Inhalation toxicity studies with 1,3-butadiene. 3. Two year toxicity/carcinogenicity study in rats

Groups of 110 male and 110 female CD (Sprague-Dawley) rats were exposed to atmospheres containing 0 (control), 1000 or 8000 ppm v/v butadiene for 6 hr/day and 5 days/week. Ten of each sex from each group were killed at 52 weeks. The study was terminated when it was predicted that survival would drop to 20% to 25% (105 weeks for females and 111 weeks for males). High dose rats had wet, ruffled fur and showed slight incoordination during the first exposure each week. During the second year, mortality in both treated female groups was increased because of humanitarian sacrifice of animals with large subcutaneous masses, while increased mortality in the high dose males was accompanied by an increase of the severity of nephropathy. Body weight was slightly lower than controls in both sexes at the high dose, but statistically significant only over the first 12 weeks. There were no effects in hematological analyses or tests of neuromuscular function that definitely could be associated with treatment. Liver weights at both doses were increased in both sexes with no associated pathological change. Kidney weight was increased in males at the high dose, together with an increase in the severity of nephrosis. There were increases in the incidences of pancreatic exocrine adenoma (high dose, male); uterine sarcoma (both doses, female); Zymbal gland carcinoma (high dose, female); mammary tumors (both doses, female); thyroid follicular cell tumors; and testis Leydig-cell tumors (high dose). These data suggest that butadiene is a weak oncogen to the rat under the conditions of exposure used in this study.     

The apolipoprotein C-II variant apoC-IILys19→Thr is not associated with dyslipidemia in an affected kindred

The rare apolipoprotein C-II (apoC-II) mutation, apoC-II_Lys19→Thr, also known as apoC-II-v, has been found previously in association with hyperlipoproteinemia. From a lipid clinic screening we identified three unrelated individuals who had the apoC-II_Lys19→Thr mutation. Among eight family members of one proband, we have found another four who were affected. None of the inviduals in this kindred is dyslipidemic and there is no difference in lipid levels between affected and unaffected family members. Therefore, we conclude that the presence of this apolipoprotein variant by itself has no effect on lipoprotein levels. In addition, the apolipoprotein E (apoE) isoform, apoE4 does not have a synergistic effect on lipoprotein levels in this kindred, in contrast to observations on the interaction of apoE4 with another apoC-II mutant (apoC-II_Toronto). The single nucleotide substitution that causes the apoC-II_Lys19→Thr variant introduces a previously unrecognized restriction site (for Mae III), that provides for easy screening.     

Ratiometric analysis in hyperpolarized NMR (I): test of the two‐site exchange model and the quantification of reaction rate constants

Conventional methods for the analysis of in vivo hyperpolarized ¹³C NMR data from the lactate dehydrogenase (LDH) reaction usually make assumptions on the stability of rate constants and/or the validity of the two‐site exchange model. In this study, we developed a framework to test the validity of the assumption of stable reaction rate constants and the two‐site exchange model in vivo via ratiometric fitting of the time courses of the signal ratio L(t)/P(t). Our analysis provided evidence that the LDH enzymatic kinetics observed by hyperpolarized NMR are in near‐equilibrium and satisfy the two‐site exchange model for only a specific time window. In addition, we quantified both the forward and reverse exchange rate constants of the LDH reaction for the transgenic and mouse xenograft models of breast cancer using the ratio fitting method developed, which includes only two modeling parameters and is less sensitive to the influence of instrument settings/protocols, such as flip angles, degree of polarization and tracer dosage. We further compared the ratio fitting method with a conventional two‐site exchange modeling method, i.e. the differential equation fitting method, using both the experimental and simulated hyperpolarized NMR data. The ratio fitting method appeared to fit better than the differential equation fitting method for the reverse rate constant on the mouse tumor data, with less relative errors on average, whereas the differential equation fitting method also resulted in a negative reverse rate constant for one tumor. The simulation results indicated that the accuracy of both methods depends on the width of the transport function, noise level and rate constant ratio; one method may be more accurate than the other based on the experimental/biological conditions aforementioned. We were able to categorize our tumor models into specific conditions of the computer simulation and to estimate the errors of rate quantification. We also discussed possible approaches to the development of more accurate rate quantification methods for hyperpolarized NMR. Copyright © 2013 John Wiley & Sons, Ltd.     

Trauma history in diagnostic groups of temporomandibular disorders

Trauma history was studied for association with disease among six diagnostic subgroups of 230 patients with temporomandibular disorder (TMD) from a private practice setting with (1) disk displacement (DD) with reduction, (2) DD without reduction, (3) osteoarthrosis (OA) with prior derangement history, (4) primary OA, (5) myalgia only, and (6) subluxation only. Except for subluxation (29%), trauma history typified TMD patient groups 1 to 5 (63%, 79%, 44%, 53%, 54%) (p less than 0.001) compared with 13% and 18% of asymptomatic (n = 61) and symptomatic (n = 161) student control subjects, and 11% of general dental patients (n = 150). TMD groups 2 and 3 differed significantly (p less than 0.05). The high prevalence of trauma in the myalgia-only group complicates the concept of myofascial pain-dysfunction syndrome as solely a stress or centrally mediated disorder. DD without reduction (43%) and with reduction (38%) had the highest prevalences of motor vehicle accident trauma, myalgia and OA groups had less, and subluxation-only cases had none. On the other hand, patients with DD without reduction were also the only group to report multiple trauma (29%), suggesting that although specific traumatic events may seem to precipitate clinical symptoms, they may not always have initiated the problem. Trauma may be both an important cumulative and precipitating event in TMDs.     

Establishing better biological models to understand occlusion. I: TM joint anatomic relationships

Belief in and rejection of a relationship of occlusion and temporomandibular joint (TMJ) condyle–fossa position with normal and abnormal function are still contentious issues. Clinical opinions can be strong, but support in most published data (mostly univariate) is problematic. Distribution overlap, low sensitivity and specificity are a common basis to reject any useful prediction value. Notwithstanding, a relationship of form with function is a basic tenet of biology. These are multifactor problems, but the questions mostly have not been analysed as such. This review moves the question forward by focusing on TM joint anatomic organisation as the multifactor system it is expected to be in a closed system like a synovial joint. Multifactor analysis allows the data to speak for itself and reduces bias. Classification tree analysis revealed useful prediction values and usable clinical models which are illustrated, backed up by stepwise logistic regression. Explained variance, R², predicting normals from pooled TMJ patients was 32·6%, sensitivity 67·9%, specificity 85·7%; 37% versus disc displacement with reduction; and 28·8% versus disc displacement without reduction. Significant osseous organisational differences between TM joints with clicking and locking suggest that this is not necessarily a single disease continuum. However, a subset of joints with clicking contained characteristics of joints with locking that might contribute to symptom progression versus resistance. Moderately strong models confirm there is a relationship between TMJ osseous organisation and function, but it should not be overstated. More than one model of normals and of TM derangement organisation is revealed. The implications to clinical decision‐making are discussed.     

Primary hypercholesterolemia: genetic causes and treatment of five monogenic disorders

Coronary heart disease is a major cause of death in Europe and the USA. Insudation of atherogenic lipoproteins, including low-density lipoprotein (LDL), into the artery wall is integral to atherosclerosis. It is clear that numerous genetic loci contribute to increased plasma levels of LDL. However, five specific monogenic disorders, three of which have been reported recently, are known to increase LDL. These are familial hypercholesterolemia (LDL receptor gene: LDLR); familial ligand-defective apoB- 100 (apoB gene: APOB); autosomal recessive hypercholesterolemia (ARH gene); sitosterolemia (ABCG5 or ABCG8 genes) and cholesterol 7alpha-hydroxylase deficiency (CYP7A1 gene). This review relates the mechanisms underlying these five disorders with specific therapeutic interventions.     

Relationship of TMJ articular soft tissue to underlying bone in young adult condyles

This investigation used a histological model to study the relationship of articular soft-tissue thickness and contour to the underlying bone in the TMJ condyle of young adults. The usefulness of selected dental and demographic factors in the prediction of the articular soft-tissue thickness and contour was also tested. One sagittal histological section was studied from the lateral, central, and medial thirds of 53 left mandibular condyles. Outline tracings of the articular and compact bone surface were divided into anterior, superior, and posterior sectors for the study of curvature measured by the overlaying of a template of a harmonic series of arcs. The thickness and composition of the articular tissues were measured in each sector by light microscopy. The fibrous connective tissue layer always maintained the articular surface, even in the absence of a cartilage layer. The histological character, including the presence or absence of cartilage, rather than the overall tissue thickness, was considered to be a more useful marker of functionally thickness was not related to surface deviation in form and was not correlated with age in this young adult sample. Reduced soft-tissue thickness in the anterior part of the condyle was more common in cases with lack of molar support. Dental attrition was not a useful predictor of soft-tissue thickness. Compact bone contour correlated with soft-tissue contour in the superior (r = 0.816) and posterior (r = 0.808) sectors, explaining only 64% of the variance, but not in the anterior sector (r = 0.265). Thicker or thinner articular soft tissue was not predictable by the underlying compact bone contour or thickness. Therefore, the clinician should not automatically assume that the radiographic osseous image represents the actual articular surface.