bluuebunny/crossref_metadata_2025 huggingface dataset:
Modifying Effects of 1'-Acetoxychavicol Acetate (ACA) and the Novel Synthetic Retinoids Re-80, Am-580 and Am-55P in a Two-Stage Carcinogenesis Model in Female Rats
Authors: Orita Shinichiro , Hirose Masao , Takahashi Satoru , Imaida Katsumi , Ito Nobuyuki , Shudo Koichi , Ohigashi Hajime , Murakami Akira , Shirai Tomoyuki
Published: April 2004

Effects of dietary administration of 1'-acetoxychavicol acetate (ACA) and the novel synthetic retinoids 4-[1-hydroxy-3-oxo-3-(5,6,7,8-tetrahydro-3-hydroxy-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid (Re-80); 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]benzoic acid (Am-580); and 6-[(3,5-di-tert-butylphenyl) carbamoyl]nicotinic acid (Am-55P) were examined using a two-stage rat carcinogenesis model. A total of 190 female SD rats was treated sequentially with 1,2-dimethylhydrazine (DMH, s.c.); 7,12-dimethylbenz(a)anthracene (DMBA, i.g.); and 2,2'-dihydroxy-di- n-propylnitrosamine (DHPN, in the drinking water) during the first three weeks (DDD-initiation), and an additional 60 rats received the vehicle alone (non-initiation). One week after the completion of the initiation period, they were divided into nine groups and administrated Re-80 (at dose levels of 1.0 or 0.4 ppm), Am-580 (20 or 4 ppm), Am-55P (20 ppm), ACA (100 ppm), all- trans-retinoic acid (10 or 2 ppm) or no supplement in the diet for 33 weeks, until survivors were euthanatized at week 37 weeks. After DDD-initiation, all- trans-retinoic acid at the high dose delayed the development of mammary tumors. The multiplicity of colon tumors in the group fed Am-55P and the incidences of nephroblastomas with ACA or Am-580 were decreased as compared with the control values, but the other chemicals had no modifying effects on tumor development in any organs. Thus, among ACA and the novel synthetic retinoids tested, only Am-55P showed a weak inhibitory effect on a neoplasm of general interest under the present experimental conditions.
Invited Review: A Contemporary Overview of Chronic Progressive Nephropathy in the Laboratory Rat, and Its Significance for Human Risk Assessment
Authors: Hard Gordon C. , Kanwar Nasir Khan
Published: April 2004

CPN (chronic progressive nephropathy) is a spontaneous age-related disease that occurs in high incidence in the strains of rat commonly used in preclinical toxicology studies, exhibiting a male predisposition. Although increasing in incidence and severity with age, evidence indicates that CPN should be regarded as a specific disease entity and not just a manifestation of the aging process. A number of factors, mainly dietary manipulations, have been shown to modify the expression of CPN. Amongst these, restriction of caloric intake is the most effective for inhibiting the disease process. The precise etiology of CPN and the mechanism(s) underlying its pathogenesis remain unknown, but the long-standing assumption that glomerular dysfunction is the primary basis is challenged in the light of contemporary developments in understanding filtration and postglomerular cellular processing of albumin. CPN is not only a degenerative disease, but also has regenerative aspects with a high cell proliferative rate in affected tubules. Accordingly, evidence is emerging that advanced, particularly end-stage CPN, is a risk factor for a marginal increase in the background incidence of renal tubule tumors. Many chemicals are known to exacerbate the severity of CPN to an advanced stage, and this interaction between chemical and CPN can result in a small increase in the incidence of renal adenomas in 2-year carcinogenicity bioassays. Review of the pathological entities associated with chronic renal failure in man emphasizes that this rodent condition has no strict human counterpart. Because CPN is a rodent-specific entity, the finding of a small, statistically significant increase in renal tubule tumors, linked to exacerbation of CPN by a test chemical in a preclinical study for carcinogenicity, can be regarded as having no relevance for extrapolation in human risk assessment.
Influence of ACTH‐(1‐24) and Plasma Hyperviscosity on Free Radical Production and Capillary Perfusion After Hemorrhagic Shock
Authors: BERTUGLIA S. , GIUSTI A.
Published: April 2004

Objective: The authors investigated the effects of ACTH‐(1‐24) and a high‐viscosity solution in the restoration of microvascular function during resuscitation. They injected NG‐monomethyl‐l‐arginine (l‐NMMA) and superoxide dismutase (SOD) before ACTH‐(1‐24) in hamsters resuscitated with the hyperviscous solution to determine the role of ROS and NO in ACTH‐(1‐24) protective mechanism in the cheek pouch. Hemorrhagic shock (HS) was induced by withdrawing blood to reduce mean arterial pressure (MAP) to 30 mm Hg for 45 min.

Methods: Animals were injected with ACTH‐(1‐24) and resuscitated with dextran of low molecular weight (70 kDa) and a small amount (4%) of dextran of high molecular weight (500 kDa) plus ACTH‐(1‐24), or autologous (shed) blood withdrawn during HS. Microvascular effects were characterized by measuring blood flow, perfused capillary length (PCL), arteriolar diameter, and red blood cell (RBC) velocity. ROS were assayed at the beginning and after 45 min of HS and after 10 and 90 min of resuscitation.

Results: Resuscitation with either shed blood or dextrans 70/500 resulted in the restoration of MAP, whereas PCL, RBC velocity, and arterial diameter decreased significantly. ROS increased significantly after HS, 10 and 45 min of resuscitation. ACTH‐(1‐24) plus dextrans 70/500 increased MAP immediately; it increased vasodilation and PCL, and attenuated significantly ROS production and leukocyte adhesion during resuscitation. l‐NMMA injected after 30 min of HS did not change the protection exerted by ACTH‐(1‐24) and dextrans 70/500, while SOD increased their protective effects.

Conclusions: ACTH‐(1‐24) appears to enhance the protective effects on the endothelium exerted by increased plasma viscosity by significantly decreasing the oxidative stress and the leukocyte adhesion during resuscitation.
Mouse Cremaster Venules are Predisposed to Light/Dye‐Induced Thrombosis Independent of Wall Shear Rate, CD18, ICAM‐1, or P‐Selectin
Authors: RUMBAUT ROLANDO E. , RANDHAWA JASPREET KAUR , SMITH C. WAYNE , BURNS ALAN R.
Published: April 2004

Objective: Microvascular adhesion of platelets to endothelium occurs in response to various inflammatory stimuli, and in venules is often accompanied by adherent leukocytes. In a light/dye injury model, platelet adhesion and thrombi occur preferentially in venules, though the reasons for this predisposition are unknown. The authors sought to determine whether lower wall shear rates or leukocyte–endothelial interactions accounted for preferential platelet thrombi formation in venules relative to arterioles.

Methods: A light/dye injury model of microvascular thrombosis was used in the mouse cremaster microcirculation.

Results: In wild‐type mice (n = 17), the time to form microvascular platelet aggregates was delayed in arterioles by 3.1‐fold relative to venules (p < .0001). However, arterioles with spontaneously low wall shear rates, as well as arterioles manipulated to reduce wall shear rate to venous levels, still had delayed thrombosis as compared to venules. Similarly, in animals deficient in CD18, P‐selectin, or ICAM‐1, the time to form platelet thrombi in arterioles was > 3.0‐fold higher than in venules.

Conclusions: Mouse cremaster venules are predisposed to light/dye‐induced microvascular thrombosis. The data suggest that functional differences between arteriolar and venular endothelial cells (independent of wall shear rate and of CD18, P‐selectin, and ICAM‐1) account for the venular predisposition to thrombosis.
Recovery of Nitric Oxide from Acetylcholine‐Mediated Vasodilatation in Human Skin In Vivo
Authors: BOUTSIOUKI PARASKEVI , GEORGIOU SOPHIA , CLOUGH GERALDINE F.
Published: April 2004

Objectives: To investigate the relative contribution of nitric oxide (NO) to the vascular and neural mechanisms underlying the ACh‐induced vasodilatation in human skin.

Methods: ACh was delivered to the skin of the forearm of 28 healthy volunteers using intradermal microdialysis. Subsequent changes in tissue levels of NO and histamine were measured in the dialysate outflow and the associated changes in skin blood flux followed with the use of scanning laser Doppler imaging.

Results: ACh caused a dose‐dependent increase in skin blood flux measured directly above the probe, associated with a twofold increase in dialysate NO. l‐NAME (5 mM) delivered simultaneously via the dialysis probe totally blocked the increase in dialysate NO but only partially attenuated (∼ 30%) the ACh‐induced increase in blood flux. At concentrations ≥6.25 mM, ACh also induced a widespread flare response, up to 40 mm in width, accompanied by the sensation of itch. The flare was not blocked by l‐NAME or the H1 receptor antagonist levocetirizine, but was reduced by C‐fiber blockade. Dialysate histamine levels remained unchanged at all times.

Conclusions: These experiments offer further insight into the use of dialysis as an experimental technique in the skin. They provide direct evidence that the skin microvascular response to ACh is only partially mediated by NO. Further they suggest that ACh at higher concentrations can induce an axon‐reflex‐mediated response that is independent of NO release at the site of dermal provocation or of local histamine release.
Telomerase‐Immortalized Lymphatic and Blood Vessel Endothelial Cells are Functionally Stable and Retain Their Lineage Specificity
Authors: SCHOPPMANN SEBASTIAN F. , SOLEIMAN AFSCHIN , KALT ROMANA , OKUBO YUKARI , BENISCH CHRISTIAN , NAGAVARAPU USHA , HERRON G. SCOTT , GELEFF SILVANA
Published: April 2004

Objective: Microvasculature plays an important role in a variety of physiological and pathological processes. The authors have previously shown that primary cultures of human microvascular endothelial cells consist of 2 distinct populations of blood vascular and lymphatic endothelial cells. These subtypes are ephemeral and lose purity through passaging. To generate reproducible in vitro and in vivo experiments stable blood and lymphatic endothelial cell lines are an essential prerequisite.

Methods: In this study they have used human telomerase gene‐immortalized nontransformed human microvascular endothelial cell cloned pure cultures of blood and lymphatic endothelial cell subpopulations. Flow cytometry, immunofluorescence, Northern and Western blotting, microarray gene analysis, as well as basic functional assays were used to characterize these clones.

Results and Conclusions: Immortalized blood and lymphatic subpopulations are stable and functionally specialized cell lineages that expressed pan‐endothelial and cell‐type‐specific markers. They are excellent candidates for long‐term culture studies on microvascular‐related diseases.
Myocardial Contrast Echocardiography in Assessing Microcirculation in Baboons with Chagas Disease
Authors: ZABALGOITIA MIGUEL , VENTURA JAIME , LOZANO JOSE L. , ANDERSON LORI , CAREY K. D. , HUBBARD G. B. , WILLIAMS JEFF T. , VANDEBERG JOHN L.
Published: April 2004

Objective: Microvascular abnormalities have been postulated in the pathogenesis of chagasic cardiomyopathy. The objective of this study was to evaluate the relationship between coronary microcirculation and systolic function impairment in baboons with Chagas disease using myocardial contrast echocardiography (MCE).

Methods: Seventeen seropositive (5 males, 12 females; mean age 20 years) and 13 age‐ and gender‐matched seronegative baboons underwent MCE using intravenous octafluoropropane human albumin microspheres. Color‐coding was used to enhance tissue contrast in assessing regional myocardium uniformity and texture. Dipyridamole (0.54 mg/kg) was given to a subset of 4 animals to challenge coronary flow reserve. Systolic indices included left ventricular fractional shortening, velocity of circumferential fiber shortening, and left and right ventricular ejection fractions.

Results: Four of the 17 (24%) seropositive primates had decreased fractional shortening (25 ± 8% vs. 40 ± 5%, p < .005), velocity of circumferential fiber shortening (1.05 ± 0.36 circ/s vs. 1.84 ± 0.23 circ/s, p < .0001), and reduced right ventricular ejection fraction (44 ± 9% vs. 54 ± 4%, p < .05) compared to other seropositive animals. Seropositive and seronegative groups showed no significant differences on the coronary microcirculation pattern as evaluated by MCE, including the 4 baboons with systolic function impairment. Moreover, coronary flow vasoreactivity resulted in a significant increase in myocardial flow as detected by color‐coding masking.

Conclusions: Chagasic heart disease is present in 24% of seropositive baboons spontaneously infected with Trypanosoma cruzi. MCE reveals a discrepancy between coronary microcirculation at rest and alterations in myocardial contractility, suggesting preservation of the microvascular integrity in this unique animal model.
K+‐Induced Dilation of Hamster Cremasteric Arterioles Involves Both the Na+/K+‐ATPase and Inward‐Rectifier K+ Channels
Authors: BURNS WENDY R. , COHEN KENNETH D. , JACKSON WILLIAM F.
Published: April 2004

Objective: The mechanism by which elevated extracellular potassium ion concentration ([K+]o) causes dilation of skeletal muscle arterioles was evaluated.

Methods: Arterioles (n = 111) were hand‐dissected from hamster cremaster muscles, cannulated with glass micropipettes and pressurized to 80 cm H2O for in vitro study. The vessels were superfused with physiological salt solution containing 5 mM KCl, which could be rapidly switched to test solutions containing elevated [K+]o and/or inhibitors. The authors measured arteriolar diameter with a computer‐based diameter tracking system, vascular smooth muscle cell membrane potential with sharp micropipettes filled with 200 mM KCl, and changes in intracellular Ca2 + concentration ([Ca2 +]i) with Fura 2. Membrane currents and potentials also were measured in enzymatically isolated arteriolar muscle cells using patch clamp techniques. The role played by inward rectifier K+ (KIR) channels was tested using Ba2 + as an inhibitor. Ouabain and substitution of extracellular Na+ with Li+ were used to examine the function of the Na+/K+ ATPase.

Results: Elevation of [K+]o from 5 mM up to 20 mM caused transient dilation of isolated arterioles (27 ± 1 μ m peak dilation when [K+]o was elevated from 5 to 20 mM, n = 105, p < .05). This dilation was preceded by transient membrane hyperpolarization (10 ± 1 mV, n = 23, p < .05) and by a fall in [Ca2 +]i as indexed by a decrease in the Fura 2 fluorescence ratio of 22 ± 5% (n = 4, p < .05). Ba2 + (50 or 100 μ M) attenuated the peak dilation (40 ± 8% inhibition, n = 22) and hyperpolarization (31 ± 12% inhibition, n = 7, p < .05) and decreased the duration of responses by 37 ± 11% (n = 20, p < 0.05). Both ouabain (1 mM or 100 μM) and replacement of Na+ with Li+ essentially abolished both the hyperpolarization and vasodilation.

Conclusions: Elevated [K+]o causes transient vasodilation of skeletal muscle arterioles that appears to be an intrinsic property of the arterioles. The results suggest that K+‐induced dilation involves activation of both the Na+/K+ ATPase and KIR channels, leading to membrane hyperpolarization, a fall in [Ca2 +]i, and culminating in vasodilation. The Na+/K+ ATPase appears to play the major role and is largely responsible for the transient nature of the response to elevated [K+]o, whereas KIR channels primarily affect the duration and kinetics of the response.
Effect of Fibrinogen on Leukocyte Margination and Adhesion in Postcapillary Venules
Authors: PEARSON MARK J. , LIPOWSKY HERBERT H.
Published: April 2004

Objective: To quantitatively evaluate the role of fibrinogen (Fb) as a determinant of leukocyte (WBC) margination in postcapillary venules in light of its ability to induce red blood cell (RBC) aggregation with reductions in shear rate () and increase adhesiveness of WBCs to endothelium (EC).

Methods: Red cell aggregation (RCA), WBC margination (flux at the EC), rolling velocity, and adhesion to the EC were measured in rat mesenteric postcapillary venules upon reducing , prior to and following systemic infusion of Fb. Proximal occlusion of feeding microvessels with a blunted probe facilitated reductions in from 600 to 50 s−1. An index of aggregation (G) was derived from light‐scattering properties of RBCs, where G was proportional to the number of RBCs per aggregate. WBC margination was measured as the percentage of total luminal WBC flux that rolled on the EC, F *WBC.

Results: For normal levels of Fb (0.07 g%), reductions in resulted in a 4‐fold rise in F WBC* and no change in G as was reduced to 50 s−1. Infusion of Fb to achieve a plasma concentration to 0.7 g% caused a modest 20% increase in G and a 2.5‐fold increase in F WBC* at = 50 s−1. WBC‐EC adhesion appeared to increase significantly, but much less than with infusion of high molecular weight dextran (Dx). With Dx, G increased 3‐fold, with reductions in , but F WBC* increased only half the amount incurred with Fb at low shear. The greater margination in the presence of Fb results from RBC rouleaux that promote radial migration of WBCs. In contrast, clumps of RBCs resulting from high molecular weight Dx entrain WBCs within plasma gaps along the vessel centerline.

Conclusions: In the presence of Fb, margination of WBCs increases dramatically at low shear due to rouleaux formation, which enhances radial migration of WBCs. This effect is much greater than with Dx because disruption of the much weaker Fb induced rouleaux precludes reductions in HMICRO, whereas clumping aggregates induced by Dx form plasma gaps. Thus, modest levels of RCA caused by increased Fb may greatly enhance margination and with an enhancement of adhesiveness synergistically promote firm WBC‐EC adhesion in the low flow state.
Risk from Inhaled Mycotoxins in Indoor Office and Residential Environments
Authors: Kelman Bruce J. , Robbins Coreen A. , Swenson Lonie J. , Hardin Bryan D.
Published: April 2004

Mycotoxins are known to produce veterinary and human diseases when consumed with contaminated foods. Mycotoxins have also been proposed to cause adverse human health effects after inhalation exposure to mold in indoor residential, school, and office environments. Epidemiologic evidence has been inadequate to establish a causal relationship between indoor mold and nonallergic, toxigenic health effects. In this article, the authors model a maximum possible dose of mycotoxins that could be inhaled in 24 h of continuous exposure to a high concentration of mold spores containing the maximum reported concentration of aflatoxins B1 and B2, satratoxins G and H, fumitremorgens B and C, verruculogen, and trichoverrols A and B. These calculated doses are compared to effects data for the same mycotoxins. None of the maximum doses modeled were sufficiently high to cause any adverse effect. The model illustrates the inefficiency of delivery of mycotoxins via inhalation of mold spores, and suggests that the lack of association between mold exposure and mycotoxicoses in indoor environments is due to a requirement for extremely high airborne spore levels and extended periods of exposure to elicit a response. This model is further evidence that human mycotoxicoses are implausible following inhalation exposure to mycotoxins in mold-contaminated home, school, or office environments.
The Involvement of p53 in Paraquat-Induced Apoptosis in Human Lung Epithelial-Like Cells
Authors: Takeyama Naoshi , Tanaka Takaya , Yabuki Teru , Nakatani Toshio
Published: April 2004

To investigate the possible role of p53 in the progression of paraquat-induced apoptosis, the authors used two cell lines that were wild-type p53–expressing human lung epithelial-like cell line (L132) and a p53-deficient human promyelocytic leukemia cell line (U937) and explored the linkage between p53, DNA damage, and apoptosis. Following paraquat exposure to L132 cells, the percentage of S-phase cells decreased significantly and the expression of p53 protein increased, suggesting that entry into S phase from G1 phase was blocked. U937 cells showed complete resistance to paraquat, although paraquat-evoked initial single-stranded DNA breaks was shown equally in either L132 or U937 cells, as assessed by single-cell gel electrophoresis. U937 and L132 cells die normally with similar kinetics when exposed to tumor necrosis factor in the presence of cycloheximide, indicating that their capacity to undergo p53-independent mechanisms of inducing apoptosis has an equal rate. These results suggest that paraquat-induced DNA damage caused G1 arrest and apoptosis only in L132 cells, and that p53 protein accumulation is required for the induction of apoptosis by paraquat.
Acute and Genotoxic Profile of a Dimeric Impurity of Cefotaxime
Authors: Agarwal Shiv Kumar , Bhatnagar Upendra , Rajesh Navin
Published: April 2004

The manufacturing and storage of cefotaxime produces different impurities of various concentrations, which may influence the efficacy and safety of the drugs. Because no report of toxicity data is available on the impurities of cefotaxime, the present acute and genotoxicity studies were designed and conducted to provide the information for establishing the safety profile and qualification of the dimeric impurity. Histidine-requiring mutants of Salmonella typhimurium TA97a, TA98, TA100, TA102, and TA1535 strains, with or without metabolic activation (S-9), were used for point-mutation tests. Neither increase in numbers of revertants, indicative of mutagenic activity, nor inhibition of bacterial growth, indicative of cytotoxicity, was observed when the dimeric impurity of cefotaxime at concentrations of 0.62, 1.85, 5.56, 16.67, and 50 μg/plate was incorporated into plates containing S. typhimurium bacterial strains. Cultures of Chinese hamster ovary (CHO) cells at a cell density of 2 × 105 cells per culture were exposed to the dimeric impurity of cefotaxime at the concentration of 11.25, 22.5, and 45 mg per culture, with or without metabolic activation, and harvested at 18 h after exposure. No chromosomal aberrations in the cultured mammalian cells were recorded. Acute intramuscular administration of the dimeric impurity of cefotaxime in Sprague-Dawley rats did not result in any clinical signs and gross pathological changes up to 2000 mg/kg-body weight. The results of these studies indicated that the dimeric impurity of cefotaxime is nonmutagenic in Ames test, nonclastogenic in vitro, and acutely nontoxic in rats.
Fetal ADH2*3, Maternal Alcohol Consumption, and Fetal Growth
Authors: Arfsten Darryl P. , Silbergeld Ellen K. , Loffredo Christopher A.
Published: April 2004

There is some evidence suggesting the allele for alcohol dehydrogenase 2*3 ( ADH2*3) is associated with a protective effect against alcohol-related intrauterine growth retardation (IUGR). This study was conducted to explore the affect of the ADH2*3 allele on fetal growth. Bloodspots ( n =1016) belonging to individual infants of a subgroup of the Baltimore-Washington Infant Study (BWIS) were assayed for the presence of the ADH2*3 allele by a polymerase chain reaction (PCR)-based method. Infants genotyped for ADH2*3 were those for whom bloodspots were identified and obtained from the Maryland Newborn Screening Program. The effect of ADH2*3 and maternal alcohol consumption on intrauterine growth was explored by multivariable linear regression analysis. Twenty-six percent of the 306 blood spots belonging to African-American infants were positive for ADH2*3 (4% were homozygous and 22% were heterozygous). Only a small percentage of bloodspots for Caucasian (1.3%) were positive for the ADH2*3 allele. Consequently, further analysis concentrated on gene-exposure interactions for African-American infants. It was found that the incidence of being small-for-gestation-age (SGA) was lower for ADH2*3-positive infants (2.5% versus 8.8%; p =.08). SGA infants had elevated odds for being ADH2*3 negative (OR: 3.15, 95% C.I.: 0.70–14.26) and for being born to mothers that consumed alcohol during pregnancy (OR: 2.31, 95% C.I.: 0.77–6.91). A negative trend between maternal alcohol consumption and mean offspring birthweight was found; however, ADH2*3 did not have a significant impact on mean birthweight for infants born to mothers that drank during pregnancy. These results could be interpreted as possible support for the hypothesis that ADH2 genotype in the infant may impact risk for alcohol-related IUGR. However, this study has limitations in that it is a “nested study of convenience” and involves a relatively small number of infants born to mothers reporting moderate to heavy alcohol use during pregnancy.
Toxicity of Methanol to Fish, Crustacean, Oligochaete Worm, and Aquatic Ecosystem
Authors: Kaviraj A. , Bhunia F. , Saha N. C.
Published: April 2004

Static renewal bioassays were conducted in the laboratory and in outdoor artificial enclosures to evaluate toxic effects of methanol to one teleost fish and two aquatic invertebrates and to limnological variables of aquatic ecosystem. Ninety-six-hour acute toxicity tests revealed cladoceran crustacea Moina micrura as the most sensitive to methanol (LC50, 4.82 g/L), followed by freshwater teleost Oreochromis mossambicus (LC50, 15.32 g/L) and oligochaete worm Branchiura sowerbyi (LC50, 54.89 g/L). The fish, when exposed to lethal concentrations of methanol, showed difficulties in respiration and swimming. The oligochaete body wrinkled and fragmented under lethal exposure of methanol. Effects of five sublethal concentrations of methanol (0, 23.75, 47.49, 736.10, and 1527.60 mg/L) on the feeding rate of the fish and on its growth and reproduction were evaluated by separate bioassays. Ninety-six-hour bioassays in the laboratory showed significant reduction in the appetite of fish when exposed to 736.10 mg/L or higher concentrations of methanol. Chronic toxicity bioassays (90 days) in outdoor enclosures showed a reduction in growth, maturity index and fecundity of fish at 47.49 mg/L or higher concentrations of methanol. Primary productivity, phytoplankton population, and alkalinity of water were also reduced at these concentrations. Chronic exposure to 1527.60 mg/L methanol resulted in damages of the epithelium of primary and secondary gill lamellae of the fish. The results revealed 23.75 mg/L as the no-observed-effect concentration (NOEC) of methanol to freshwater aquatic ecosystem.
Determination of Mercury by Cold Vapor Atomic Absorption Spectrophotometer in Tongkat Ali Preparations Obtained in Malaysia
Authors: Ang Hooi-Hoon , Lee Ee-Lin , Cheang Hui-Seong
Published: April 2004

The DCA (Drug Control Authority), Malaysia, has implemented the phase 3 registration of traditional medicines on 1 January 1992, with special emphasis on the quality, efficacy, and safety (including the presence of heavy metals) in all pharmaceutical dosage forms of traditional medicine preparations. As such, a total of 100 products in various pharmaceutical dosage forms of a herbal preparation, containing Tongkat Ali, were analyzed for mercury content using cold vapor atomic absorption spectrophotometer. Results showed that 36% of the above products possessed 0.52 to 5.30 ppm of mercury and, therefore, do not comply with the quality requirement for traditional medicines in Malaysia. Out of these 36 products, 5 products that possessed 1.05 to 4.41 ppm of mercury were in fact have already registered with the DCA, Malaysia. However, the rest of the products that contain 0.52 to 5.30 ppm of mercury still have not registered with the DCA, Malaysia. Although this study showed that only 64% of the products complied with the quality requirement for traditional medicines in Malaysia pertaining to mercury, they cannot be assumed safe from mercury contamination because of batch-to-batch inconsistency.
Dermal Irritation Assessment of Three Benzene Sulfonate Compounds
Authors: Tay Chin H. , Pugh Barbara T. , Clough Stephen R. , Magee Brian H.
Published: April 2004

Three benzene sulfonate compounds, benzene sulfonate, benzene meta-disulfonate, and para-phenol sulfonate, were reported to be present in groundwater sampled from residential wells near a former disposal site. Concentrations ranged from <0.005 mg/L to 474 mg/L. Acute dermal irritation studies were performed on rabbits for each of the three sulfonate compounds to determine if they had the potential to cause irritation to the skin of persons using this groundwater for bathing, showering, or other uses where skin would be exposed. The studies were performed by Toxikon Corporation (Bedford, MA) in accordance with the United States Environmental Protection Agency (USEPA)’s 1998 Health Effects Test Guidelines. At the highest concentration tested (5000 mg/L), all three sulfonate compounds were considered to be slight irritants, producing very slight to mild erythema (Draize Score 1). In all cases, the reactions were reversible. At 2000 mg/L, benzene meta-disulfonate and para-phenol sulfonate caused no irritation and were considered not to be irritants. At 2000 mg/L, only benzene sulfonate was considered to be a slight irritant, producing a mild erythema that was completely reversible within 24 hours. Benzene sulfonate was not considered an irritant at 1000 mg/L or at 500 mg/L. It is important to note that all three sulfonate compounds produced only a slight irritation at the highest concentration tested. None of the compounds produced a moderate to severe irritation response (i.e., severe erythema, edema). Furthermore, any irritation response observed at the highest concentrations tested was reversible within 72 hours. The only irritation response observed at the second highest dose was also reversible within 24 hours.
Evidence for Competitive Inhibition of Iodide Uptake by Perchlorate and Translocation of Perchlorate into the Thyroid
Authors: Clewell Rebecca A. , Merrill Elaine A. , Narayanan Latha , Gearhart Jeffery M. , Robinson Peter J.
Published: April 2004

Various published data sets that investigate the potential effect of exogenous perchlorate ( [Formula: see text]) on the uptake of iodide in the thyroid and subsequent changes in thyroid hormone levels are available. In order to best use the data towards the prediction of human health effects resulting from [Formula: see text] exposure, the available literature data must be integrated into a self-consistent, coherent, and parsimonious quantitative model based on the most likely mode of action of perchlorate effect on thyroid function. We submit that the simplest mode of action for [Formula: see text] in the thyroid that remains consistent with all available data involves competitive inhibition of iodide transport into the thyroid follicle, transport of perchlorate into the thyroid follicle against a concentration gradient, further transport into the thyroid lumen (where it may again interfere with iodide transport), and, finally, passive diffusion back into the blood. We believe this description of perchlorate’s kinetic behavior should serve as the foundation for predictive physiologically based pharmacokinetic (PBPK) models and as a working hypothesis for further experimental exploration.
N-Acetyltransferase (NAT2) Polymorphism and Breast Cancer Susceptibility: A Lack of Association in a Case-Control Study of Turkish Population
Authors: Kocabaş Neslihan Aygün , Şardaş Semra , Cholerton Suzanne , Daly Ann K. , Karakaya Ali Esat
Published: April 2004

Increased exposure to environmental carcinogens, including several aromatic and heterocyclic amines (HAs), is suspected to be one factor contributing to incidence of breast cancer. The N-acetyltransferase 2 ( NAT2) acetylation polymorphism have been associated with a number of drug-induced toxicities and cancer in various tissues, resulting from decreased capacity to activate/deactivate several aromatic amine, hydrazine drugs, as well as HA carcinogens. Ethnic differences exist in NAT2 genotype frequencies, which may be a factor in cancer incidence. Our present case-control study in Turkey was performed to explore the association between NAT2 genetic polymorphism and individual susceptibility to breast cancer. The NAT2 genotypes (* 4, * 12A, *5 A, * 5B, * 5C, * 6, * 7) were determined using the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) assay in 84 breast cancer patients and 103 healthy controls, and 50% and 56.3%, respectively, were found to be slow acetylator genotypes. There was no significant difference in risk for breast cancer development among patients with rapid and slow acetylators, with adjusted odds ratio 0.78 (95% confidence interval 0.44 to 1.38). Also, risk was not affected by different variables. To our knowledge, this is the first genetic study on the association of NAT2 genotypes with breast cancer in the Turkish population, and this finding showed that NAT2 polymorphism does not play an important role in breast cancer risk of Turkish women by altering the capacity in deactivation of environmental carcinogens, even though small sample size and wide confidence interval.
Job strain, effort - reward imbalance, and stress at work: competing or complementary models?
Authors: Calnan Michael , Wadsworth Emma , May Margaret , Smith Andrew , Wainwright David
Published: April 2004

Background: The Demand Control Model (DCM) and the Effort - Reward Imbalance Model (ERI) offer putative explanations of the relationship between stressful working conditions, job strain, and psychological and physical ill health. Aims: The aims of this study are to: (a) compare the predictive powers of the two models for explaining perceived job stress and mental distress amongst workers as a whole, (b) identify whether a model which combines dimensions of the DCM and ERI might have more predictive power than either of them separately, and (c) ascertain whether the models make distinct contributions to explaining stress at work in specific occupational settings. Methods: Statistical analysis was carried out on data collected from a cross-sectional postal survey of a random sample (n=7,069), of the adult population in an urban area in Southern England. The analysis focused on the 4,135 respondents who were in paid employment. Results: There was little support for combining the models as the combined model was dominated by the predictive power of dimensions from the ERI. However, the results also showed that the models or dimensions of the models made distinct contributions to explaining perceived work stress in different types of occupation. Conclusions: There is little evidence to support a combined model of work characteristics. The ERI appears to be the stronger of the two models although the DCM has explanatory value for specific occupations.
Sickness absence due to musculoskeletal diagnoses: association with occupational gender segregation
Authors: Leijon Margareta , Hensing Gunnel , Alexanderson Kristina
Published: April 2004

Background: Musculoskeletal disorders represent a considerable public health problem and the most common diagnoses behind sickness absence and disability pensions. However, little is known about how sickness absence with these diagnoses varies with the strong gender segregation of the labour market. Aims: A study was undertaken to investigate the association between musculoskeletal-related sickness absence and occupational gender segregation. Methods: The study was population based, and included all new sick-leave spells exceeding seven days due to musculoskeletal diagnoses, comprising neck/ shoulder pain, low back pain, and osteoarthritis in Östergötland county, Sweden, which has 393,000 inhabitants (5% of the national population). The participants were all sick-leave insured employed persons in Östergötland (n=182,663) in 1985. Results: Cumulative incidence of musculoskeletal-related sickness absence (>7 days) was higher for women (7.5%, 95% confidence interval [C.I.] 7.3-7.7) than for men, (5.8%, C.I. 5.6-5.9), and the same was true for the mean number of sick-leave days (women 81, C.I. 78-83; men 65, C.I. 63-68). Grouping occupations according to degree of numerical gender segregation revealed the highest incidence and duration of sickness absence for women in male-dominated occupations. For both genders, the lowest cumulative incidence and duration occurred in gender-integrated occupations. Conclusions: Our results indicate a strong association between occupational gender segregation and musculoskeletal-related sickness absence. Further studies are needed to elucidate gender segregation of the labour market in relation to health and rehabilitation measures.
Voluntary HIV testing in Europe
Authors: Renzi Cristina , Zantedeschi Ester , Signorelli Carlo
Published: April 2004

Aims: A study was undertaken to examine patterns of voluntary HIV testing among heterosexuals across Europe. Methods: Cross-sectional surveys on sexual behaviour and HIV were performed including probability samples of the general population ages 18 - 49 years in Greece (n=2,000), Italy (n=2,603), Switzerland (n=2,777), and Norway (n=3,704). Results: Prevalence of lifetime voluntary HIV testing among heterosexuals is 10.1%, 15.5%, 17.4%, and 40.9% in Greece, Italy, Norway, and Switzerland, respectively. Between 49.0% and 89.3% of individuals reporting risk behaviours never sought voluntary testing. Multivariate analysis shows that in some countries the likelihood of HIV testing is significantly higher for individuals aged 24 - 29 and 30 - 39 years, compared with younger respondents with the same risky behaviour. Among Swiss men and women higher educational level also significantly increases the probability of testing. Conclusions: The prevalence of voluntary HIV testing among heterosexuals with histories of risk is low. The needs of specific groups should be considered to improve HIV prevention and access to care.
Male and female physicians show different patterns of gender bias: A paper-case study of management of irritable bowel syndrome
Authors: Hamberg Katarina , Risberg Gunilla , Johansson Eva E.
Published: April 2004

Aims: Research has raised concerns about gender bias in medicine, i.e. that men and women might be treated differently due to gender-stereotyped attitudes among physicians. The authors investigated gender differences in medical management of a common health problem, irritable bowel syndrome (IBS). Method: In a national examination for Swedish house officers, the examinees were allocated to suggest management of IBS in either a male or female paper-patient. The case description was identical in both genders with the exception of prior prostate and gynaecological symptoms. The open answers were coded for analysis. A total of 289 physicians (45% women) participated. Chi-squared tests were used to measure differences in proportions. Results: In variables focusing on medication, weight, gynaecological problems, tobacco, alcohol, thyroid function, proposed diagnoses, X-ray of the colon, and advice about lifestyle, significant or close to significant gender differences were seen. Both male and female physicians made gender differences but they did not show the same pattern of differences. Conclusions: The results suggest that gender bias is involved in medical management of IBS but men and women physicians may show disparate patterns of gender bias. There is a need for larger studies on gender differences in medical management with designs making it possible to consider the gender of both the patient and the physician. Furthermore, the results call attention to `knowledge-mediated gender bias', a phenomenon implying that once knowledge about gender differences in a condition has been established, this might in fact cause gender-biased assessments of individual patients in clinical practice.
The validity of self-reported fractures among Danish female nurses: comparison with fractures registered in the Danish National Hospital Register
Authors: Hundrup Yrsa Andersen , Høidrup Susanne , Obel Erik B. , Rasmussen Niels Kr.
Published: April 2004

Background: The authors compared self-reported non-spine fractures obtained from a cohort of Danish female nurses with fracture diagnoses registered in the Danish National Hospital Register (DNHR). Method: The self-reported fracture history was obtained from a questionnaire and was related to fracture information registered with the DNHR by means of the unique person identification code of Danish citizens. A total of 166 self-reported hip fractures, 391 self-reported wrist fractures, and 121 self-reported upper arm fractures were available for the comparison. The self-reported fractures were initially compared with the anatomic specific fracture diagnoses registered in the DNHR. Second, the comparison also included fracture diagnoses of adjacent skeletal sites (unspecific fracture diagnoses). Results: The positive predictive value of a positive report of hip fracture was 89%. Inclusion of unspecific registered hip fractures increased the positive predictive value to 94%. The same figures for wrist fractures were 75% and 84%, respectively, and for upper arm fractures 54% and 83%, respectively. The predictive value of a negative report of hip fracture was 99.5%. The fracture year was correctly reported in 76% of the hip fracture cases, 81% of the wrist fracture cases, and 82% of the upper arm fracture cases. Predictors of false-positive report of fractures were young age (<60 years), report of indoor falls in the previous year, and use of hormone replacement therapy (HRT). Conclusion: The authors conclude that self-report of hip, wrist, or upper arm fractures among Danish nurses is relatively accurate but varies by the site of fracture. False positive reports of fracture introduce only modest bias fracture risk estimates and tend to dilute the association between exposures and fracture.
Long-term sick leave and its risk factors during pregnancy among Danish hospital employees
Authors: Kærlev Linda , Jacobsen Lene B. , Olsen Jørn , Bonde Jens Peter
Published: April 2004

Aim: The authors sought to describe risk indicators of long-term sick leave during pregnancy among hospital employees. Methods: A register-based study was undertaken of 4,852 female hospital employees aged 20 - 45 years from the second largest hospital in Denmark during 1995 - 99 based on job titles, working time, sick leave, and births combined with a survey among a total of 773 women who had been pregnant during their employment (response rate 85%). Results: Altogether 236 (31%) were on sick leave for at least 10% of their scheduled work time during their latest pregnancy and 169 (22%) had been absent at least 20% of the time. The pregnant women had an average sickness absence of 6.1 days per month, non-pregnant women 0.95 days per month. Sick leave was more frequent in late than in early gestation. Women employed as nursing aides or hospital orderlies, launderers, and nurses had more sick leave days than other hospital employees. Part-time work, previous sickness absence not related to pregnancy, and previous chronic back pain were risk factors for long-term sick leave as were much walking or standing, long working days, high work level, little practical support from supervisors and colleagues, low job control, much lifting and night or shift work. Sick leave was unrelated to family size, support from the family and number of working years. Conclusion: Long-term sick leave during pregnancy was frequent and to some extent predictable. Efforts should be made to organize work for pregnant women in a manner that optimizes their health and well-being.
Adverse events due to change in organization of problem drug users' treatment?
Authors: Buhl Lars , Sælan Henrik , Sørensen Tine Møller
Published: April 2004

Aims: This study set out to identify any undesirable consequences of legislative change in the organization of the treatment of problem drug users (PDUs), which aimed to combine their social and medical care. Method: The method used was a register-based three-year follow-up prevalent cohort study. Results: On 1 January 1996, the law was changed to allocate unambiguous and undivided responsibility for the combined social and medical care of PDUs in Denmark. The main objective of the legislative change was to move PDUs from treatment by general practitioners (GPs) and at private clinics to treatment institutions under the control of the counties. The possibility remained that medical treatment could, however, continue to be given by GPs or private clinics, based on specific agreements. The study showed that at the end of the period, 31 December 1998, two-thirds remained in treatment at private clinics or at GP surgeries. During the period only 8% of users were at some time without methadone treatment; 2% remained without methadone treatment throughout the study period. Conclusion: The transition from GPs and private clinics to the county treatment centres went smoothly. The number of PDUs in MMT (methadone maintenance treatment) in the city of Copenhagen increased in the period 1995 to 1998. The average quantity of methadone given to the cohort increased during these years from 72 mg per day to 92 mg per day. The legislative change therefore did not result in a higher threshold for treatment or a more restrictive prescription of methadone. No adverse effect on crime, hospital admissions, or death could be attributed to the legislative change in treatment organization.
The C2 domain of the Rsp5 ubiquitin ligase binds membrane phosphoinositides and directs ubiquitination of endosomal cargo
Authors: Dunn Rebecca , Klos Deborah A. , Adler Adam S. , Hicke Linda
Published: April 2004

Ubiquitin ligases of the Nedd4 family regulate membrane protein trafficking by modifying both cargo proteins and the transport machinery with ubiquitin. Here, we investigate the role of the yeast Nedd4 homologue, Rsp5, in protein sorting into vesicles that bud into the multivesicular endosome (MVE) en route to the vacuole. A mutant lacking the Rsp5 C2 domain is unable to ubiquitinate or sort biosynthetic cargo into MVE vesicles, whereas endocytic cargo is ubiquitinated and sorted efficiently. The C2 domain binds specifically to phosphoinositides in vitro and is sufficient for localization to membranes in intact cells. Mutation of a lysine-rich patch on the surface of the C2 domain abolishes membrane interaction and disrupts sorting of biosynthetic cargo. Translational fusion of ubiquitin to a biosynthetic cargo protein alleviates the requirement for the C2 domain in its MVE sorting. These results demonstrate that the C2 domain specifies Rsp5-dependent ubiquitination of endosomal cargo and suggest that Rsp5 function is regulated by membrane phosphoinositides.
Misfolded proteins are sorted by a sequential checkpoint mechanism of ER quality control
Authors: Vashist Shilpa , Ng Davis T.W.
Published: April 2004

Misfolded proteins retained in the endoplasmic reticulum (ER) are degraded by the ER-associated degradation pathway. The mechanisms used to sort them from correctly folded proteins remain unclear. Analysis of substrates with defined folded and misfolded domains has revealed a system of sequential checkpoints that recognize topologically distinct domains of polypeptides. The first checkpoint examines the cytoplasmic domains of membrane proteins. If a lesion is detected, it is retained statically in the ER and rapidly degraded without regard to the state of its other domains. Proteins passing this test face a second checkpoint that monitors domains localized in the ER lumen. Proteins detected by this pathway are sorted from folded proteins and degraded by a quality control mechanism that requires ER-to-Golgi transport. Although the first checkpoint is obligatorily directed at membrane proteins, the second monitors both soluble and membrane proteins. Our data support a model whereby “properly folded” proteins are defined biologically as survivors that endure a series of distinct checkpoints.