85 months after transplantation. The incidence of polymorphism for TLR-4 Asp299Gly, Thr399Ile or both were 8.9% in recipients and 8.0% in donors. Patients who received a kidney with polymorphism, Asp299Gly, or Thr399Ile, or both, did not show a difference in rate of acute tubular necrosis compared with controls (no polymorphism). Acute rejection occurred in 17.6% of recipients with Asp299Gly/Thr399Ile polymorphisms and in 39.5% of wild-type recipients (P = .400). The incidence of bacterial infection was equal in both groups. CONCLUSION: The incidence of polymorphism in this study was similar in both groups, and donor or recipient polymorphisms were not associated with different renal graft outcomes.     

Association Between Toll-like Receptors 4 and 2 Gene Polymorphisms With Chronic Allograft Nephropathy in Turkish Children

Toll-like receptor (TLR) gene polymorphism is known to impair intracellular signaling pathways following adaptive immune responses. Our aim was to investigate the distribution of TLR4 and TLR2 gene polymorphisms among pediatric renal transplantation patients in relation to chronic allograft nephropathy (CAN). In addition to 115 healthy controls, we included 69 renal recipients, 19 of whom were identified as CAN by biopsy scored according to the Banff criteria. Polymorphisms at TLR4 Asp299Gly and/or Thr399Ile were present in 11.6% of renal transplant recipients. None of these subjects was identified in cosegregation with the Thr399Ile allele, whereas three had an isolated Asp299Gly and five had an isolated Thr399Ile. Neither renal recipients nor healthy controls were homozygous for both Asp299Gly and Thr399Ile polymorphisms. However, TLR4 Thr399Ile polymorphism and Ile allele was greater among CAN (?) versus CAN (+) recipients (P > .05). The frequency of TLR2 mutant type Gln allele was significantly higher in recipients than among healthy controls (P < .0001). However, the Gln allele frequency was similar between CAN (+) and CAN (?) patients. The results of present study may be speculated to show TLR4 and TLR2 gene polymorphisms as protective factors from CAN development due to impaired immune responses.     

Toll样受体4的基因多态性与脓毒症

脓毒症是指机体感染微生物后发生的全身炎性反应综合征.在该疾病发生发展中是基因多态性影响着机体对该综合征的遗传易感性.其中Toll样受体4(toll-like receptor4,TLR4)作为识别病原微生物的主要受体之一,在自身免疫中起着重要的作用.已有研究表明TLR4的基因多态性与脓毒症的遗传易感性密切相关,其中TLR4基因的Asp299Gly和Thr399Ile位点的突变与脓毒症的发生发展及预后有关.现就TLR4的功能、信号转导通路及其基因多态性与脓毒症易感性的相关关系作一综述.     

Influence of toll-like receptor 4, CD14, tumor necrosis factor, and interleukine-10 gene polymorphisms on clinical outcome in Japanese critically ill patients

The innate recognition of microbial components and subsequent activation of cytokine network are important in the pathophysiology of sepsis. Recently, functional gene polymorphisms in molecules associated with these responses were demonstrated. On the other hand, it has been claimed that there are ethnic differences in genetic polymorphisms. This study investigated toll-like receptor (TLR) 4, CD14, tumor necrosis factor (TNF)-alpha and -beta, and interleukin (IL)-10 gene polymorphisms in 197 Japanese critically ill patients and 214 healthy control subjects to evaluate the influence of these polymorphisms on clinical outcome. No Japanese participant carrying TLR4Asp299Gly or Thr399Ile was detected. No association of CD14-159C/T polymorphisms with genotype frequency or sepsis mortality was observed. Frequency of TNF-alpha-308 GA genotype was significantly higher in the sepsis group than in the control group and TNF-alpha-308GA and IL-10-592CC genotypes were related to poor outcome of sepsis. Ethnic differences in genetic variations are very important issues and the frequencies in this study differ from those previously reported in Caucasians. In conclusion, this study may indicate that TNF-alpha-308G/A and IL-10-592C/A polymorphisms involved in subsequent activation of cytokine network had a larger effect on clinical outcome in patients with sepsis than TLR4Asp299Gly, Thr399Ile, and CD14-159C/T polymorphisms associated with the initial host-microbial interaction.     

Association between toll-like receptor polymorphisms and the outcome of liver transplantation for chronic hepatitis C virus

BACKGROUND: Experimental models suggest that immune cells recognize hepatitis C virus (HCV) through toll-like receptor (TLR)-2 and TLR4. We assessed the association between the single nucleotide polymorphism in genes that encode for these receptors and the outcome of liver transplantation for chronic HCV. METHODS: A historical cohort of 92 liver transplant patients with chronic HCV were screened for TLR2 Arg753Gln and TLR4 Asp299Gly and Thr399Ile polymorphisms. The results were correlated with the predefined composite primary outcome of cirrhosis, retransplantation, and death. Statistical analysis was performed using Kaplan-Meier estimation and Cox proportional hazard model. RESULTS: The mean patient age was 49+/-9 years. Sixty percent were male and 84% were white. Twelve (13%) patients had TLR2 Arg753Gln and 32 (35%) had TLR4 Asp299Gly and/or Thr399Ile polymorphism. During the mean follow-up period of 32 months after liver transplantation, the composite primary outcome occurred in 19 (24%) of 80 patients without TLR2 polymorphism, one (14%) of seven patients with heterozygous TLR2 polymorphism, and in all five (100%) patients with homozygous TLR2 polymorphism (P=0.0007). Time-to-event analysis showed a significant association between homozygous TLR2 polymorphism and the primary outcome (P<0.0001). After adjusting for donor age and azathioprine use, homozygous TLR2 mutation (RR 5.20 [1.65-13.9]; P=0.007) remained associated with the primary outcome. TLR4 polymorphisms were not associated with primary outcome. CONCLUSION: Homozygous TLR2 Arg753Gln polymorphism is associated with allograft failure and mortality after liver transplantation for chronic HCV. The potential clinical relevance of this observation should encourage studies to assess its biologic mechanism.     

Donor polymorphisms in Toll-like receptor-4 influence the development of rejection after renal transplantation

BACKGROUND: Although innate immunity is crucial to host defense against pathogens, the extent to which innate immune mechanisms participate in the rejection of allogenic tissues in humans is unknown. We hypothesize that activation of innate immunity through Toll-like receptors (TLRs) critically regulates the development of renal allograft rejection. We have recently demonstrated decreased acute rejection in lung transplant recipients heterozygous for either of two functional polymorphisms in TLR4 associated with endotoxin hyporesponsiveness. In the present investigation, we sought to evaluate the role of innate immune activation through TLR4, in either donor or recipient, upon the development of renal allograft rejection. METHODS: Patients and donors were screened for the TLR4 functional polymorphisms (Asp299Gly and Thr399Ile) by polymerase chain reaction (PCR) using sequence-specific primers. RESULTS: The incidence of biopsy-proven acute renal allograft rejection was significantly reduced in patients receiving donor grafts heterozygous for the Asp299Gly or Thr399Ile alleles, when compared with wild type (22% vs. 0%, respectively, p = 0.02). There was no association with recipient TLR4 allele and rejection. CONCLUSIONS: The results suggest activation of innate immunity through TLR4 in the donor kidney contributes to the development of acute rejection after renal transplantation.     

Toll-like receptors gene polymorphisms may confer increased susceptibility to breast cancer development

Toll-like receptor (TLR) activation may be an important event in tumor cell immune evasion. TLR2 and TLR4 gene polymorphisms have been related to increased susceptibility to cancer development in various organs. 261 patients and 480 health individuals were investigated for genotype and allelic frequencies of a 22-bp nucleotide deletion (-196 to -174del) in the promoter of TLR2 gene as well as two polymorphisms causing amino acid substitutions (Asp299Gly and Thr399Ile) in TLR4 gene. As far as (-196 to -174del) in TLR2 gene is concerned ins/del and del/del genotypes and del allele were significantly more frequent in breast cancer patients compared to healthy controls. Considering Asp299Gly replacement of TLR4 gene, Gly carriers (Asp/Gly & Gly/Gly genotype) and Gly allele were overrepresented among the breast cancer cases. The -174 to -196del of TLR2 gene and Asp299Gly of TLR4 gene polymorphisms may confer an increased susceptibility to breast cancer development.     

Glutamine downregulates TLR-2 and TLR-4 expression and protects intestinal tract in preterm neonatal rats with necrotizing enterocolitis

Background/Purpose

Toll-like receptor (TLR)-4 and TLR-2 play an essential role in the pathogenesis of necrotizing enterocolitis (NEC). In this study, we investigated the protective effect of glutamine (Gln) in an NEC neonatal rat model, and the potential association with TLR-4 and TLR-2 expression in local intestinal tissues.

Methods

Preterm neonatal rats were randomly divided into 3 groups: normal control; NEC model; and NEC plus Gln intervention. NEC was induced by feeding with artificial milk substitutes, plus exposure to hypoxia and cold stress. All preterm rats were sacrificed at 3 days after birth. The intestinal tissues were taken for pathological analysis. Protein and mRNA expression of TLR-2, TLR-4, and caspase-3 was examined by immunohistochemistry and real-time RT-PCR, respectively.

Results

Compared with the normal control, the NEC neonatal rats showed mucosal injury and upregulated mRNA and protein expression of TLR-2, TLR-4, and caspase-3 in ileum and colon. Gln intervention significantly reduced the mucosal injury and suppressed the upregulated expression of TLR-2, TLR-4, and caspace-3 in the ileum and colon of NEC neonatal rats.

Conclusions

Gln protects the intestinal tract of NEC neonatal rats, which may be associated with the reduction of TLR-2 and TLR-4 expression in intestines     

Predictive value of urinary and serum biomarkers in young children with febrile urinary tract infections

Background

Early predictive biomarkers for the diagnosis and management of febrile urinary tract infections (UTIs) can be valuable diagnostic tools in children.

Methods

The study cohort comprised 73 pediatric patients with febrile UTIs [46 with acute pyelonephritis (APN) and 27 with lower UTIs] and 56 healthy children. Urine neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury molecule-1 (uKIM-1) levels and serum cystatin C (sCysC) levels were measured.

Results

The uNGAL/creatinine (Cr) and uKIM-1/Cr levels were higher in the UTI group than in the controls (P?P?P?C-reactive protein, CysC and with uKIM-1/Cr (P?P?Conclusions Our results suggest that uNGAL, uKIM-1 and sCysC levels may be useful for predicting and managing febrile UTIs in children.     

Functional polymorphisms in the P2X7 receptor gene are associated with osteoporosis

Summary

The P2X₇ receptor is an ATP-gated cation channel. We investigated the effect of both loss-of-function and gain-of-function polymorphisms in the P2X₇ receptor gene on BMD and risk of vertebral fractures and found that five polymorphisms and haplotypes containing three of these polymorphisms were associated with BMD and fracture risk.

Introduction

The P2X₇ receptor is an ATP-gated cation channel. P2X₇ receptor knockout mice have reduced total bone mineral content, and because several functional polymorphisms have been identified in the human P2X₇ receptor gene, we wanted to investigate the effect of these polymorphisms on BMD and risk of vertebral fractures in a case–control study including 798 individuals.

Methods

Genotyping was carried out using TaqMan assays. BMD was measured using dual energy X-ray absorptiometry, and vertebral fractures were assessed by lateral spinal X-rays.

Results

The rare allele of a splice site polymorphism, 151?+?1: G-T, was associated with increased fracture risk and reduced BMD in women. Two other loss-of-function polymorphisms, Glu496Ala and Gly150Arg, were also associated with BMD. The Glu496Ala variant allele was associated with decreased lumbar spine BMD in women and decreased total hip BMD in men. The 150Arg allele was associated with decreased total hip BMD in women and men combined. The minor allele of the gain-of-function polymorphism, Ala348Thr, was associated with reduced fracture risk and increased BMD at all sites in men. The Gln460Arg variant allele, which has been associated with increased receptor function in monocytes, was associated with increased total hip BMD in women. With the exception of His155Tyr for which we found conflicting results in men and women, our results are consistent with the phenotype of the knockout mouse. Analysis of a haplotype containing Ala348Thr, Gln460Arg, and Glu496Ala showed that the effects of the haplotypes on BMD and fracture were driven by Ala348Thr in men and by Gln460Arg and Glu496Ala in women.

Conclusion

In conclusion, we found that functional polymorphisms in the P2X₇ receptor gene and haplotypes containing three of these polymorphisms are associated with osteoporosis.     

Lipopolysaccharide-binding protein: a potential marker of febrile urinary tract infection in childhood

Background

Urinary tract infections (UTIs) are encountered frequently in children, and their early diagnosis and treatment are important. This study evaluates the diagnostic value of serum concentrations of lipopolysaccharide-binding protein (LBP), an acute-phase protein, in children with febrile UTI and compares it to those of the total white blood cell count (WBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6).

Methods

The study population comprised 77 consecutive patients with a first-episode febrile UTI (33 boys) with a median age of 11 months [interquartile range (IQR), 5.5–33 months], 21 healthy controls (11 boys) with a median age of 10 months (IQR, 5–20.5 months) and 58 febrile controls with a fever due to other causes (28 boys) with a median age of 12.5 months (IQR, 7–30 months). LBP, IL-6, PCT, and CRP were measured for both patients and control groups.

Results

The serum levels of LBP (p? < ?0.001), CRP (p? < ?0.001), PCT (p? = ?0.001), IL-6 (p? = ?0.002), ESR (p? = ?0.020), and WBC (p? < ?0.001) were higher in patients with febrile UTI than in the healthy and febrile control groups. The LPB cut-off value for best sensitivity and specificity in patients with febrile UTI was >43.23 mg/l. Furthermore, the area under the receiver operating characteristic curve was significantly greater for LBP than for CRP (p? = ?0.014), PCT (p? < ?0.001), ESR (p? < ?0.001), WBC (p? = ?0.002) and IL-6 (p? = ?0.006).

Conclusions

The results of this study suggest that the serum LBP concentration constitutes a reliable biologic marker for the diagnosis of a febrile UTI in children.     

Mutations in innate immune system NOD2/CARD 15 and TLR-4 (Thr399Ile) genes influence the risk for severe acute graft-versus-host disease in patients who underwent an allogeneic transplantation

BACKGROUND: NOD2 and TLR-4 genes belong to the innate immune system that detects invading pathogens through several pattern-recognition receptors. Here we analyzed 403 patients for NOD2 gene mutations and 307 patients for TLR-4 gene mutations (Thr399Ile) with their respective donors and correlated the results with the incidence of acute graft-versus-host disease (aGVHD), severe acute GVHD (saGVHD), the risk for transplant-related mortality (TRM), overall survival (OS) and incidence of infectious complications. METHODS: We performed a retrospective single-center study. Genotyping of TLR-4 and NOD2 were evaluated by real-time polymerase chain reaction. RESULTS: Surprisingly, we found a significant reduced incidence of aGVHD, saGVHD, and intestinal GVHD for patients with NOD2 gene mutations on the donor side with 50%, 0% and 2% compared to patients with the wild-type NOD2 gene with 65%, 17%, and 26%, respectively (P<0.02). However, the incidence of saGVHD increased in patients with NOD2 mutations on the patient and donor (P/D) side with 44% versus 17% compared to patients with the wild-type gene (P<0.03). TLR-4 gene mutations at P/D side had an increased risk for saGVHD with 42% versus 15% of patients with wild-type gene (P<0.04). OS, TRM, and incidence of infectious complications were not influenced by the mutated genes. Multivariate analysis confirmed that NOD2 gene mutations on the donor side had a reduced risk for saGVHD (P<0.001), whereas mutations of the NOD2 gene on P/D side had an increased risk for saGVHD (P<0.01) in our analysis. CONCLUSIONS: These results suggest that NOD2 mutations have influence on the occurrence of acute GVHD after transplantation.     

Toll-Like Receptor 4 and CD14 Gene Polymorphisms in Tunisian Kidney Transplantation

BackgroundAcute and chronic rejections remain an important cause of graft loss after renal transplantation. Currently, activation of innate immune responses through Toll-like receptors (TLRs) is suspected to be implied in the loss of the transplant tolerance.ObjectivesWe investigated functional single nucleotide polymorphisms (SNPs) of TLR4 and its coreceptor CD14 in kidney transplantation and looked for any potential role in acute rejection (AR) and chronic allograft nephropathy (CAN) and impact on graft survival.Patients and MethodsTLR4 (Asp299Gly) and CD14 (C/T -159) SNPs were detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 209 kidney transplant recipients (KTRs) including 132 treated with mycophenolate mofetil (MMF+). AR occurred in 59 patients and 24 were identified as having CAN by biopsy and scored according to the Banff criteria.ResultsThere were no significant associations between TLR4 and CD14 genotypes and alleles and the occurrence of both AR episodes and CAN. Moreover, TLR4 and CD14 SNPs did not seem to influence kidney graft survival. Analysis according to human leukocyte antigen (HLA) compatibility status, positivity of anti-HLA antibodies, and immunosuppression by MMF confirmed the absence of correlation of the investigated SNPs with the graft outcome. In addition, incidence of post-transplantation infections, including cytomegalovirus (CMV) infections, was not influenced by both TLR4 and CD14 SNPs.ConclusionThese results suggest that TLR4 (Asp299Gly) and CD14 (C/T -159) functional SNPs do not play a major role in AR, CAN, and kidney graft survival. Therefore, intragraft monitoring of TLR4/CD14 genes expression by messenger RNA (mRNA) would provide clarity on the exact role of these receptors in graft injuries.     

Relationship between post-SARS osteonecrosis and PAI-1 4G/5G gene polymorphisms

Objective

To explore the correlation between post-severe acute respiratory symptom (SARS) patients with osteonecrosis, investigate the etiology of post-SARS osteonecrosis and select the sensitive molecular symbols for early diagnosis and distinguish the high-risk population.

Methods

The studied subjects were divided into two groups. Sixty-two post-SARS patients with osteonecrosis were one group, and 52 age- and sex-matched healthy people were as normal controlled group. Empty stomach blood samples from cubital veins were collected from both groups. Plasminogen activator inhibitor (PAI) by means of enzyme-linked immunosorbent assay and PAI-1 4G/5G polymorphism was detected by polymerase chain reaction and solid phase oligonucleotide assay.

Results

The blood agents of post-SARS patients changed obviously with 15.64 ± 13.85 U/ml while the control group 7.96 ± 4.27 U/ml; 4G/4G genotype for the PAI-1 polymorphism detected in post-SARS group was more than that of the control group, but had no statistical significance. The plasma PAI activity was related to homozygote 4G/4G genotype. This reveals that homozygote 4G/4G genotype may be a susceptible gene mark to Chinese osteonecrosis patients.

Conclusion

Plasminogen activator inhibitor-1 is sensitive blood symbol for screening high-risk susceptible population; 4G/4G PAI-1 genotype may be an etiological factor in osteonecrosis.     

The Fibroblast Growth Factor Receptor-4 Arg388 Allele is Associated with Gastric Cancer Progression

Background  

Fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism, located in the FGFR4 gene exon 9, was reported to be associated with malignant tumors prognosis; however, there has been no relevant research for gastric cancer. The purpose of this study was to investigate the clinical significance of FGFR4 Gly388Arg polymorphism as well as the mRNA expression of FGFR4 in patients with gastric cancer.     

Lack of association of TLR4 polymorphisms with susceptibility to rheumatoid arthritis and ankylosing spondylitis: A meta-analysis

ObjectiveThe aim of the study was to determine whether polymorphisms of toll-like receptor 4 (TLR4) confer susceptibility to rheumatoid arthritis (RA) and ankylosing spondylitis (AS).MethodsA meta-analysis was conducted on the association between the D299G/T399I polymorphisms and RA/AS (when available) using (1) the allelic contrast, (2) the recessive, (3) the dominant, and (4) the additive models.ResultsA total of eleven relevant studies met the inclusion criteria were identified, including RA:D299G (six studies), T399I (three studies); AS: D299G (five studies), T399I (four studies). Meta-analysis was performed with fixed/random effect models. Overall, no significant RA/AS risk was found in all genetic models when all studies were pooled into the meta-analysis (P > 0.05).ConclusionsThe present study might suggest that TLR4 D299G/T399I polymorphisms are not associated with RA/AS susceptibility.     

Screening high-grade vesicoureteral reflux in young infants with a febrile urinary tract infection

Background

The lack of good evidence for improved outcomes in children and young infants with febrile urinary tract infection (UTI) after aggressive treatment for vesicoureteral reflux (VUR) has raised doubts regarding the need for routine voiding cystourethrography (VCUG), and the appropriate imaging evaluation in these children remains controversial.

Objectives

This prospective study aimed to determine whether abnormalities found on acute dimercaptosuccinic acid (DMSA) scan and ultrasound (US) can help indicate the necessity of voiding cystourethrography (VCUG) in young infants.

Methods

For 3.5?years, all infants younger than 3?months presenting with first febrile UTI were prospectively studied. All infants were hospitalized and investigated using US (<3?days after admission), DMSA scan (<5?days after admission), and VCUG (7–10?days after antibiotic treatment) after diagnosis. The association among findings of US, DMSA scan, and VCUG were evaluated.

Results

From 220 infants, there were abnormal results in 136 (61.8%) US and in 111 (50.5%) DMSA scans. By US, ten infants (4.5%) with abscess or structural abnormalities other than VUR were diagnosed. High-grade (III–V) VUR was present in 39 patients (17.7%). The sensitivities for high-grade VUR of renal US alone (76.9%) or DMSA scan alone (82.1%) were not as good as that of the “OR rule” strategy, which had 92.3% sensitivity and 94.3% negative predictive value.

Conclusions

To screen high-grade VUR in young infants with febrile UTI, US and acute DMSA scan could be performed first. VCUG is only indicated when abnormalities are apparent on either US or DMSA scan or both.     

Synergistical action of the β2 adrenoceptor and fatty acid binding protein 2 polymorphisms on the loss of glomerular filtration rate in Chinese patients with type 2 diabetic nephropathy

Purpose

Since altered sympathetic nerve activity and insulin resistance are implicated in the pathogenesis of type 2 diabetic nephropathy, we investigated the effect of polymorphic Arg16Gly and Gln27Glu in the β2 adrenoceptor gene and Ala54Thr in the fatty acid binding protein 2 gene on the estimated glomerular filtration rate (eGFR) in Chinese patients with the above disease.

Methods

A total of 552 diabetic subjects recruited from annual health examinations were studied. The eGFR was calculated from the Modification of Diet in Renal Disease equation for the Chinese. Plasma norepinephrine level and genotype were determined by high-performance liquid chromatography–tandem mass spectrometry and TaqMan method, respectively. Holter-derived heart rate viability (HRV) and the MRI-generated renal apparent diffusion coefficient (ADC) were evaluated.

Results

The Gly16Gly and Thr54Thr homozygotes had significantly higher microalbuminuria and lower eGFR against other genotypes in their individual polymorphism. Besides, the Gly16Gly variant exhibited markedly elevated norepinephrine level, whereas indicative of insulin resistance was increased in the Thr54Thr one. Multiple linear regression analysis further confirmed the independent genetic effect on the eGFR. Moreover, multifactor dimensionality reduction method detected a gene–gene synergistic action that subjects with the Gly16Gly/Thr54Thr genotype were exposed to higher risk of eGFR loss. Finally, these findings were accompanied by lower HRV and ADC, indicating sympathetically mediated hemodynamic changes.

Conclusions

By uncovering the genetic component of the coherent interplay between the elevated sympathetic nerve activity and metabolic disorders, our observations might promote the development of novel personalized prevention and management strategies against the diabetic nephropathy, especially in the genetically susceptible individuals.

     

d-mannose powder for prophylaxis of recurrent urinary tract infections in women: a randomized clinical trial

Purpose

To test whether d-mannose powder is effective for recurrent urinary tract infection (UTI) prevention.

Materials and methods

After initial antibiotic treatment of acute cystitis, 308 women with history of recurrent UTI and no other significant comorbidities were randomly allocated to three groups. The first group (n = 103) received prophylaxis with 2 g of d-mannose powder in 200 ml of water daily for 6 months, the second (n = 103) received 50 mg Nitrofurantoin daily, and the third (n = 102) did not receive prophylaxis.

Results

Overall 98 patients (31.8 %) had recurrent UTI: 15 (14.6) in the d-mannose group, 21 (20.4) in Nitrofurantoin group, and 62 (60.8) in no prophylaxis group, with the rate significantly higher in no prophylaxis group compared to active groups (P < 0.001). Patients in d-mannose group and Nitrofurantoin group had a significantly lower risk of recurrent UTI episode during prophylactic therapy compared to patients in no prophylaxis group (RR 0.239 and 0.335, P < 0.0001). In active groups, 17.9 % of patients reported side effects but they were mild and did not require stopping the prophylaxis. Patients in d-mannose group had a significantly lower risk of side effects compared to patients in Nitrofurantoin group (RR 0.276, P < 0.0001), but the clinical importance of this finding is low because Nitrofurantoin was well tolerated.

Conclusions

In our study, d-mannose powder had significantly reduced the risk of recurrent UTI which was no different than in Nitrofurantoin group. More studies will be needed to validate the results of this study, but initial findings show that d-mannose may be useful for UTI prevention.     

Endothelial nitric oxide synthase gene polymorphisms and the risk of osteonecrosis of the femoral head in systemic lupus erythematosus

Purpose

Nitric oxide (NO), a short-lived gaseous free radical, is a potent mediator of biological responses involved in the pathogenesis of autoimmune rheumatic diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Nitric oxide also serves as an important signal in physiological processes, including angiogenesis, thrombosis, and bone turnover, which are known to be related to the pathogenesis of osteonecrosis. We investigated whether NOS3 gene polymorphisms are associated with risk of osteonecrosis of the femoral head (ONFH).

Methods

Five polymorphisms in the NOS3 gene were genotyped using TaqMan assays in 306 controls, 150 SLE patients, and 50 SLE patients with ONFH (SLE_ONFH).

Results

We found that Asp258Asp and Glu298Asp (G894T) polymorphisms in the NOS3 gene were significantly associated with risk of ONFH. Additionally, we calculated haplotype frequencies of a linkage disequilibrium (LD) block in NOS3 (rs1799983???rs1800780) and tested for haplotype associations. The haplotypes G-A and T-A showed significant protective (P?=?1.6?×?10^-3; OR 0.39, 95 % confidence intervals (CI) 0.22–0.7) and increased risk (P?=?2.0 x 10^-5–6.0 x 10^-4; OR 3.17?3.73) effects for ONFH, respectively.

Conclusions

These results suggest that exonic NOS3 polymorphisms may increase the risk of ONFH in Korean SLE patients