Search tips
Search criteria

Results 1-17 (17)

Clipboard (0)

Select a Filter Below

more »
Year of Publication
Document Types
1.  Pregnane X receptor knockout mice display osteopenia with reduced bone formation and enhanced bone resorption 
The Journal of endocrinology  2010;207(3):257-263.
The steroid and xenobiotic receptor (SXR) and its murine ortholog pregnane X receptor (PXR) are nuclear receptors that are expressed mainly in the liver and intestine where they function as xenobiotic sensors. In addition to its role as a xenobiotic sensor, previous studies in our laboratories and elsewhere have identified a role for SXR/PXR as a mediator of bone homeostasis. Here, we report that systemic deletion of PXR results in marked osteopenia with mechanical fragility in female mice as young as 4 months old. Bone mineral density (BMD) of PXR knockout (PXRKO) mice was significantly decreased compared with the BMD of wild-type (WT) mice. Micro-computed tomography analysis of femoral trabecular bones revealed that the three-dimensional bone volume fraction of PXRKO mice was markedly reduced compared with that of WT mice. Histomorphometrical analysis of the trabecular bones in the proximal tibia showed a remarkable reduction in bone mass in PXRKO mice. As for bone turnover of the trabecular bones, bone formation is reduced, whereas bone resorption is enhanced in PXRKO mice. Histomorphometrical analysis of femoral cortical bones revealed a larger cortical area in WT mice than that in PXRKO mice. WT mice had a thicker cortical width than PXRKO mice. Three-point bending test revealed that these morphological phenotypes actually caused mechanical fragility. Lastly, serum levels of phosphate, calcium, and alkaline phosphatase were unchanged in PXRKO mice compared with WT. Consistent with our previous results, we conclude that SXR/PXR promotes bone formation and suppresses bone resorption thus cementing a role for SXR/PXR as a key regulator of bone homeostasis.
PMCID: PMC4476281  PMID: 20876238
2.  Pregnane X Receptor Knockout Mice Display Aging-Dependent Wearing of Articular Cartilage 
PLoS ONE  2015;10(3):e0119177.
Steroid and xenobiotic receptor (SXR) and its murine ortholog, pregnane X receptor (PXR), are nuclear receptors that are expressed at high levels in the liver and the intestine where they function as xenobiotic sensors that induce expression of genes involved in detoxification and drug excretion. Recent evidence showed that SXR and PXR are also expressed in bone tissue where they mediate bone metabolism. Here we report that systemic deletion of PXR results in aging-dependent wearing of articular cartilage of knee joints. Histomorphometrical analysis showed remarkable reduction of width and an enlarged gap between femoral and tibial articular cartilage in PXR knockout mice. We hypothesized that genes induced by SXR in chondrocytes have a protective effect on articular cartilage and identified Fam20a (family with sequence similarity 20a) as an SXR-dependent gene induced by the known SXR ligands, rifampicin and vitamin K2. Lastly, we demonstrated the biological significance of Fam20a expression in chondrocytes by evaluating osteoarthritis-related gene expression of primary articular chondrocytes. Consistent with epidemiological findings, our results indicate that SXR/PXR protects against aging-dependent wearing of articular cartilage and that ligands for SXR/PXR have potential role in preventing osteoarthritis caused by aging.
PMCID: PMC4352085  PMID: 25749104
3.  Inflammatory stimuli induce inhibitory S-nitrosylation of the deacetylase SIRT1 to increase acetylation and activation of p53 and p65 
Science signaling  2014;7(351):ra106.
Inflammation increases the abundance of inducible nitric oxide synthase (iNOS), leading to enhanced production of nitric oxide (NO), which can modify proteins by S-nitrosylation. Enhanced NO production increases the activities of the transcription factors p53 and nuclear factor κB (NF-κB) in several models of disease-associated inflammation. S-Nitrosylation inhibits the activity of the protein deacetylase SIRT1. SIRT1 limits apoptosis and inflammation by deacetylating p53 and p65 (also known as RelA), a subunit of NF-κB. We showed in multiple cultured mammalian cell lines that NO donors or inflammatory stimuli induced S-nitrosylation of SIRT1 within CXXC motifs, which inhibited SIRT1 by disrupting its ability to bind zinc. Inhibition of SIRT1 reduced deacetylation and promoted activation of p53 and p65, leading to apoptosis and increased expression of proinflammatory genes. In rodent models of systemic inflammation, Parkinson’s disease, or aging-related muscular atrophy, S-nitrosylation of SIRT1 correlated with increased acetylation of p53 and p65 and activation of p53 and NF-κB target genes, suggesting that S-nitrosylation of SIRT1 may represent a proinflammatory switch common to many diseases and aging.
PMCID: PMC4340581  PMID: 25389371
4.  Metabolic Syndrome, Sarcopenia and Role of Sex and Age: Cross-Sectional Analysis of Kashiwa Cohort Study 
PLoS ONE  2014;9(11):e112718.
Recent epidemiological evidence suggests that effects of cardiovascular risk factors may vary depending on sex and age. In this study, we assessed the associations of metabolic syndrome (MetS) with sarcopenia and its components in older adults, and examined whether the associations vary by sex and age. We also tested if any one of the MetS components could explain the associations. We conducted a cross-sectional analysis of the baseline data from the cohort study conducted in Kashiwa city, Chiba, Japan in 2012 which included 1971 functionally-independent, community-dwelling Japanese adults aged 65 years or older (977 men, 994 women). Sarcopenia was defined based on appendicular skeletal muscle mass, grip strength and usual gait speed. MetS was defined based on the National Cholesterol Education Program’s Adult Treatment Panel-III criteria. The prevalence of sarcopenia was 14.2% in men and 22.1% in women, while the prevalence of MetS was 43.6% in men and 28.9% in women. After adjustment for potential confounders, MetS was positively associated with sarcopenia in men aged 65 to 74 years (odds ratio 5.5; 95% confidence interval 1.9–15.9) but not in older men or women. Among the sarcopenia components, MetS was associated with lower muscle mass and grip strength, particularly in men aged 65 to 74 years. The associations of MetS with sarcopenia and its components were mainly driven by abdominal obesity regardless of sex or age. In conclusion, MetS is positively associated with sarcopenia in older men. The association is modified by sex and age, but abdominal obesity is the main contributor to the association across sex and age.
PMCID: PMC4236117  PMID: 25405866
5.  Large-scale analysis reveals a functional single-nucleotide polymorphism in the 5′-flanking region of PRDM16 gene associated with lean body mass 
Aging Cell  2014;13(4):739-743.
Genetic factors are important for the development of sarcopenia, a geriatric disorder characterized by low lean body mass. The aim of this study was to search for novel genes that regulate lean body mass in humans. We performed a large-scale search for 250K single-nucleotide polymorphisms (SNPs) associated with bone mineral density (BMD) using SNP arrays in 1081 Japanese postmenopausal women. We focused on an SNP (rs12409277) located in the 5′-flanking region of the PRDM16 (PRD1-BF-1-RIZ1 homologous domain containing protein 16) gene that showed a significant P value in our screening. We demonstrated that PRDM16 gene polymorphisms were significantly associated with total body BMD in 1081 postmenopausal Japanese women. The rs12409277 SNP affected the transcriptional activity of PRDM16. The subjects with one or two minor allele(s) had a higher lean body mass than the subjects with two major alleles. Genetic analyses uncovered the importance of the PRDM16 gene in the regulation of lean body mass.
PMCID: PMC4326941  PMID: 24863034
aging; body lean mass; genetics; genome-wide association study; PRDM16; single-nucleotide polymorphism
6.  Liver-Specific γ-Glutamyl Carboxylase-Deficient Mice Display Bleeding Diathesis and Short Life Span 
PLoS ONE  2014;9(2):e88643.
Vitamin K is a fat-soluble vitamin that plays important roles in blood coagulation and bone metabolism. One of its functions is as a co-factor for γ-glutamyl carboxylase (Ggcx). Conventional knockout of Ggcx causes death shortly after birth in homozygous mice. We created Ggcx-floxed mice by inserting loxP sequences at the sites flanking exon 6 of Ggcx. By mating these mice with albumin-Cre mice, we generated Ggcx-deficient mice specifically in hepatocytes (GgcxΔliver/Δliver mice). In contrast to conventional Ggcx knockout mice, GgcxΔliver/Δliver mice had very low activity of Ggcx in the liver and survived several weeks after birth. Furthermore, compared with heterozygous mice (Ggcx+/Δliver), GgcxΔliver/Δliver mice had shorter life spans. GgcxΔliver/Δliver mice displayed bleeding diathesis, which was accompanied by decreased activity of coagulation factors II and IX. Ggcx-floxed mice can prove useful in examining Ggcx functions in vivo.
PMCID: PMC3919827  PMID: 24520408
7.  C-Reactive Protein, Bone Strength, and Nine-Year Fracture Risk: Data From the Study of Women’s Health Across the Nation (SWAN) 
Higher levels of C-reactive protein (CRP), an inflammatory marker, are associated with increased fracture risk, although previous studies on CRP and bone mineral density (BMD) have yielded conflicting results. We aimed to test the hypotheses that composite indices of femoral neck strength relative to load, which are inversely associated with fracture risk, would also be inversely associated with CRP, and would explain part of the association between CRP and fracture risk. We analyzed data from a multisite, multiethnic prospective cohort of 1872 community-dwelling women, premenopausal or early perimenopausal at baseline. Femoral neck composite strength indices in three failure modes were calculated using dual-energy X-ray absorptiometry (DXA)-derived femoral neck width (FNW), femoral neck axis length (FNAL), femoral neck BMD and body size at baseline, as BMD*FNW/weight for compression strength, BMD*(FNW)2/(FNAL*weight) for bending strength, and BMD*FNW*FNAL/(height*weight) for impact strength. Incident nondigital, noncraniofacial fractures were ascertained annually over a median follow-up of 9 years. In analyses adjusted for age, race/ethnicity, diabetes, menopause transition stage, body mass index, smoking, alcohol use, physical activity, medications, prior fracture, and study site, CRP was associated inversely with each composite strength index (0.035–0.041 SD decrement per doubling of CRP, all p< 0.001), but not associated with femoral neck or lumbar spine BMD. During the follow-up, 194 women (10.4%) had fractures. In Cox proportional hazards analyses, fracture hazard increased linearly with loge(CRP), only for CRP levels ≥ 3 mg/L. Addition of femoral neck or lumbar spine BMD to the model did not attenuate the CRP-fracture association. However, addition of any of the composite strength indices attenuated the CRP-fracture association and made it statistically nonsignificant. We conclude that fracture risk increases with increasing CRP, only above the threshold of 3 mg/L. Unlike BMD, composite strength indices are inversely related to CRP levels, and partially explain the increased fracture risk associated with inflammation.
PMCID: PMC3880424  PMID: 23456822
8.  Respiratory dysrhythmia in dementia with Lewy bodies: a cross-sectional study 
BMJ Open  2013;3(9):e002870.
Dementia with Lewy bodies (DLB) is the second most common form of neurodegenerative dementia after Alzheimer's disease (AD). DLB is characterised by intracytoplasmic inclusions called Lewy bodies that are often seen in the brainstem. Because modulation of the respiratory rhythm is one of the most important functions of the brainstem, patients with DLB may exhibit dysrhythmic breathing. This hypothesis has not yet been systematically studied. Therefore, we evaluated the association between DLB and dysrhythmic breathing.
In this cross-sectional study consecutive inpatients who were admitted for the evaluation of progressive cognitive impairment were enrolled. We assessed breathing irregularity using polysomnographic recordings on bed rest with closed eyes, without reference to the clinical differentiation among DLB, AD and having no dementia.
Single centre in Japan.
14 patients with DLB , 21 with AD and 12 without dementia were enrolled in this study.
Primary outcome measures
The coefficient of variation (CV) of the breath-to-breath time was calculated. We also examined the amplitude spectrum A(f) obtained using the fast Fourier transform and Shannon entropy S of A(f) in patients with DLB compared with patients with AD and patients without dementia.
The values of CV and entropy S were significantly higher in patients with DLB than in patients with AD and patients without dementia. No significant differences were observed between patients with AD and patients without dementia.
Patients with DLB exhibit dysrhythmic breathing compared with patients with AD and patients without dementia. Dysrhythmic breathing is a new clinical feature of DLB and the spectral analysis of breathing patterns can be clinically useful for the diagnostic differentiation of DLB from AD.
PMCID: PMC3773650  PMID: 24022387
9.  Clinical Significance of Amyloid Precursor Protein in Patients with Testicular Germ Cell Tumor 
Advances in Urology  2013;2013:348438.
Introduction. The biological role of amyloid precursor protein (APP) is not well understood, especially in testicular germ cell tumors (TGCTs). Therefore, we aimed to investigate the immunoreactivity (IR) and expression of APP in TGCTs and evaluated its clinical relevance. Materials and Methods. We performed an analysis of immunohistochemistry and mRNA expression of APP in 64 testicular specimens and 21 snap-frozen samples obtained from 1985 to 2004. We then evaluated the association between APP expression and clinicopathological status in TGCTs. Results. Positive APP IR was observed in 9.8% (4/41) of seminomatous germ cell tumors (SGCTs) and 39.1% (9/23) of nonseminomatous germ cell tumors (NGCTs). NGCTs showed significantly more cases of positive IR (P = 0.00870) and a higher mRNA expression level compared with those of SGCTs (P = 0.0140). Positive APP IR was also significantly associated with α-fetoprotein (αFP) elevation (P = 0.00870) and venous invasion (P = 0.0414). Conclusion. We observed an elevated APP expression in TGCTs, especially in NGCTs. APP may be associated with a more aggressive cancer in TGCTs.
PMCID: PMC3639667  PMID: 23662100
10.  Ginsenoside Rb1 Prevents MPP+-Induced Apoptosis in PC12 Cells by Stimulating Estrogen Receptors with Consequent Activation of ERK1/2, Akt and Inhibition of SAPK/JNK, p38 MAPK 
Ginsenoside Rb1 shows neuroprotective effects in various neurons, including dopaminergic cells. However, the precise mechanisms of action are uncertain. In this paper, we examine whether Rb1 has a neuroprotective effect on MPP+-induced apoptosis and attempt to clarify the signaling pathway in PC12 cells. Apoptosis of PC12 cells was determined by DNA fragmentation assay, the activation of caspase-3, or by the inactivation of Bcl-xL. Rb1 inhibited MPP+-induced caspase-3 activation and DNA fragmentation and activated Bcl-xL in MPP+-treated PC12 cells. These antiapoptotic effect was abrogated in PC12 cells transfected with estrogen receptor siRNA. Levels of DNA fragmentation were increased by wortmannin or PD 98059, while they were decreased by SB 203580 or SP 600125 in MPP+-treated PC12 cells. Rb1 increased phosphorylation levels of ERK1/2 or Akt in MPP+-treated PC12 cells, while it reduced phosphorylated p38 or SAPK/JNK. The increased phosphorylation of ERK/1/2 or Akt by Rb1 was abrogated by estrogen receptor siRNA. Rb1-induced inhibition of SAPK/JNK or p38 phosphorylation was also abolished by estrogen receptor siRNA. These results suggest that ginsenoside Rb1 protects PC12 cells from caspase-3-dependent apoptosis through stimulation of estrogen receptor with consequent activation of ERK1/2 and Akt and inhibition of SAPK/JNK and p38.
PMCID: PMC3457685  PMID: 23024694
11.  Antimicrobial peptide defensin: Identification of novel isoforms and the characterization of their physiological roles and their significance in the pathogenesis of diseases 
Defensins comprise a family of cationic antimicrobial peptides containing a specific six-cysteine motif. Their contribution to the host defense against microbial invasion and the control of normal flora have been previously described. Some of the β-defensin isoforms are predominantly expressed in the epididymis and showed a region-specific expression pattern in the epididymis, which thus suggested that these isoforms may possess epididymis-specific functions in addition to antimicrobial activities. A sequence variant of the β-defensin 126 gene has been shown to be associated with reductions in the human sperm function, thus supporting this hypothesis. Furthermore, defensins have the capacity to chemoattract immune cells and induce the secretion of inflammatory cytokines. Mice expressing human neutrophil α-defensin showed more severe lung injuries after the aspiration of acidic contents than did control mice. Recent investigations regarding copy number variations of human defensin genes also suggest the significance of defensin in the pathogenesis or the worsening of chronic obstructive pulmonary diseases, sepsis and psoriasis.
PMCID: PMC3406309  PMID: 22498979
defensin; antimicrobial peptide; epididymis; cytotoxicity; lipopolysaccharide; inflammation
12.  Single-nucleotide polymorphism in the hyaluronan and proteoglycan link protein 1 (HAPLN1) gene is associated with spinal osteophyte formation and disc degeneration in Japanese women 
European Spine Journal  2010;20(4):572-577.
Spinal osteoarthritis including disc degeneration is a very common condition in the axial skeletons of aged people. Recently, spinal osteoarthritis has been shown to be influenced by specific genetic risk factors. Vertebral osteophytes, endplate sclerosis, and intervertebral disc narrowing are recognized as radiographic features of spinal disc degeneration. HAPLN1 is a key component of the cartilage extracellular matrix; thus, variations in this gene may affect the pathogenesis of cartilage-related diseases such as spinal degeneration. Here, we examine the association between an HAPLN1 gene polymorphism and the radiographic features of spinal degeneration. We evaluated the degree of endplate sclerosis, osteophyte formation, and disc space narrowing in 622 Japanese postmenopausal women. Four SNPs in the HAPLN1 gene—in the 5′ flanking region, intron 1, intron 2, and intron 4—were analyzed using the TaqMan polymerase chain reaction method. We found that compared to subjects with the CC or CT genotype, those with the TT genotype for an SNP at intron 2 (rs179851) were significantly overrepresented among the subjects with higher scores for osteophyte formation (P = 0.0001; odds ratio 2.12; 95% confidence interval 1.45–3.11, as determined by logistic regression analysis) and disc space narrowing (P = 0.0057; odds ratio 1.83; 95% confidence interval 1.19–2.83). Consistent with the involvement of the HAPLN1 gene in cartilage metabolism, a variation in a specific HAPLN1 gene locus may be associated with spinal degeneration.
PMCID: PMC3065599  PMID: 20953637
Single-nucleotide polymorphism (SNP); Hyaluronan and proteoglycan link protein gene (HAPLN1); Osteoarthritis; Cartilage; Disc degeneration
13.  Testosterone Deficiency Accelerates Neuronal and Vascular Aging of SAMP8 Mice: Protective Role of eNOS and SIRT1 
PLoS ONE  2012;7(1):e29598.
Oxidative stress and atherosclerosis-related vascular disorders are risk factors for cognitive decline with aging. In a small clinical study in men, testosterone improved cognitive function; however, it is unknown how testosterone ameliorates the pathogenesis of cognitive decline with aging. Here, we investigated whether the cognitive decline in senescence-accelerated mouse prone 8 (SAMP8), which exhibits cognitive impairment and hypogonadism, could be reversed by testosterone, and the mechanism by which testosterone inhibits cognitive decline. We found that treatment with testosterone ameliorated cognitive function and inhibited senescence of hippocampal vascular endothelial cells of SAMP8. Notably, SAMP8 showed enhancement of oxidative stress in the hippocampus. We observed that an NAD+-dependent deacetylase, SIRT1, played an important role in the protective effect of testosterone against oxidative stress-induced endothelial senescence. Testosterone increased eNOS activity and subsequently induced SIRT1 expression. SIRT1 inhibited endothelial senescence via up-regulation of eNOS. Finally, we showed, using co-culture system, that senescent endothelial cells promoted neuronal senescence through humoral factors. Our results suggest a critical role of testosterone and SIRT1 in the prevention of vascular and neuronal aging.
PMCID: PMC3251570  PMID: 22238626
14.  Primary Role of Functional Ischemia, Quantitative Evidence for the Two-Hit Mechanism, and Phosphodiesterase-5 Inhibitor Therapy in Mouse Muscular Dystrophy 
PLoS ONE  2007;2(8):e806.
Duchenne Muscular Dystrophy (DMD) is characterized by increased muscle damage and an abnormal blood flow after muscle contraction: the state of functional ischemia. Until now, however, the cause-effect relationship between the pathogenesis of DMD and functional ischemia was unclear. We examined (i) whether functional ischemia is necessary to cause contraction-induced myofiber damage and (ii) whether functional ischemia alone is sufficient to induce the damage.
Methodology/Principal Findings
In vivo microscopy was used to document assays developed to measure intramuscular red blood cell flux, to quantify the amount of vasodilatory molecules produced from myofibers, and to determine the extent of myofiber damage. Reversal of functional ischemia via pharmacological manipulation prevented contraction-induced myofiber damage in mdx mice, the murine equivalent of DMD. This result indicates that functional ischemia is required for, and thus an essential cause of, muscle damage in mdx mice. Next, to determine whether functional ischemia alone is enough to explain the disease, the extent of ischemia and the amount of myofiber damage were compared both in control and mdx mice. In control mice, functional ischemia alone was found insufficient to cause a similar degree of myofiber damage observed in mdx mice. Additional mechanisms are likely contributing to cause more severe myofiber damage in mdx mice, suggestive of the existence of a “two-hit” mechanism in the pathogenesis of this disease.
Evidence was provided supporting the essential role of functional ischemia in contraction-induced myofiber damage in mdx mice. Furthermore, the first quantitative evidence for the “two-hit” mechanism in this disease was documented. Significantly, the vasoactive drug tadalafil, a phosphodiesterase 5 inhibitor, administered to mdx mice ameliorated muscle damage.
PMCID: PMC1950086  PMID: 17726536
15.  Influences of age, sex, and LDL-C change on cardiovascular risk reduction with pravastatin treatment in elderly Japanese patients: A post hoc analysis of data from the Pravastatin Anti-atherosclerosis Trial in the Elderly (PATE) 
The Pravastatin Anti-atherosclerosis Trial in the Elderly (PATE) found that the prevalence of cardiovascular events (CVEs) was significantly lower with standard-dose (10–20 mg/d) pravastatin treatment compared with low-dose (5 mg/d) pravastatin treatment in elderly (aged ⩾ 60 years) Japanese patients with hypercholesterolemia. Small differences in on-treatment total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels between the 2 dose groups in the PATE study were associated with significant differences in CVE prevalence. However, the reasons for these differences have not been determined. How sex and age differences influence the effectiveness of pravastatin also remains unclear.
The aims of this study were to determine the relationship between reduction in LDL-C level and CVE risk reduction in the PATE study and to assess the effects of sex and age on the effectiveness of pravastatin treatment (assessed using CVE risk reduction).
In this post hoc analysis, Cox regression analysis was performed to study the relationship between on-treatment (pravastatin 5–20 mg/d) LDL-C level and CVE risk reduction using age, sex, smoking status, presence of diabetes mellitus and/or hypertension, history of cardiovascular disease (CVD), and high-density lipoprotein cholesterol level as adjustment factors. To explore risk reduction due to unspecified mechanisms other than LDLrC reduction, an estimated Kaplan-Meier curve from the Cox regression analysis was calculated and compared with the empirical (observed) Kaplan-Meier curve.
A total of 665 patients (527 women, 138 men; mean [SD] age, 72.8 [5.7] years) were enrolled in PATE and were followed up for a mean of 3.9 years (range, 3–5 years). Of those patients, 50 men and 173 women were ⩾75 years of age. Data from 619 patients were included in the present analysis. In the calculation of model-based Kaplan-Meier curves, data from an additional 32 patients were excluded from the LDL-C analysis because there were no data on pretreatment LDL levels; hence, the data from 587 patients were analyzed. A reduction in LDL-C level of 20 mg/dL was associated with an estimated CVE risk reduction of 24.7% (hazard ratio [HR] = 0.753; 95% CI, 0.625-0.907; P = 0.003). Risk was reduced by 22.2% in patients aged <75 years (HR = 0.778; 95% CI, 0.598–1.013; P = NS) and 29.9% in patients aged ⩾75 years (HR = 0.701; 95% CI, 0.526–0.934; P = 0.015). The risk reductions were 19.8% in women (HR = 0.802; 95% CI, 0.645–0.996; P = 0.046) and 35.8% in men (HR = 0.642; 95% CI, 0.453–0.911; P = 0.013). The risk reduction was 32.4% in patients without a history of CVD at enrollment (HR = 0.676; 95% CI, 0.525–0.870; P = 0.002) and 15.1% in those with a history of CVD (HR = 0.849; 95% CI, 0.630–1.143; P= NS). The estimated Kaplan-Meier curve strongly suggested that the effects of pravastatin were only partially associated with changes in LDLrC level.
The results from this post hoc analysis suggest that pravastatin 5 to 20 mg/d might elicit CVE risk reduction by mechanisms other than cholesterol-lowering effects alone. They also suggest that pravastatin treatment might be effective in reducing the risk for CVEs in both female and male patients aged ⩾75 years.
PMCID: PMC3965978  PMID: 24678100
PATE study; elderly; hypercholesterolemia; pravastatin; PROBE trial; post hoc
16.  Increased risk for cardiovascular outcomes and effect of cholesterol-lowering pravastatin therapy in patients with diabetes mellitus in the pravastatin anti-atherosclerosis trial in the elderly (PATE) 
The Pravastatin Anti-atherosclerosis Trial in the Elderly (PATE) was the first large-scale, prospective clinical trial to show that cholesterol-lowering therapy with pravastatin is effective in reducing the risk for cardiovascular events (CVEs) in elderly (aged ≥60 years) patients with hypercholesterolemia. PATE also included a subgroup of patients with diabetes mellitus (DM).
The aim of this post hoc analysis was to assess the effects of lon-gtermpravastatin therapy on cardiovascular outcomes in the subgroup of patients with DM compared with a subgroup without it.
PATE was conducted at 50 hospitals, universities, and clinics acrossJapan. Patients were randomly allocated to 1 of 2 treatment groups: low-dose pravastatin (5 mg PO QD; L group) or standard-lose pravastatin (in Japan, 10 mg PO QD; S group). Treatment was given for 3 to 5 years. Serum cholesterol levels were measured and the prevalence of CVEs was determined. The primary end point of the study was the S:L risk ratio for fatal or nonfatal CVEs. The secondary end point was the effect of diabetic patients' glycemic control on CVEs.
A total of 665 patients (527 women, 138 men; mean [SD] age, 72.8[5.7] years) were followed up for a mean of 3.9 years (range, 3–5 years). Among these, 199 patients had DM; 104 patients with DM were allocated to the L group and 95 to the S group. Four hundred sixty-six patients did not have DM (L group, 230 patients; S group, 236 patients). Overall, between 3 months and 3 years after the initiation of treatment, patients in the L group (mean dose, 4.5 mg/d) experienced reductions from baseline total cholesterol level of 11% to 13%. Those in the S group (mean dose, 8.3 mg/d) experienced reductions from baseline of 15% to 17%. Decreases in low-density lipoprotein cholesterol (LDL-C) levels were 17% to 20% and 23% to 26% in the L and S groups, respectively. Statistically similar reductions were noted between patients with DM and those without it in response to either dose. The DM subgroup experienced 32 CVEs (L group, 17; S group, 15) compared with 39 CVEs (L group, 25; S group, 14) in the subgroup without DM. The S:L CVE risk ratio (primary end point) was 0.94 (95% Cl, 0.46–1.92) in patients with DM and 0.54 (95% Cl, 0.28–1.05) in those without DM; the differences between the treatment groups were not statistically significant. The risk for CVEs in patients with DM whose glycosylated hemoglobin concentrations were <8.0% and ≥8.0% were, respectively, 1.87-fold (95% Cl, 1.09–3.20; P = 0.02) and 3.79-fold (95% Cl, 1.92–7.48; P < 0.01) higher than that in patients without DM.
In this post hoc analysis of the effects of long-term cholesterol-loweringtherapy (low- and standard-dose pravastatin) on cardiovascular outcomes in elderly patients with DM, dose had no effect on the risk for CVEs in these patients as it did in those without DM. Poorer glycemic control in patients with DM was related to a higher risk for CVEs. The lack of pravastatin efficacy found in the subgroup with DM may have been attributable to the small differences in LDL-C levels found between the 2 treatment groups and/or the small sample size of the study.
PMCID: PMC3964557  PMID: 24672112
PATE study; elderly patients; pravastatin; hyperlipidemia; diabetes mellitus; prospective interventional trial
17.  Platelet-activating factor mediates acid-induced lung injury in genetically engineered mice 
Journal of Clinical Investigation  1999;104(8):1071-1076.
Adult respiratory distress syndrome (ARDS) is an acute lung injury of high mortality rate, and the molecular mechanisms underlying it are poorly understood. Acid aspiration–induced lung injury is one of the most common causes of ARDS, characterized by an increase in lung permeability, enhanced polymorphonuclear neutrophil (PMN) sequestration, and respiratory failure. Here, we investigated the role of platelet-activating factor (PAF) and the PAF receptor (PAFR) gene in a murine model of acid aspiration–induced lung injury. Overexpression of the PAFR gene in transgenic mice enhanced lung injury, pulmonary edema, and deterioration of gas exchange caused by HCl aspiration. Conversely, mice carrying a targeted disruption of the PAFR gene experienced significantly less acid-induced injury, edema, and respiratory failure. Nevertheless, the efficiency of PMN sequestration in response to acid aspiration was unaffected by differences in PAFR expression level. The current observations suggest that PAF is involved in the pathogenesis of acute lung injury caused by acid aspiration. Thus, inhibition of this pathway might provide a novel therapeutic approach to acute lung injury, for which no specific pharmaceutical agents are currently available.
PMCID: PMC481051  PMID: 10525045

Results 1-17 (17)