Impact of denosumab on cardiovascular calcification in patients with secondary hyperparathyroidism undergoing dialysis: a pilot study.

The receptor activator of nuclear factor-kappa B ligand (RANKL)/RANK/osteoprotegerin system is dysregulated in hyperparathyroid bone diseases. The introduction of denosumab preceding elective surgery as an alternative option when surgery is not possible immediately. INTRODUCTION: The effects of denosumab on vascular calcification in patients with chronic renal failure and low bone mass have been a subject of interest. Therefore, this investigation aimed to determine the short-term changes in vascular calcification after denosumab treatment using a serial electrocardiography-gated computed tomography (CT) to measure coronary artery calcification (CAC) in patients with secondary hyperparathyroidism (SHPT) and low bone mass. METHODS: This 6-month study enrolled patients with SHPT and low bone mass (T-score < - 2.5) owing to dialysis. The 2 groups administered denosumab at a dose of 60 mg (denosumab group), and conventional treatment (control group) had 21 patients each. All patients underwent CT scans at baseline and at the follow-up examination at 6 months to determine the bone mineral density and CAC. RESULTS: The control group demonstrated a significant increase in Agatston scores (187.79 ± 72.27) (P = 0.004). However, no significant change was noted in the denosumab group (P = 0.41). In the denosumab group, only the baseline serum alkaline phosphatase levels correlated negatively with changes in the CAC score (P = 0.01); the baseline alkaline phosphatase levels were the deciding biomarkers for non-responsive CAC scores by Berry Criteria after denosumab treatment (P = 0.02). The denosumab group demonstrated significantly increased bone mineral density in the femoral neck and lumbar spine (P < 0.01). CONCLUSION: The findings provide evidence that denosumab may suppress the progression of CAC and also regress osseous calcification in severe cases of high bone turnover.

Identifying pulmonary nodules or masses on chest radiography using deep learning: external validation and strategies to improve clinical practice.

AIM: To test the diagnostic performance of a deep learning-based system for the detection of clinically significant pulmonary nodules/masses on chest radiographs. MATERIALS AND METHODS: Using a retrospective study of 100 patients (47 with clinically significant pulmonary nodules/masses and 53 control subjects without pulmonary nodules), two radiologists verified clinically significantly pulmonary nodules/masses according to chest computed tomography (CT) findings. A computer-aided diagnosis (CAD) software using a deep-learning approach was used to detect pulmonary nodules/masses to determine the diagnostic performance in four algorithms (heat map, abnormal probability, nodule probability, and mass probability). RESULTS: A total of 100 cases were included in the analysis. Among the four algorithms, mass algorithm could achieve a 76.6% sensitivity (36/47, 11 false negative) and 88.68% specificity (47/53, six false-positive) in the detection of pulmonary nodules/masses at the optimal probability score cut-off of 0.2884. Compared to the other three algorithms, mass probability algorithm had best predictive ability for pulmonary nodule/mass detection at the optimal probability score cut-off of 0.2884 (AUCMass: 0.916 versus AUCHeat map: 0.682, p<0.001; AUCMass: 0.916 versus AUCAbnormal: 0.810, p=0.002; AUCMass: 0.916 versus AUCNodule: 0.813, p=0.014). CONCLUSION: In conclusion, the deep-learning based computer-aided diagnosis system will likely play a vital role in the early detection and diagnosis of pulmonary nodules/masses on chest radiographs. In future applications, these algorithms could support triage workflow via double reading to improve sensitivity and specificity during the diagnostic process.

Comparison of four contrast medium delivery protocols in low-iodine and low-radiation dose CT angiography of the aorta.

AIM: To evaluate contrast medium delivery protocols for the optimal enhancement profile of the aorta with both a reduced dose of radiation and contrast medium, called double-low computed tomography (CT) angiography (DLCTA). MATERIALS AND METHODS: DLCTA was performed with 70 kVp and 200 mg iodine/kg in 205 patients following four protocols, namely slow rate (n=52), short duration (n=52), low concentration (n=50), and combined method (n=51), in comparison with a conventional group (120 kVp, 400 mg iodine/kg, n=51). The quantitative measurement of aortic attenuation, homogeneity, and subjective scores were evaluated. RESULTS: Overall, in the four DLCTA groups, the radiation dose was reduced by 62%, and the iodine dose was reduced by 50%. Among the four DLCTA groups, the signal to noise ratio (SNR) and contrast to noise ratio (CNR) of the thoracic aorta were similar, but a significant difference was noted in the abdominal aorta. The short-duration group had the highest peak enhancement, least homogeneity, and worst subjective scores. Good contrast enhancement and good homogeneity were significantly more frequent in the slow-rate (86.6% and 90.4%, respectively) and low-concentration groups (78% and 96.0%, respectively). Subjective scores exhibited a trend of higher scores in the low-concentration group and lower scores in the slow-rate group (p=0.071). CONCLUSION: DLCTA with 70 kVp and 200 mg iodine/kg is feasible for whole-aortic CT angiography. The low-concentration protocol is recommended owing to its most consistent optimal aortic enhancement profile. Alternatively, the slow-rate protocol can be considered for patients with limited venous access.

Evaluation of Oxacillin and Cefoxitin Disk and MIC Breakpoints for Prediction of Methicillin Resistance in Human and Veterinary Isolates of Staphylococcus intermedius Group.

Staphylococcus pseudintermedius is a coagulase-positive species that colonizes the nares and anal mucosa of healthy dogs and cats. Human infections with S. pseudintermedius range in severity from bite wounds and rhinosinusitis to endocarditis; historically, these infections were thought to be uncommon, but new laboratory methods suggest that their true incidence is underreported. Oxacillin and cefoxitin disk and MIC tests were evaluated for the detection of mecA- or mecC-mediated methicillin resistance in 115 human and animal isolates of the Staphylococcus intermedius group (SIG), including 111 Staphylococcus pseudintermediusand 4 Staphylococcus delphini isolates, 37 of which were mecA positive. The disk and MIC breakpoints evaluated included the Clinical and Laboratory Standards Institute (CLSI) M100-S25 Staphylococcus aureus/Staphylococcus lugdunensis oxacillin MIC breakpoints and cefoxitin disk and MIC breakpoints, the CLSI M100-S25 coagulase-negative Staphylococcus (CoNS) oxacillin MIC breakpoint and cefoxitin disk breakpoint, the CLSI VET01-S2 S. pseudintermedius oxacillin MIC and disk breakpoints, and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) S. pseudintermedius cefoxitin disk breakpoint. The oxacillin results interpreted by the VET01-S2 (disk and MIC) and M100-S25 CoNS (MIC) breakpoints agreed with the results of mecA/mecC PCR for all isolates, with the exception of one false-resistant result (1.3% of mecA/mecC PCR-negative isolates). In contrast, cefoxitin tests performed poorly, ranging from 3 to 89% false susceptibility (very major errors) and 0 to 48% false resistance (major errors). BD Phoenix, bioMérieux Vitek 2, and Beckman Coulter MicroScan commercial automated susceptibility test panel oxacillin MIC results were also evaluated and demonstrated >95% categorical agreement with mecA/mecC PCR results if interpreted by using the M100-S25 CoNS breakpoint. The Alere penicillin-binding protein 2a test accurately detected all mecA-positive isolates, although for four isolates, cefoxitin induction was required prior to testing. These data demonstrate that the cefoxitin surrogate test does not reliably detect the presence of mecA in S. pseudintermedius isolates and that laboratories should perform oxacillin disk or MIC tests of these isolates when they are encountered.

[Scan time and accuracy of full-arch scans with intraoral scanners: a comparative study on conditions of the intraoral head-simulator and the hand-held model].

Objective: To comparatively evaluate the scan time and the accuracy of maxillary full-arch scans using four intraoral scanners (IOS) on conditions of the intraoral head-simulator and the hand-held model, and to evaluate the influence of different scanning conditions on digital scan. Methods: A upper dental arch model with melamine-formaldehyde resin teeth and silica gel gingiva that could be fixed on a head simulator was scanned with an optical scanner (ATOS Core) in order to obtain the standard tessellation language dataset as reference. Intraoral scans were performed on the model fixed on the head simulator by three researchers with four IOS [A: TRIOS 3; B: CS 3600; C: CEREC Omnicam; D: iTero]. For each scanner and each researcher, six scans were performed, to obtain the datasets as the head simulator group. And another six scans with each of the four intraoral scanners were performed by each researcher on the hand-held model to obtain the STL datasets as the hand-held group. The scan time were recorded for each scan. In the Geomagic Wrap software, the digital models were trimmed with only the teeth information retained and supreimposed by best fit alignment function and compared to obtain the root mean square (RMS) values of the discrepancies by three-dimensional compare function. The test datasets of each group were compared with the reference dataset for trueness. The six test scanning datasets with the same scanner of the same researcher were cross compared for precision. Mann Whitney U test was used to statistically analyze the difference values of the scan time, trueness and precision of the same intraoral scanner between head simulator group and hand-held group. Results: Compared to the hand-held group, the scan time of A [142(82) s] and D [119(52) s], which two IOS both with handle, were longer in head simulator group [A: 98(28) s; D: 85(22) s] (P<0.01). However there were no significant differences between the two groups for scan time of IOS B and C (P>0.05). For full-arch scan accuracy (trueness and precision), there were no significant differences between the two groups of IOS A and B (P>0.05), while the trueness of C (P<0.05) and the precision of D (P<0.01) were better in head simulator group [C: 112(38) µm; D: 43(13) µm] compared to hand-held group [C: 135(47) µm; D: 53(18) µm]. However, there were no significant differences for the precision of C (P>0.05) and the trueness of D (P>0.05). Conclusions: The scan time and the accuracy of full-arch digital scans with different IOS may be effected by the scan conditions. For in vitro study of intraoral scanning, head-simulator can simulate the intraoral environment of the real patient to some extent. Meanwhile, the position of the dentist and the patient, and also the limited intraoral space during intraoral scanning are also simulated.

[Effect of digital intraoral full-arch scan strategies on scan time and accuracy on conditions of intraoral head-simulator].

Objective: To comparatively evaluate the accuracy and the scan time of three full-arch scan strategies on the head-simulator, to explore a full-arch scan strategy with better clinical operability and high accuracy. Methods: A cross-controlled study design was used. A model with melamine-formaldehyde resin teeth and silica gel gingiva of an upper dental arch which can be fixed on a head simulator was scanned with an optical scanner (ATOS Core) in order to obtain the standard tessellation language (STL) dataset as reference. Intraoral scans were performed on the model fixed on the head simulator with four intraoral scanners (IOS) [A (TRIOS 3), B (CS 3600), C (CEREC Omnicam), D (iTero)]. The STL datasets were obtained from each of the four different IOS systems by using three scan strategies (scan strategies 1, 2 and 3 were composed of 10, 5 and 7 paths respectively) all by one attending doctor with 3 years of intraoral scanning experience. For each scanner and each scan strategy, nine scans were acquired. And the scan time was recorded for each scan. Following the scan strategy, the scan path was completed to obtain a full-arch digital model, and the scan time was recorded as full-arch scan time. Complementary scans were performed to fill the missing image, and this scan time was recorded as complementary scan time. The total scan time was obtained by adding full-arch scan time and complementary scan time. Through the Geomagic Wrap software, the three-dimensional (3D) models were overlaid by best fit alignment function and compared to obtain the root mean square values of the discrepancies by 3D compare function. The intraoral scanning datasets were compared with the reference for trueness. The nine intraoral scanning datasets were cross compared with same scan strategy and same intraoral scanner for precision. Results: There were no significant differences among the three scan strategies for trueness (P>0.05), while the differences among the three scan strategies for precision were affected by difference IOSs (P<0.05), and only scan strategy 3 showed the highest precision with all the four IOS. The full-arch scan time of scan strategies 1, 2 and 3 were (130±24), (72±17) and (90±19) s respectively (P<0.05). For complementary scan time, scan strategy 2 [(50±24) s] took longer time than scan strategy 1 [(26±18) s] and scan strategy [(25±21) s] (P<0.05), while no significant differences between the latter two (P>0.05). For total scan time, scan strategy 1 [(156±31) s] took longer time than scan strategy 2 [(122±30) s ] and scan strategy 3 [(115±29) s ] (P<0.05), while no significant differences between the latter two (P>0.05). Conclusions: Full-arch scanning on the head-simulator with scan strategy 3 which can obtain scanning datasets with high accuracy, was more convenient to operate and took shorter scan time, and is generally suitable for intraoral scanners commonly used in clinic.

Response of extranodal natural killer/T-cell lymphoma, nasal type, to interferon-alpha, corticosteroid and narrowband ultraviolet B phototherapy.

Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTLN), is characterized by higher prevalence in East Asians and South Americans, association with Epstein-Barr virus infection, aggressive nature in most cases, and resistance to conventional treatment strategies such as chemotherapy and radiotherapy. The optimum treatment for this disease has not yet been established. We report a successful treatment experience in a case of ENKTLN, with a combination regimen including interferon-alpha, corticosteroid and narrowband ultraviolet B, which may serve as a promising therapy for this aggressive disease at earlier stages.

A notable accessory screening program for detection of cervical intraepithelial neoplasia.

OBJECTIVE: Papanicolaou (Pap) smear test is implemented to detect cervical intraepithelial neoplasia (CIN) in Taiwan. However, the utility of that has limitations. High-risk human papillomavirus (HR-HPV) is an important risk factor in development of cervical cancer. In this study, we estimate the utility of HR-HPV testing in the screening of CIN. METHODS: Firstly, 726 subjects were recruited and willing to prove cervical exfoliated epithelial cells for Pap smear screening and HR-HPV DNA testing. Subsequently, 205 of the eligible subjects with greater than or equal to CIN1 of Pap smear results were asked to perform histologic diagnosis that served as a gold standard for the estimation of the effects of both Pap smear and HR-HPV testing. RESULTS: The histology is significantly associated with HR-HPV infection, as well as significantly highly correlated with the individuals who have both Pap smear greater than or equal to CIN1 and positive HR-HPV infection but not significantly correlated with the individuals who only have Pap smear greater than or equal to CIN1 but without HR-HPV infection. CONCLUSIONS: Combinative surveillance of HR-HPV infection and Pap smear is a useful tool to detect and monitor precancerous lesions in the screening program. HR-HPV testing is a notable accessory screening program for detection of CIN in Taiwanese women.

Apoptotic effect of Helicobacter pylori on oesophageal squamous-cell carcinoma cells in vitro.

BACKGROUND: The relationship between Helicobacter pylori (Hp) infection and oesophageal squamous-cell carcinoma (ESCC) risk is still inconclusive. Our previous study found an inverse association between the two, but its mechanism is still unknown. Thus, we conducted in vitro studies to clarify the issue. MATERIALS AND METHODS: One ESCC (CE 81T/VGH) cell line was co-cultured with Hp, using one gastric adenocarcinoma (AGS) cell line as the control. Hp-induced cell apoptosis was determined by flow cytometry, terminal transferase-mediated dUTP nick end labelling (TUNEL) assay and staining; caspase-3 protein expressions in cell lysates were detected by Western immunoblot. RESULTS: Increased apoptosis was found in CE 81T/VGH, but not in AGS cells, by flow cytometry and TUNEL assay after being co-cultured with Hp at the multiplicity of infection of 1/100 (but not at 1/400) for 36 h. The amount of activated caspase-3 (17/19 kDa) also increased in CE 81T/VGH, but not in AGS cells, after co-culturing with Hp at MOI of 1/100 for 36 h. The results were confirmed by triplicate experiments in which the different apoptotic assays remained consistent. CONCLUSIONS: Our study provides indirect evidence of the inverse association between Hp infection and ESCC risk, which is possibly due to Hp-induced apoptosis in ESCC cells. A further in vivo study is necessary to confirm our findings.

Expression of CXCR4 is associated with axillary lymph node status in patients with early breast cancer.

Recent studies have discovered that CXCR4 is associated with tumor metastasis. It is worth understanding the association between CXCR4 expression and axillary lymph node involvement in early breast cancer. Eighty-five patients with early breast cancers were divided into three groups based on their axillary lymph node status. CXCR4 expression was assessed by immunohistochemistry in all cases and its correlation with axillary lymph node involvement was evaluated. There was a significant difference in nuclear CXCR4 expression among these three groups and high nuclear expression of CXCR4 was associated with cases with no lymph node involvement. However, high cytoplasmic expression of CXCR4 was associated with patients who developed high-level axillary lymph node involvement. In conclusion, the different staining locations of CXCR4 have varying biological significance for the metastatic potential of axillary lymph nodes. In particular, it provided information that high cytoplasmic expression of CXCR4 was related to axillary internodal metastasis, and adjuvant radio-chemotherapy was suggested.

Brain ethanol levels in rats after voluntary ethanol consumption using a sweetened gelatin vehicle.

A novel procedure for initiation of voluntary ethanol consumption in the rat was evaluated in terms of ease of initiation, consistency, and resulting brain ethanol levels. The "jello shot" consists of 10% ethanol in gelatin along with a caloric source (Polycose). Initiation of "jello shot" consumption in Sprague-Dawley rats required no food or water restriction and resulted in initial daily (8.4+/-0.6 g/kg body weight) and eventual hourly (1.1+/-0.1 g/kg body weight) intake of ethanol comparable to other procedures using either alcohol-preferring or non-genetically selected rats. Rat intake of ethanol via "jello shots" recovered quickly from environmental alterations and surgical implantation of a guide cannula. During 1-h free access sessions, consumption of the "jello shot" occurred during the initial 10 min and resulted in a dose-related increase in ethanol levels in nucleus accumbens measured using microdialysis. These brain ethanol levels were comparable to those achieved using other self-administration methods. However, when 0.5 g/kg ethanol was gavaged either in "jello shot" or saline, there was about a 20% decrease in brain ethanol concentrations after gavage of the "jello shot" compared to saline. Even so, lack of a need for initial food or water deprivation and the rapidity with which stable self-administration can be achieved both suggest utility of the "jello shot" as a completely voluntary ethanol procedure.

Expression of CC chemokine receptor-7 and regional lymph node metastasis of B16 murine melanoma.

BACKGROUND: CC chemokine receptor-7 (CCR7), which plays a critical role in the migration of activated dendritic cells to regional lymph nodes via afferent lymphatic vessels, is also expressed by human breast and melanoma cell lines. Because neoplastic cells also enter lymphatic vessels before metastasis to the lymph nodes, we investigated whether CCR7 expression enhances metastasis of B16 murine melanoma cells to regional lymph nodes. METHODS: B16 cells were transduced with a retroviral vector containing CCR7 complementary DNA (CCR7-B16 cells) or with vector alone (pLNCX2-B16 control cells). The functional assay for CCR7 protein was Ca(2+) flux stimulated by the chemokine CCL21, a CCR7-specific ligand produced by lymphatic endothelial cells. B16 tumor cells were injected into the footpad of mice. Tumor cell metastasis to draining lymph nodes was assessed by measuring messenger RNA (mRNA) for tyrosinase-related protein-1 (TRP), a melanocyte-specific enzyme, with real-time, quantitative reverse transcription-coupled polymerase chain reaction. All statistical tests were two-sided. RESULTS: One week after injection into the footpad, 701-fold (95% confidence interval [CI] = 64- to 1336-fold) more TRP mRNA was detected in draining lymph nodes from CCR7-B16 cell-injected mice than in those from control cell-injected mice. Three weeks after footpad injection, 58% (11 of 19) of the draining lymph nodes from CCR7-B16 cell-injected mice and 5% (one of 19) of those from control mice showed gross metastases (P<.001). CCR7-B16 cells isolated from lymph node metastases retained functional CCR7 expression. Lymph node metastasis of CCR7-B16 cells was blocked by neutralizing anti-CCL21 antibodies (metastasis in none of five lymph nodes) but not by control immunoglobulin G (three of five). Enhanced metastasis of CCR7-B16 cells was specific for a lymphatic route because both CCR7-B16 and control cells co-injected intravenously metastasized to the lung at the same frequency. CONCLUSION: Expression of a single chemokine receptor gene, CCR7, increased B16 cell metastasis to draining lymph nodes, suggesting that cancer cells may co-opt normal mechanisms of lymph node homing during metastasis.

Novel electrodeposition behavior of Ni on porous anodic alumina templates without a conductive interlayer.

During template-assisted electrodeposition, single-crystalline metallic nanowires could be obtained only when the overpotential is low. However, an unusual electrodeposition behavior on the PAA/Si substrate without a conductive interlayer between the template and Si is described in the present study. Through the electrical breakdown of the template, Ni nanodots, nanowires and nanotubes could be obtained by only changing the electrodeposition voltage on the same substrate. The mechanisms leading to the formation of various nanostructures are described in detail and compared with those for the conventional template-assisted electrodeposition process. The electrodeposition first occurred on the pore wall instead of from the underlying substrate, leading to the formation of some Ni nanotubes at a more negative voltage. Besides, single-crystalline Ni nanowires could also be formed even when the electrodeposition voltage was as negative as -40 V, indicating that the formation of single-crystalline metallic nanowires under a large overpotential is possible.

A study on the induction of differentiation of human leukemic cells by harringtonine combined with cytarabine.

Both harringtonine (Harr) and Ara-C are effective for treatment of ANLL. Since it was suggested that Harr could induce leukemic cells to differentiate and Ara-C might be a weak inducer of leukemic cell differentiation, we investigated the effect of Harr in combination with Ara-C on inducing differentiation of leukemic cells. Ten patients with ANLL were treated with low dose Harr in combination with low dose Ara-C. Complete remission was achieved in 8 of the 10 patients. After therapy, severe pancytopenia and moderate myelosuppression occurred in two patients who achieved remission. Four patients demonstrated a decrease in blast cells with an associated transient increase in mature granulocytes during therapy. Auer bodies appeared in 7-8% mature granulocytes in peripheral blood and in bone marrow on the 14th day of combination therapy in one patient. Freshly isolated leukemic cells from six pretreatment patients were cultured in liquid in the presence of Harr in combination with Ara-C. Apparent evidence of differentiation of leukemic cells and Auer bodies in the cytoplasm of mature granulocytic cells were observed in two of the six patients. The above results seem to suggest that the therapeutic effect of low dose Harr plus low dose Ara-C may result from both differentiation induction and cytotoxicity of the leukemic cells.

Alterations in IL-6, IL-8, GM-CSF, TNF-alpha, and IFN-gamma release by peripheral mononuclear cells in patients with active vitiligo.

The purpose of this study was to clarify the relationship between the cellular and humoral immune components in the pathogenesis of vitiligo vulgaris. By using cytokines as indicators of peripheral mononuclear cell (MNC) function, we compared the effects of phytohemagglutinin (PHA) and purified IgG on MNCs derived from patients suffering from active vitiligo with those from normal controls. The results revealed (i) a significant increase in spontaneous production of IL-6 and IL-8 in patients; (ii) PHA, purified IgG from patients (IgG-anti-MC), or IgG from normal controls (N-IgG) induced a significant increase in IL-6 but diminished GM-CSF, TNF-alpha, and IFN-gamma release in patients; and (iii) IgG-anti-MC brought about a significantly higher stimulatory effect on IL-1beta and IFN-gamma production than N-IgG in normal controls. Immunologically, IL-6 can enhance melanocyte ICAM-1 expression, which may increase leukocyte-melanocyte attachment and cause melanocyte damage in vitiligo. A decrease in GM-CSF (an intrinsic growth factor for melanocyte) production may retard recovery from vitiligo by checking the proliferation of surviving melanocytes. A significant decrease in TNF-alpha and IFN-gamma production may partially explain the reduced inflammatory reaction in vitiliginous lesions. That IgG-anti-MC stimulates an increase in IL-1beta and IFN-gamma production in controls suggests that IgG-anti-MC may play a role in melanocyte destruction mediated by monocytes.

Cytochrome P450 1A1 MspI polymorphism and urinary 1-hydroxypyrene concentrations in coke-oven workers.

Coke-oven workers are regularly exposed to a high concentration of the benzene-soluble fraction (BSF) of total particulates, which are comprised mainly of polycyclic aromatic hydrocarbons (PAHs). A metabolite of pyrene, 1-hydroxpyrene (1-OHP), is readily measured in the urine of exposed individuals. Epidemiological studies have shown that P4501A1 (CYP1A1) genotypes are associated with PAH-related lung cancer risk. The purpose of this study was to investigate whether CYP1A1 MspI genotypes modulate the relationship of individual occupational exposure to air BSF to urinary 1-OHP concentrations among coke-oven workers. We monitored individual breathing zone air BSF over 3 consecutive days in 80 coke-oven workers in Taiwan from August 1995 to February 1996. Exposure was also dichotomized by work area (topside oven workers and sideoven workers). Preshift urine on the morning of day 1 and postshift urine on the afternoon of day 3 were measured by fluorescent spectrophotometry, and blood samples were analyzed to determine the relative distributions of CYP1A1 MspI polymorphisms. The frequency of the MspI homozygous variant genotypes of CYP1A1 was 15%. Multiple linear regression showed significant effects of individual occupational exposure to air BSF and preshift 1-OHP on postshift urinary 1-OHP concentrations (P = 0.002 and P < 0.001, respectively). After adjusting for preshift 1-OHP concentrations and air BSF, subjects with the homozygous variant genotype have a 2-fold higher postshift 1-OHP levels than the combined wild-type and heterozygous (P = 0.04). In addition, a positive trend was found in postshift 1-OHP and across-shift change of 1-OHP (postshift 1-OHP - preshift 1-OHP) in decreasing order, as follows: topside oven workers with the homozygous variant trait, topside oven workers with the heterozygous variant trait, sideoven workers with the homozygous variant trait, and sideoven workers with the heterozygous trait (P < 0.001). We conclude that CYP1A1 MspI variant genotype can modify the metabolism of PAHs in coke-oven workers.

The p53 codon 72 polymorphism and lung cancer risk.

The p53 tumor suppressor gene frequently is mutated in many forms of human carcinomas. A common polymorphism occurs at codon 72 of exon 4, with two alleles encoding either arginine (CGC) or proline (CCC). This p53 polymorphism reportedly is associated with lung cancer susceptibility. However, not all investigations have been consistent, and this hypothesized association remains controversial. We tested the hypothesis that the Pro/Pro genotype is associated with increased lung cancer risk in a large case-control study of lung cancer that included 482 cases and 510 controls from the Massachusetts General Hospital in Boston, Massachusetts. DNA from peripheral blood samples was examined by PCR-RFLP. Pro/Pro homozygotes were found more frequently in adenocarcinomas (cases, 16.4%; controls, 12.0%; P = 0.03). The prevalence of the Pro/Pro homozygous genotype increased in frequency with increasing pack-years of smoking. The combined susceptible genotype homozygous Pro/Pro and heterozygous Arg/Pro was associated with a 1.45-fold higher risk of adenocarcinoma compared with Arg/Arg genotype (95% confidence interval = 1.01-2.06; P = 0.04) after adjustment for relevant variables. Lung adenocarcinoma risk increased with the presence of one or both variant alleles across smoking strata. In addition, at each level of smoking (except nonsmoker and light smoker), the risk associated with smoking was higher for the population with the combined variant (Arg/Pro + Pro/Pro) genotype. The risk for the combined genotype was associated with tobacco exposure status. In conclusion, the codon 72 germ-line polymorphism (Arg/Pro) of the common tumor suppressor gene p53 contributes to heritable susceptibility for smoke-induced lung adenocarcinoma. The modifications by p53 polymorphism and pack-years resulted in an increased risk of the susceptible genotype to lung adenocarcinoma. The p53 gene may modulate the response to environment carcinogens and thereby affect the risk of developing lung adenocarcinoma.

Temporal changes in urinary 1-hydroxypyrene concentrations in coke-oven workers.

Coke-oven workers are exposed to high concentrations of coke-oven emissions, which are comprised mainly of polycyclic aromatic hydrocarbons. We conducted a pilot study to determine the time changes in urinary 1-hydroxypyrene (1-OHP) concentrations, as a metabolite of pyrene, in coke-oven workers after exposure to a benzene-soluble fraction (BSF) of total particulates. Thirteen subjects, including 2 men (referents) from an administrative area, 6 workers who work at the sideoven, and 5 who work on the top of the oven in one coke-oven plant were studied. After 1.5 to 2 days off, subjects were monitored individually for breathing zone air BSF over 3 consecutive days in August 1995. Seven spot urine samples, including preshift and postshift urine over 3 days and preshift urine on a fourth-day morning, were collected to determine 1-OHP concentrations by fluorescent spectrophotometry. The mean ambient BSF concentrations in the sideoven and topside oven workers ranged from 18 to 159 microg/m3 and from 251 to 1362 microg/ m3, respectively, whereas the BSF concentrations in the referents were low but detectable (11 and 29 microg/m3). Urinary 1-OHP concentrations increased during the work period, from 10+/-3 and 41+/-9 microg/g creatinine (mean+/-SE) on the preshift first day to 57+/-26 and 334+/-63 microg/g creatinine on the postshift third day in the sideoven and topside oven workers, respectively. However, the urinary 1-OHP concentrations were relatively flat in the two referents. The across-shift change in urinary 1-OHP defined as postshift 1-OHP on the third day minus preshift 1-OHP on the first day was highly associated with individual mean occupational exposure to air BSF (r = 0.80, P = 0.001). Repeated-measures regression analyses revealed that daily postshift 1-OHP concentrations were marginally associated with daily air BSF. A 10-fold increase of daily air BSF resulted in a 1.67-fold increase of daily postshift 1-OHP levels (95% confidence interval = 0.99-2.83; P = 0.07). After adjusting for daily preshift 1-OHP concentrations, we found that a 10-fold increase of daily air BSF resulted in a 1.90-fold increase of daily postshift 1-OHP levels (95% confidence interval = 1.10-3.28; P = 0.03). Although the sample size is small in this study, these results indicate that daily postshift 1-OHP levels in urine are determined mainly by current occupational exposure to coke-oven emissions.

4-amino-6-(trichloroethenyl)-1,3-benzenedisulfonamide, a new, potent fasciolicide.

The synthesis and fasciolicidal activity of 4-amino-6-(trichloroethenyl)-1,3-benzenedisulfonamide are reported. A single dose of 15 mg/kg was effective in removing over 90% of immature Fasciola hepatica from sheep (6 weeks after infection) and calves (8 weeks after infection). A 2.5 mg/kg dose removed over 90% of mature (16 weeks old) liver fluke from sheep. Single oral doses up to 400 mg/kg were tolerated by sheep without gross toxic symptoms.

The delta-aminolevulinic acid dehydratase (ALAD) polymorphism and bone and blood lead levels in community-exposed men: the Normative Aging Study.

Recent research has indicated that a polymorphic variant of delta-aminolevulinic acid dehydratase (ALAD) may influence an individual's level of lead in bone and blood and, as a result, may also influence an individual's susceptibility to lead toxicity. In this study, we investigated whether this ALAD polymorphism is associated with altered levels of lead in bone and blood among 726 middle-aged and elderly men who had community (nonoccupational) exposures to lead. We measured levels of blood and bone lead by graphite furnace atomic absorption spectroscopy and a K X-ray fluorescence (KXRF) instrument, respectively. We determined the ALAD MspI polymorphism in exon 4 by a polymerase chain reaction restriction fragment length polymorphism (RFLP). Of the 726 subjects, 7 (1%) and 111 (15%) were, respectively, homozygous and heterozygous for the variant allele. The mean (SD) of blood lead (micrograms per deciliter), cortical bone (tibia) lead (micrograms per gram), and trabecular bone (patella) lead (micrograms per gram) were 6.2 (4.1), 22.1 (13.5), and 31.9 (19.5) in subjects who did not have the variant allele (ALAD 1-1), and 5.7 (4.2), 21.2 (10.9), and 30.4 (17.2) in the combined subjects who were either heterozygous or homozygous for the variant allele (ALAD 1-2 and ALAD 2-2). In multivariate linear regression models that controlled for age, education, smoking, alcohol ingestion, and vitamin D intake, the ALAD 1-1 genotype was associated with cortical bone lead levels that were 2.55 microg/g [95% confidence interval (CI) 0.05-5.05] higher than those of the variant allele carriers. We found no significant differences by genotype with respect to lead levels in trabecular bone or blood. In stratified analyses and a multivariate regression model that tested for interaction, the relationship of trabecular bone lead to blood lead appeared to be significantly modified by ALAD genotype, with variant allele carriers having higher blood lead levels, but only when trabecular bone lead levels exceeded 60 microg/g. These results suggest that the variant ALAD-2 allele modifies lead kinetics possibly by decreasing lead uptake into cortical bone and increasing the mobilization of lead from trabecular bone.