CD154 deficiency uncouples allograft CD8+ T-cell effector function from proliferation and inhibits murine airway obliteration.

Obliterative bronchiolitis (OB) limits the long-term success of lung transplantation, while T-cell effector mechanisms in this process remain incompletely understood. Using the murine heterotopic tracheal transplant model of obliterative airway disease (OAD) to characterize airway allograft rejection, we previously reported an important role for CD8(+) T cells in OAD. Herein, we studied the role of CD154/CD40 costimulation in the regulation of allospecific CD8(+) T cells, as airway rejection has been reported to be CD154-dependent. Airway allografts from CD154(-/-) recipients had significantly lower day 28 OAD scores compared to wild-type (WT) recipients, and adoptive transfer of CD8(+) T cells from WT recipients, but not CD154(-/-) recipients, were capable of airway rejection in fresh CD154(-/-) allograft recipients. Intragraft CD8(+) T cells from CD154(-/-) mice showed similar expression of the surface markers CD69, CD62L(low) CD44(high) and PD-1, but markedly impaired IFN-gamma and TNF-alpha secretion and granzyme B expression versus WT controls. Unexpectedly, intragraft and systemic CD8(+) T cells from CD154(-/-) recipients demonstrated robust in vivo expansion similar to WT recipients, consistent with an uncoupling of proliferation from effector function. Together, these data suggest that a lack of CD154/CD40 costimulation results in ineffective allospecific priming of CD8(+) T cells required for murine OAD.

Synthesis and evaluation of unsymmetrically substituted polyamine analogues as modulators of human spermidine/spermine-N1-acetyltransferase (SSAT) and as potential antitumor agents.

Spermidine/spermine-N1-acetyltransferase (SSAT), the rate-limiting step in polyamine catabolism, is critical for the interconversion and modulation of cellular polyamines. Inhibitor-initiated induction of this enzyme also appears to correlate with the sensitivity of tumor cells to a class of novel polyamine analogues, the bis(ethyl)polyamines. Thus, terminally alkylated polyamines which modulate the cellular level of SSAT could be of great value for understanding the role of this enzyme both in analogue-mediated cytotoxicity and in overall cellular polyamine metabolism. Such analogues could also become important therapeutic agents by disrupting cellular polyamine metabolism. The structure-activity relationships defining the interaction of polyamine analogues with SSAT have not been fully elucidated, and, in particular, unsymmetrically alkylated polyamines have not been synthesized and evaluated as modulators of SSAT. To this end, we now report the synthesis and preliminary biological evaluation of N1-ethyl-N11-propargyl-4,8-diazaundecane and N1-ethyl-N11-((cyclopropyl)methyl)-4,8-diazaundecane via a synthetic pathway which represents an efficient route to a variety of unsymmetrically substituted polyamine analogues. The title compounds act as effective inhibitors of isolated human SSAT and produce a differential superinduction of SSAT in situ which appears to be associated with a cell specific cytotoxic response in two human lung cancer cell lines. In so doing, these analogues exhibit promising antitumor activity against cultured human lung cancer cells.

Prediction of mandibular rotation: an empirical test of clinician performance.

An experiment was conducted in an attempt to determine empirically how effective a number of expert clinicians were at differentiating "backward rotators" from "forward rotators" on the basis of head-film information which might reasonably have been available to them prior to instituting treatment for the correction of Class II malocclusion. As a result of a previously reported ongoing study, pre- and posttreatment head films were available for 188 patients treated in the mixed dentition for the correction of Class II malocclusion and for 50 untreated Class II subjects. These subjects were divided into 14 groups (average size of group, 17; range, 6 to 23) solely on the basis of type of treatment and the clinician from whose clinic the records had originated. From within each group, we selected the two or three subjects who had exhibited the most extreme backward rotation and the two or three subjects who had exhibited the most extreme forward rotation of the mandible during the interval between films. The sole criterion for classification was magnitude of change in the mandibular plane angle of Downs between the pre- and posttreatment films of each patient. The resulting sample contained 32 backward-rotator subjects and 32 forward-rotator subjects. Five expert judges (mean clinical experience, 28 years) were asked to identify the backward-rotator subjects by examination of the pretreatment films. The findings may be summarized as follows: (1) No judge performed significantly better than chance. (2) There was strong evidence that the judges used a shared, though relatively ineffective, set of rules in making their discriminations between forward and backward rotators. (3) Statistical analysis of the predictive power of a set of standard cephalometric measurements which had previously been made for this set of subjects indicated that the numerical data also failed to identify potential backward rotators at a rate significantly better than chance. We infer from these findings that the ability of clinicians to identify backward rotators on the basis of information available at the outset of treatment is poor. Hence, we believe that it is unlikely that such predictions play any consequential operational role in the planning of successful orthodontic therapy at the present state of the art.

Distal displacement of the maxilla and the upper first molar.

Data from a sample of 198 Class II cases treated with various appliances which deliver distally directed forces to the maxilla were examined to determine the frequency of absolute distal displacement of the upper first molar and of the maxilla. Analysis revealed that such distal displacement is possible and that it is, in fact, a frequent finding following treatment. Long-range stability of distal displacement was not assessed.

Superimpositional assessment of treatment-associated changes in the temporomandibular joint and the mandibular symphysis.

This article analyzes differences in the measured displacement of the condyle and of progonion when different vectors of force are delivered to the maxilla in the course of non-full-banded, Phase 1, mixed-dentition treatment for the correction of Class II malocclusion. The 238-case sample is identical to that for which changes in other parameters of facial form have been reported previously. Relative to superimposition on anterior cranial base and measured in a Frankfort-plane-determined coordinate system, we have attempted to identify and quantitate (1) the displacement of each structure which results from local remodeling and (2) the displacement of each structure which occurs as a secondary consequence of changes in other regions of the skull. We have also attempted to isolate treatment effects from those attributable to spontaneous growth and development. At the condyle, we note that in all three treatment groups and in the control group there is a small but real downward and backward displacement of the glenoid fossa. This change is not treatment induced but, rather, is associated with spontaneous growth and development. (See Fig. 5.) Some interesting differences in pattern of "growth at the condyle" were noted between samples. In the intraoral (modified activator) sample, there were small but statistically significant increases in growth rate as compared to the untreated group of Class II controls. To our surprise, similar statistically significant increases over the growth rate of the control group were noted in the cervical sample. (See Table III, variables 17 and 18.) Small but statistically significant differences between treatments were also noted in the patterns of change at pogonion. As compared to the untreated control group, the rate of total displacement in the modified activator group was significantly greater in the forward direction, while the rate of total displacement in the cervical group was significantly greater in the downward direction. There were no statistically significant differences in the rate of total displacement of pogonion between the high-pull sample and the control sample. (See Table IV, variables 21 and 22.

Quantitative analysis of the orthodontic and orthopedic effects of maxillary traction.

This article analyzes differences in displacement of ANS and of the upper first molar when different vectors of force are delivered to the maxilla in non-full-banded Phase I mixed-dentition treatment of Class II malocclusion. The sample is identical to that for which we have previously reported differences in change in several key measures of mandibular and facial shape. It includes a cervical-traction group, a high-pull-to-upper-molar group, a modified-activator group, and an untreated Class II control group. Using newly developed computer-conducted procedures, which are described, we have been able to partition the orthodontic and orthopedic components of upper molar displacement and also to isolate treatment effects from those attributable to spontaneous growth and development. In the region of ANS, small but statistically significant and clinically meaningful differences were noted between treatments. When the intercurrent effects of growth and development had been factored out (Table III), orthopedic distal displacement of ANS was significantly greater in the high-pull and cervical groups than in the activator group. Orthopedic downward displacement of ANS was seen to be significantly greater in the cervical group than in the high-pull and activator groups. In the region of the first molar cusp, mean distal displacement of the tooth as an orthopedic effect was found to be almost identical in the cervical and high-pull groups (although variability was greater in the cervical group), but the mean orthodontic effect was significantly greater in the high-pull group than in the cervical group. In the cervical group, where relatively light forces were used for relatively long treatment periods on average, more of the total distal displacement of the upper molar was of an orthopedic character than of an orthodontic character. Conversely, in the high-pull group, in which relatively heavier forces tended to be used for briefer treatment periods, most of the distal displacement at the upper molar was of an orthodontic character. These observations are contrary to expectations from conventional orthodontic theory. In the activator-treated group, roughly equal components of the treatment-associated distal displacement of the upper molar were of the orthodontic and orthopedic types. As concerns changes in the vertical direction in the region of the molar cusp, significant intrusion of both the orthopedic and orthodontic types was seen in the high-pull sample as compared to each of the other groups examined.(ABSTRACT TRUNCATED AT 400 WORDS)

Quantitation of maxillary remodeling. 1. A description of osseous changes relative to superimposition on metallic implants.

Lateral skull radiographs for a set of 31 human subjects were examined using computer-aided methods in an attempt to quantify modal trends of maxillary remodeling during the mixed dentition and adolescent growth periods. Cumulative changes in position of anterior nasal spine (ANS), posterior nasal spine (PNS), and Point A are reported at annual intervals relative to superimposition on previously placed maxillary metallic implants. This in vivo longitudinal study confirms at a high level of confidence earlier findings by Enlow, Björk, Melsen, and others to the effect that the superior surface of the maxilla remodels downward during the period of growth and development being investigated. However, the inter-individual variability is relatively large, the mean magnitudes of change are relatively small, and the rate of change appears to diminish by 13.5 years. For the 19 subjects for whom data were available for the time interval from 8.5 to 15.5 years, mean downward remodeling at PNS was 2.50 mm with a standard deviation of 2.23 mm. At ANS, corresponding mean value was 1.56 mm with a standard deviation of 2.92 mm. Mean rotation of the ANS-PNS line relative to the implant line was 1.1 degree in the "forward" direction. However, this rotational change was particularly variable with a standard deviation of 4.6 degrees and a range of 11.3 degrees "forward" to 6.7 degrees "backward." The study provides strong evidence that the palate elongates anteroposteriorly mainly by the backward remodeling of structures located posterior to the region in which the implants were placed. There is also evidence that supports the idea of modal resorptive remodeling at ANS and PNS, but here the data are somewhat more equivocal. It appears likely, but not certain, that there are real differences in the modal patterns of remodeling between treated and untreated subjects. Because of problems associated with overfragmentation of the sample, sex differences were not investigated.

Quantitation of maxillary remodeling. 2. Masking of remodeling effects when an "anatomical" method of superimposition is used in the absence of metallic implants.

We report the results of a study aimed at quantifying the differences in the perceived pattern of maxillary remodeling that are observed when different methods are used to superimpose maxillary images in roentgenographic cephalometrics. In a previous article, we reported cumulative changes in the positions of anterior nasal spine (ANS), posterior nasal spine (PNS), and Point A for a sample of 31 subjects with maxillary metallic implants. Measurements had been made on lateral cephalograms taken at annual intervals relative to superimposition on the implants. In the present article, we quantify the differences in the perceived displacement of the same landmarks in the same sample when a standard "anatomical best bit" rule was used in lieu of superimposition on the implants. The anatomical best fit superimposition as herein defined was found in this sample to lose important information on the downward remodeling of the superior surface of the maxilla that had been detected when the implant superimposition was used. In fact, we observed a small artifactual upward displacement of the ANS-PNS line. In the anteroposterior direction, the tendency toward backward displacement of skeletal landmarks through time that had been detected with the implant superimposition was replaced by a small forward displacement of ANS and Point A together with reduced backward displacement of PNS. To the extent that the implant superimposition is to be considered the true and correct one, the anatomical best fit superimposition appears to understate the true downward remodeling of the palate by an average of about 0.3 and 0.4 mm per year, although this value differs at different ages and timepoints. The anatomical best fit superimposition also misses entirely the small mean tendency toward backward remodeling that was observed when the implant superimposition was used. In situations in which there are no implants, clinicians and research workers must necessarily continue to use anatomically based superimpositions with definitions more or less similar to that of the anatomical best fit superimposition used here. When they do so, some systematic errors will be incurred. For grouped data, we believe that the best currently available estimates of the mean errors involved in using the anatomical best fit superimposition to approximate an implant superimposition are the "bias" values included in Table IIC. The secondary implications of these differences to the perceived displacements of the maxillary teeth will be considered in our next article.