The Relationship between Use of the Maximum Tolerated Dose and Study Sensitivity for Detecting Rodent Carcinogenicity

The relationship between maximum tolerated dose (MTD) and studysensitivity for detecting rodent carcinogenicity was evaluatedfor 216 chemicals found to be carcinogens in laboratory animalstudies conducted by the National Cancer Institute (NCI) andthe National Toxicology Program (NTP). Approximately two-thirdsof these rodent carcinogens would have been detected even withoutthe top dose (estimated MTD), but in many of these studies,some site-specific carcinogenic effects would have been missed.Among the remaining one-third of the rodent carcinogens thatrequired the top dose for statistical significance, approximately80% had numerically elevated rates of the same site-specifictumors at lower doses as well. Only 13 of the NCI/NTP rodentcarcinogens had increased tumor rates limited to the top dosefor all sites of carcinogenicity. Alternatively, of the 838site-specific carcinogenic effects observed in the NCI/NTP studies,447 (53%) would have been detected even without the top dose.Of the remaining effects, 75% (294/391) showed numerically elevatedsite-specific tumor rates at lower doses. Our evaluation indicatesthat most carcinogenic effects ob served at the top dose inrodent studies are also present (with reduced incidence thatmight or might not be statistically significant) at the lowerdoses typically employed (MTD, MTD).     

Retention of dental sealants placed on sound teeth and incipient caries lesions as part of a service‐learning programme in rural areas in Mexico

International Journal of Paediatric Dentistry 2012; 22: 451–458 Background. Dental sealants are an effective treatment for the prevention and management of caries. Objective. To determine the retention of sealants placed in a rural setting in Mexico as part of an international service‐learning (ISL) programme and to determine associations between dental sealant’s retention and caries diagnosis at the time of sealant placement. Methods. Children aged 6–15 were examined for dental caries, received sealants by dental students as part of an ISL programme, and were re‐examined 4, 2, or 1 years after placement to assess sealant survival. Sealants were placed on permanent sound surfaces and enamel caries lesions [International Caries Assessment and Detection System (ICDAS) criteria]. Sealant survival was explored using Cochran–Mantel–Haenszel tests and multivariate prediction models. Results. 219 (46%) of 478 (mean age = 10.53 SD = 5.11) children who had received sealants returned for a recall examination (mean age = 10.89 SD = 3.11). After 1–4 years, 96.4% to 60.6% of the sealants placed on sound teeth had survived, and for sealants placed on surfaces with enamel caries lesions (ICDAS 1–3), 94.2% to 55.6% had survived. Differences were not statistically significant. Conclusions. Sealants had survival rates comparable to those previously reported in the literature. Sealants placed on sound and enamel caries lesions had similar survival rates.     

Quantitative Hemagglutination Studies in the Rh Blood Group System. II. A Study of the D (Rho) Agglutinogen

The reactivity of Rh positive red cells with saline anti-D sera has beeninvestigated by means of quantitative hemagglutination methods. The inhibitory effect of C on the D antigen has been confirmed and the possibility ofinhibition by this antigen in the cis position suggested. It is also suggested thatthe e antigen has suppressive effect on D. The presence of companion antigensresults in a -D-> R₂ > R_o > R₁ progression of decreasing agglutinability.Within families differences in the agglutination behavior between homozygousand heterozygous D positive cells were found. The heterogeneity of thisantigen was confirmed.

Accepted on November 20, 1960     

Differential Effect of Adenosine on Anterograde and Retrograde Fast Pathway Conduction in Patients with Atrioventricular Nodal Reentrant Tachycardia

Adenosine and Retrograde Fast Pathway Conduction . Introduction : Several studies have shown that the fast pathway is more responsive to adenosine than the slow pathway in patients with AV nodal reentrant tachycardia. Little information is available regarding the effect of adenosine on anterograde and retrograde fast pathway conduction.
Methods and Results : The effects of adenosine on anterograde and retrograde fast pathway conduction were evaluated in 116 patients (mean age 47 ± 16 years) with typical AV nodal reentrant tachycardia. Each patient received 12 mg of adenosine during ventricular pacing at a cycle length 20 msec longer than the fast pathway VA block cycle length and during sinus rhythm or atrial pacing at 20 msec longer than the fast pathway AV block cycle length. Anterograde block occurred in 98% of patients compared with retrograde fast pathway block in 62% of patients ( P < 0.001). Unresponsiveness of the retrograde fast pathway to adenosine was associated with a shorter AV block cycle length (374 ± 78 vs 333 ± 74 msec, P < 0.01), a shorter VA block cycle length (383 ± 121 vs 307 ± 49 msec, P < 0.001), and a shorter VA interval during tachycardia (53 ± 23 vs 41 ± 17 msec, P < 0.01).
Conclusion : Although anterograde fast pathway conduction is almost always blocked by 12 mg of adenosine, retrograde fast pathway conduction is not blocked by adenosine in 38% of patients with typical AV nodal reentrant tachycardia. This indicates that the anterograde and retrograde fast pathways may be anatomically and/or functionally distinct. Unresponsiveness of VA conduction to adenosine is not a reliable indicator of an accessory pathway.     

Understanding the pathogenesis of type 2 diabetes: can we get off the metabolic merry-go-rounds?

The aetiology of non-insulin-dependent diabetes mellitus (NIDDM) is not known. The concordance of NIDDM in identical twins and differences in the prevalence rate of NIDDM between different racial groups suggest a genetic cause. Hyperglycaemia in established diabetes is caused by a combination of hepatic insulin resistance, impaired peripheral (muscle and fat) glucose uptake and a defect in glucose-mediated insulin secretion. However, it is not known if these defects are all inherited or if one can cause the others. This uncertainty is due to the fact that hyperglycaemia per se can cause defects in insulin action and insulin secretion that resemble those found in NIDDM. Furthermore the elevated free fatty acid (FFA) levels found when NIDDM is associated with obesity are known to cause both peripheral and hepatic insulin resistance. Recently we have demonstrated the mechanism by which elevated FFA levels can cause hepatic insulin resistance. However, we also have evidence that the converse holds in that genetically engineered hepatic insulin resistance in a transgenic rat model leads to obesity. Thus an understanding of the pathogenesis of NIDDM is complicated by the fact that hyperglycaemia and obesity can be both causes and consequences of insulin resistance. To overcome these difficulties, studies in young, euglycaemic diabetes-prone subjects have been conducted. Results suggest that there may be different causes for NIDDM in different racial groups.     

Response to Atrial Extrastimulus During Supraventricular Tachycardia: What Is the Mechanism?

Arrhythmia Rounds . We describe a case illustrating the potential challenges in distinguishing AV nodal reentry tachycardia (AVNRT) from automatic junctional tachycardia (JT). While an early atrial extrastimulus advanced the next His and ventricular depolarization without tachycardia termination, suggesting JT, other features indicated the correct diagnosis of AVNRT. This teaching case demonstrates a novel exception to a recently reported diagnostic pacing maneuver and illustrates the importance of considering response to multiple maneuvers in reaching a diagnosis of SVT mechanism. (J Cardiovasc Electrophysiol, Vol. 24, pp. 359‐363, March 2013)