Laser Doppler blood flowmeter as a useful instrument for the early detection of lower extremity peripheral arterial disease in hemodialysis patients: an observational study.

BACKGROUND: A simpler method for detecting atherosclerosis obliterans is required in the clinical setting. Laser Doppler flowmetry (LDF) is easy to perform and can accurately detect deterioration in skin perfusion. We performed LDF for hemodialysis patients to determine the correlations between blood flow in the lower limbs and peripheral arterial disease (PAD). METHODS: This retrospective study included 128 hemodialysis patients. Patients were categorized into the non-PAD group (n = 106) and PAD group (n = 22), 14 early stage PAD patients were included in the PAD group. We conducted LDF for the plantar area and dorsal area of the foot and examined skin perfusion pressure (SPP) during dialysis. RESULTS: SPP-Dorsal Area values were 82.1 ± 22.0 mmHg in the non-PAD, and 59.1 ± 20.3 mmHg in PAD group, respectively (p < 0.05). The LDF-Plantar blood flow (Qb) values were 32.7 ± 15.5 mL/min in non-PAD group and 21.5 ± 11.3 mL/min in PAD group (p < 0.001). A total of 21 non-PAD patients underwent LDF before and during dialysis. The LDF-Plantar-Qb values were 36.5 ± 17.6 mL/min before dialysis and 29.6 ± 17.7 mL/min after dialysis (p < 0.05). We adjusted SPP and LDF for PAD using logistic regression, SPP-Dorsal-Area and LDF-P were significantly correlated with PAD (p < 0.05). The receiver-operating characteristic curve analysis indicated cut-off values of 20.0 mL/min for LDF-Plantar-Qb during dialysis. CONCLUSION: LDF is a simple technique for sensitive detection of early-stage PAD. This assessment will help physicians identify early-stage PAD, including Fontaine stage II in clinical practice, thereby allowing prompt treatment.

Cdh1 degradation is mediated by APC/C-Cdh1 and SCF-Cdc4 in budding yeast.

Cdh1, a substrate-recognition subunit of anaphase-promoting complex/cyclosome (APC/C), is a tumor suppressor, and it is downregulated in various tumor cells in humans. APC/C-Cdh1 is activated from late M phase to G1 phase by antagonizing Cdk1-mediated inhibitory phosphorylation. However, how Cdh1 protein levels are properly regulated is ill-defined. Here we show that Cdh1 is degraded via APC/C-Cdh1 and Skp1-Cullin1-F-box (SCF)-Cdc4 in the budding yeast Saccharomyces cerevisiae. Cdh1 degradation was promoted by forced localization of Cdh1 into the nucleus, where APC/C and SCF are present. Cdk1 promoted APC/C-Cdh1-mediated Cdh1 degradation, whereas polo kinase Cdc5 elicited SCF-Cdc4-mediated degradation. Thus, Cdh1 degradation is controlled via multiple pathways.

Impact of clinical trial design and execution-related factors on incidence of thromboembolic events in cancer patients: a systematic review and meta-analysis.

OBJECTIVE: The objective of this study was to quantify the incidence of thromboembolic events (specifically, deep vein thromboses [DVT] and pulmonary embolism [PE]) in patients with cancer, and to examine the effects of a major clinical trial design and execution factors on those incidence rates. RESEARCH DESIGN AND METHODS: The study included a systematic review of Medline, Current Contents, and accepted study bibliographies, as well as an analysis of studies. Studies included both longitudinal studies (prospective and retrospective) published in the English language between January 1990 and October 2005. Studies of patients with cancer that reported the incidence of thromboembolic events (DVT, PE, and total venous thromboembolic events [VTE]) were eligible for inclusion. Incidence of these events was calculated by study design, surveillance type (active or passive), length of follow-up, and other treatment risk factors. Incidence rates were estimated by random effects Poisson meta-regression modeling. RESULTS: One hundred and eighty-three studies met all inclusion criteria. Incidence rates of all outcomes (DVT, PE, and total VTE) were 3-55 times higher for active surveillance than for passive surveillance. Studies with a follow-up time 6 months. Additionally, the incidence rates for all outcome events when using passive surveillance were 3-12 times higher in non-randomized clinical trials (non-RCTs) than in RCTs. CONCLUSIONS: These results provide a benchmark for the incidence of thromboembolic events in patients with cancer. Factors such as study design, length of follow-up, and method of case ascertainment (type of surveillance - active or passive) must be considered when interpreting thromboembolic incidence rates. This review is comprehensive in its inclusion of all studies with a scientific objective of examining the risk of thromboembolic events in patients with cancer from 1990 to 2005. However, other studies published prior to 1990, more recently than 2005, or with other scientific objectives in their research may also provide supportive information to these risk estimates.

Serum pegfilgrastim concentrations during recovery of absolute neutrophil count in patients with cancer receiving pegfilgrastim after chemotherapy.

STUDY OBJECTIVE: To examine the serum concentrations of pegfilgrastim during recovery of absolute neutrophil count (ANC) in patients with cancer who received pegfilgrastim after chemotherapy. DESIGN: Retrospective analysis. DATA SOURCE: Data were pooled from seven pegfilgrastim registrational clinical trials: four open-label phase I or II studies and three randomized phase II or III studies. PATIENTS: A total of 370 patients with non-small cell lung cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, or breast cancer. MEASUREMENTS AND MAIN RESULTS: Chemotherapy was given every 3 weeks, and pegfilgrastim was given once/chemotherapy cycle, 24 hours after chemotherapy completion. Data were available from 187 patients for the serum pegfilgrastim concentration analysis and from 319 patients for the ANC data analysis. Recovery of ANC to normal levels (>or= 1 x 10(3)/mm3) correlated well with the decline of pegfilgrastim concentrations to subtherapeutic levels; this inverse correlation was observed across different tumor types. By day 12 after pegfilgrastim administration, all patients experienced ANC recovery to normal levels, and none had a serum pegfilgrastim concentration above 2 ng/ml, considered the lowest concentration to elicit clinically meaningful granulopoiesis. After administration of pegfilgrastim, a steady postnadir recovery of the ANC to normal levels was noted, and postnadir peaks of 30 x 10(3)/mm3 or higher were observed in only three patients. CONCLUSION: Serum concentrations of pegfilgrastim were consistently cleared to subtherapeutic levels by day 12 after pegfilgrastim administration, and subtherapeutic pegfilgrastim levels were predicted by ANC recovery to 1 x 10(3)/mm3 or greater.

Validation of a screening protocol for identifying low-risk candidates with type 1 diabetes mellitus for kidney with or without pancreas transplantation.

BACKGROUND: Certain clinical risk factors are associated with significant coronary artery disease in kidney transplant candidates with diabetes mellitus. We sought to validate the use of a clinical algorithm in predicting post-transplantation mortality in patients with type 1 diabetes. We also examined the prevalence of significant coronary lesions in high-risk transplant candidates. METHODS: All patients with type 1 diabetes evaluated between 1991 and 2001 for kidney with/without pancreas transplantation were classified as high-risk based on the presence of any of the following risk factors: age >or=45 yr, smoking history >or=5 pack years, diabetes duration >or=25 yr or any ST-T segment abnormalities on electrocardiogram. Remaining patients were considered low risk. All high-risk candidates were advised to undergo coronary angiography. The primary outcome of interest was all-cause mortality post-transplantation. RESULTS: Eighty-four high-risk and 42 low-risk patients were identified. Significant coronary artery stenosis was detected in 31 high-risk candidates. Mean arterial pressure was a significant predictor of coronary stenosis (odds ratio 1.68; 95% confidence interval 1.14-2.46), adjusted for age, sex and duration of diabetes. In 75 candidates who underwent transplantation with median follow-up of 47 months, the use of clinical risk factors predicted all eight deaths. No deaths occurred in low-risk patients. A significant mortality difference was noted between the two risk groups (p = 0.03). CONCLUSIONS: This clinical algorithm can identify patients with type 1 diabetes at risk for mortality after kidney with/without pancreas transplant. Patients without clinical risk factors can safely undergo transplantation without further cardiac evaluation.

Interval from prostate biopsy to radical prostatectomy: effect on PSA, Gleason sum, and risk of recurrence.

OBJECTIVES: To determine whether the change in prostate-specific antigen (PSA), change in Gleason sum, and/or interval between prostate biopsy and radical prostatectomy have an association with biochemical recurrence. METHODS: The relationship between biochemical recurrence and the interval between biopsy and surgery, as well as the rate and amount of change in PSA and Gleason sum from biopsy to surgery, was evaluated in 151 patients with prostate cancer treated with radical prostatectomy. RESULTS: A statistically significant increase was found in PSA level and Gleason sum between biopsy and surgery (P = 0.01 and P < 0.0001, respectively). No significant association was found between prebiopsy PSA level (P = 0.27) or biopsy Gleason sum (P = 0.07) with biochemical recurrence as independent variables or in a combined model (P = 0.12). An association was also not found between recurrence and preprostatectomy PSA level (P = 0.15) or the rate of PSA change (P = 0.28) as independent variables. However, a significant association was found with the prostatectomy Gleason sum (P = 0.001). In a combined model, a significant association was noted between the preprostatectomy PSA level and prostatectomy specimen Gleason sum and biochemical recurrence (P = 0.003). No increased risk of biochemical recurrence was noted with increasing time from biopsy to prostatectomy (odds ratio 1.00) or the rate (odds ratio 1.03) and degree (odds ratio 1.30) of serum PSA or Gleason sum (odds ratio 1.07). CONCLUSIONS: The interval between biopsy and radical prostatectomy is not a predictor of biochemical failure. An association was noted between an increased risk of biochemical failure and the amount of serum PSA and Gleason sum increase between biopsy and surgery.

Single high-dose intravenous immunoglobulin therapy for kawasaki disease increases plasma viscosity.

BACKGROUND: Intravenous immunoglobulin therapy, widely used for various autoimmune and systemic inflammatory diseases including Kawasaki disease (KD), is occasionally associated with thromboembolic adverse effects caused by an abrupt increase in blood viscosity. Scarce information is available, however, regarding the effect of single high-dose immunoglobulin therapy for KD on blood viscosity. METHODS AND RESULTS: Eleven boys and 5 girls (mean age: 2.1 years) with acute-phase KD underwent single high-dose immunoglobulin therapy. Plasma viscosity before the treatment was 1.18 centipoises (SD = 0.06), but it significantly rose to 1.34 centipoises (SD = 0.06) (p < 0.001). Multiple regression analysis revealed that, among various factors including hematocrit, plasma concentrations of total protein, immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin M (IgM), only plasma IgG concentration was included in the model to explain plasma viscosity (R2 = 0.59, p < 0.001). CONCLUSIONS: Single high-dose regimen for acute-phase KD increases blood viscosity and therefore might increase the risk of thromboembolism.

Increasing colorectal cancer incidence rates in Japan.

We examined trends of colorectal cancer incidence rates among Japanese (Miyagi Prefecture) and United States (US) whites (State of Connecticut) between 1959 and 1992. Age-standardized rates in Japan have increased dramatically and are now similar to US white rates. For both colon and rectum, age-specific rates in Japanese men born after 1930 exceed those in US whites, and the Japanese excess increases with year of birth. Similar patterns are evident for women. The current trends suggest that colorectal cancer will become a major source of morbidity and mortality in Japan, as these young Japanese age and their risks increase.

ABO blood type, Lewis and Secretor genotypes, and chronic atrophic gastritis: a cross-sectional study in Japan.

BACKGROUND: the H type I structure, synthesized by the secretor (Se) enzyme in gastric foveolar cells, and its metabolite, Lewis b (le(b)) antigen, mediate the adhesion of Helicobacter pylori ( H. Pylori) to the gastric epithelium, whereas H. Pylori does not bind to modified forms of Le(b) specific for blood types A and B. Such host factors as Le and Se genotypes and ABO blood type may affect the establishment of H. Pylori infection and, once infected, the risk of chronic atrophic gastritis. METHODS: we investigated the cross-sectional relation of abo blood type and Le and Le genotypes to gastric atrophy, assessed by serum pepsinogen levels, in japanese residents from two sources. RESULTS: among the 151 h. Pylori-positive participants of the h. Pylori eradication program, odds ratios (ors) for gastric atrophy, adjusted for age, sex, and smoking, were elevated for blood types a (or = 5.35; 95% confidence interval (ci), 2.11-13.58) and b (or = 4.79; 95% ci, 1.77-12.93) relative to type o. Ors for blood types a and b were also elevated in h. Pylori-negative subjects. These associations were not observed among 250 h. Pylori-positive health check-up examinees. The le genotype was not associated with gastric atrophy in either study population. The se/ se genotype was associated with statistically nonsignificant elevation of gastric atrophy risk in both populations. CONCLUSIONS: the present data showed a strong association of blood types a and b with gastric atrophy in one, but not the other, study population. Discrepant results between the two populations warrant further investigation. Background: the h type i structure, synthesized by the secretor (se) enzyme in gastric foveolar cells, and its metabolite, lewis b (le(b)) antigen, mediate the adhesion of helicobacter pylori ( h. Pylori) to the gastric epithelium, whereas h. Pylori does not bind to modified forms of le(b) specific for blood types a and b. Such host factors as le and se genotypes and abo blood type may affect the establishment of h. Pylori infection and, once infected, the risk of chronic atrophic gastritis. Methods: we investigated the cross-sectional relation of abo blood type and le and se genotypes to gastric atrophy, assessed by serum pepsinogen levels, in japanese residents from two sources. Results: among the 151 h. Pylori-positive participants of the h. Pylori eradication program, odds ratios (ors) for gastric atrophy, adjusted for age, sex, and smoking, were elevated for blood types a (or = 5.35; 95% confidence interval (ci), 2.11-13.58) and b (or = 4.79; 95% ci, 1.77-12.93) relative to type o. Ors for blood types a and b were also elevated in h. Pylori-negative subjects. These associations were not observed among 250 h. Pylori-positive health check-up examinees. The le genotype was not associated with gastric atrophy in either study population. The se/ se genotype was associated with statistically nonsignificant elevation of gastric atrophy risk in both populations. Conclusions: the present data showed a strong association of blood types a and b with gastric atrophy in one, but not the other, study population. Discrepant results between the two populations warrant further investigation.

Vitamin D receptor start codon polymorphism (FokI) and prostate cancer progression.

Vitamin D plays an important role in cell growth and differentiation and is proposed to protect against cancer initiation and/or progression. The vitamin D receptor (VDR) has a thymine/cytosine (T/C) polymorphism located in the first of two potential start (ATG) codons that can be detected by a RFLP using the endonuclease FokI. The C variant, which lacks the first ATG, results in a shorter VDR and is referred to as the F allele. The T variant (f allele) initiates at the first ATG. We examined the association of the VDR FokI genotype with histopathological characteristics and prognosis of prostate cancer among 191 mostly Caucasian subjects who had undergone radical prostatectomy between 1984 and 1992. The frequencies of the FF, Ff, and ff genotypes were 41%, 38%, and 21%, respectively. Subjects with the ff genotype had a lower mean percentage of Gleason grade 4/5 cancer (30.3%) than subjects with the FF or Ff genotypes (42.8% and 43.8%, respectively; P = 0.015 by t test for ff versus FF + Ff). The data suggest that the presence of an F allele increased the risk of being diagnosed with more aggressive cancer because higher percentage of Gleason grade 4/5 is associated with worse prognosis. The age-adjusted risk of prostate-specific antigen failure was lower for the ff genotype than for the FF genotype by Cox proportional hazards analysis but did not achieve statistical significance (hazard ratio = 0.76; 95% confidence interval, 0.44-1.32). This risk reduction disappeared after further adjustment for percentage of Gleason grade 4/5, cancer volume, and preoperative serum prostate-specific antigen level (hazard ratio = 1.03; 95% confidence interval, 0.58-1.85). In conclusion, the ff genotype was associated with less aggressive histopathological findings than Ff or FF genotypes. Additional studies with a larger sample size and investigation of the functional significance of the FokI polymorphism in prostate cancer cells are warranted.

Subjects with TNF-A-857TT and -1031TT genotypes showed the highest Helicobacter pylori seropositive rate compared with those with other genotypes.

BACKGROUND: A possible association between Helicobacter pylori seropositivity and tumor necrosis factor (TNF) a G-308A has been reported in Korea. The present study examined the associations of H. pylori with functional polymorphisms, TNF-A G-308A, C-857T, and T-1031C and TNF-B A252G in Japanese subjects. METHODS: The total of 1374 study subjects included 241 outpatients who participated in an H. pylori eradication program (HPE), 679 first-visit outpatients (FVO) at a regional cancer hospital, and 454 local residents who received a health checkup examination (HCE). RESULTS: The frequency of the TNF-A -308A allele was only 1.3% of 480 chromosomes in the HPE group, so the FVO and HCE groups were not genotyped for that polymorphism. The genotype frequency of TNF-A C-857T was 69.2% CC, 27.7% CT, and 3.1% TT; that of TNF-A T-1031C was 69.4% TT, 28.1% TC, and 2.5% CC; and that of TNF-B A252G was 36.8% AA, 48.2% AG, and 15.0% GG. TNF-A -857T was tightly linked to TNF-A -1031T and TNF-B 252A. No significant associations between H. pylori seropositivity and polymorphisms of TNF-A C-857T and TNF-B A252G were observed. However, a reduced odds ratio adjusted for sex, age, and recruitment source was observed for TNF-A -1031CC (0.43; 95% confidence interval, 0.20-0.91) relative to TNF-A -1031TT. Subjects with TNF-A -857CC and -1031CC showed the lowest seropositivity (38.2% of 34 participants), while those with TNF-A -857TT and -1031TT showed the highest (66.7% of 42 participants). CONCLUSIONS: This study suggests that the possibly high expression genotype of TNF-A may increase susceptibility to persistent H. pylori infection.A possible association between Helicobacter pylori seropositivity and tumor necrosis factor ( TNF) A G-308A has been reported in Korea. The present study examined the associations of H. pylori with functional polymorphisms, TNF-A G-308A, C-857T, and T-1031C, and TNF-B A252G in Japanese subjects.

Lack of consistency in the associations of Helicobacter pylori seropositivity with Se and Le polymorphisms among Japanese.

BACKGROUND: In our previous study, a marked association between Helicobacter pylori seropositivity and functional polymorphisms of the secretor and Lewis genes (odds ratio [OR], 0.32; 95% confidence interval [CI], 0.14-0.70 for se/se genotype relative to Se/Se genotype; and OR, 10.3; 95% CI, 3.16-33.8 for high-risk group defined by the combination of Se and Le relative to low-risk group) had been observed for 239 non-cancer Japanese outpatients of the gastroenterology clinic (OGC) undergoing gastroscopy at Aichi Cancer Center Hospital. METHODS: The present study was a confirmatory study to examine the association for 679 first-visit outpatients (FVO) of all clinics at the same cancer hospital and for 465 health checkup examinees (HCE) in the same city. RESULTS: The associations between H. pylori seropositivity and the Se and Le genotypes were nonsignificant or even in the opposite direction among the FVO (OR, 1.52; 95% CI, 1.00-2.32 for se/se genotype relative to Se/Se genotype; and OR, 0.77; 95% CI, 0.43-1.40 for the high-risk group defined similarly to the previous study), and among the HCE (OR, 1.25; 95% CI, 0.75-2.07; and OR, 1.07; 95% CI, 0.50-2.26, respectively). The discrepancy between the previous and present results was not explained by the difference in the distributions of age, sex, smoking, and H. pylori seroprevalence. CONCLUSION: Even in the same ethnic group, different sources of subjects may demonstrate inconsistent findings due to an unidentified effect modification. Inconsistent findings have rarely been reported by the same research group, but they are very important to understand the whole picture of the association under study.

Polymorphisms in the androgen receptor and type II 5 alpha-reductase genes and prostate cancer prognosis.

BACKGROUND: Cytosine-adenine-guanine repeat length of the androgen receptor gene and the A49T and V89L polymorphisms of the 5 alpha-reductase (SRD5A2) gene have been associated with prostate cancer. METHODS: We investigated the relationship of the three genetic polymorphisms to tumor grade among 211 men who had undergone radical prostatectomy. Subjects had prostate cancer <3 cm(3) with a percentage of cancer represented by Gleason grade 4 or 5 (% Gleason grade 4/5) of either > or = 20% or < or = 5%. We also examined the association between those genetic markers and prostate specific antigen (PSA) failure among 112 subjects with > or = 20% Gleason grade 4/5. RESULTS: In cross-sectional analysis, none of the polymorphisms was a significant predictor of % Gleason grade 4/5. In longitudinal analysis, the LL genotype at the V89L site was associated with statistically significant four- to sixfold increase in PSA failure risk after adjustment for clinicopathologic variables. CONCLUSIONS: We observed poorer prognosis among men with the LL genotype at codon 89 of the SRD5A2 gene. Lack of consistency between studies must be resolved before clinical utility of this marker is established.

CagA status of Helicobacter pylori infection and p53 gene mutations in gastric adenocarcinoma.

Infection with Helicobacter pylori (H. pylori) increases stomach cancer risk. Helicobacter pylori strains with the cag pathogenicity island (PAI) induce more severe inflammation in the gastric epithelium and are more strongly associated with stomach cancer risk than strains lacking the PAI. We examined whether the prevalence of somatic p53 mutation in gastric adenocarcinoma differed between subjects with and without infection with CagA(+) (a marker for the PAI) H. pylori strains. DNA from 105 microdissected tumor specimens was analyzed for mutation in exons 5-8 of the p53 gene by polymerase chain reaction-based single-strand conformation polymorphism followed by direct DNA sequencing. Enzyme-linked immunosorbent assays for IgG antibodies against H. pylori and CagA were performed on sera collected 2-31 years prior to cancer diagnosis. Tumors from CagA(+) subjects were significantly more likely to have p53 mutations than tumors from CagA(-) subjects (including H. pylori- and H. pylori(+)/CagA(-)): odds ratio = 3.72; 95% confidence interval, 1.06-13.07 after adjustment for histologic type and anatomic subsite of tumor and age at diagnosis and sex of subjects. Mutations were predominantly insertions and deletions (43%) as well as transition mutations at CpG dinucleotides (33%). The data suggest that CagA(+) H. pylori infection, when compared with CagA(-) infection or the absence of H. pylori infection, is associated with a higher prevalence of p53 mutation in gastric adenocarcinoma.

Concentrations of estrogens and IGFs in umbilical cord blood plasma: a comparison among Caucasian, Hispanic, and Asian-American females.

It has been hypothesized that exposure to elevated levels of estrogens and IGFs before birth may increase breast cancer risk in female offspring. We examined whether the concentrations of estrone, E2, IGF-I, IGF-II, and IGF-binding protein-1 (IGFBP-1), -2, and -3 in umbilical cord blood plasma differed in female neonates of three racial/ethnic groups with contrasting breast cancer risk. The study included 57 Caucasian, 22 Hispanic, and 22 Asian-American subjects. Relative contribution of race/ethnicity to the analyte level variability was the largest for IGFBP-1 (P = 0.06). The only statistically significant (P < 0.05) mean difference was the lower IGFBP-3 levels in Asian than in Caucasian subjects. Adjusted mean levels of estrone and E2 for Asian subjects were 128% and 109% of the Caucasian means, respectively, whereas the Hispanic group showed lower means (85% and 84% of the Caucasian means). IGF-I, IGFBP-1, and IGFBP-3 showed lower adjusted means for both Hispanics and Asians compared with Caucasians. However, these differences were not statistically significant. In summary, we have shown that concentrations of estrogens, IGF-I, IGF-II, and IGFBPs are not different in cord blood samples from Caucasian, Hispanic, and Asian-American subjects. These data do not support a link between antenatal exposure to elevated levels of estrogens and IGFs and breast cancer.