The Americleft Project: A Proposed Expanded Nasolabial Appearance Yardstick for 5- to 7-Year-Old Patients With Complete Unilateral Cleft Lip and Palate (CUCLP).

OBJECTIVE: To develop a yardstick of reference photographs for nasolabial appearance assessments of 5- to 7-year-old patients with complete unilateral cleft lip and palate (CUCLP). DESIGN: Blind retrospective analysis of clinical records and comparison to historical controls. PATIENTS: Subjects were two groups of 6- to 12-year-olds (n = 124 and n = 135) and one group of 5- to 7-year-olds (n = 149) with nonsyndromic CUCLP from three previous Americleft studies, including cohorts from seven different cleft/craniofacial centers. INTERVENTIONS: All patients received the infant management protocols of their respective centers. Eleven trained and calibrated judges (five participated in all three studies) did blind ratings of nasolabial appearance using the Asher-McDade method. MAIN OUTCOME MEASURES: Patients receiving the most consistent ratings between judges, selected first from the groups of 6- to 12-year-olds, were used to create a pilot yardstick for eventual use in the third study of 5- to 7-year-olds. For each of the Asher-McDade categories, 8 of the 5- to 7-year-old patients receiving the most consistent scores between raters were ranked by 10 judges for a final elimination to leave three per category. RESULTS: Using this method of successive changes in rating methods, a new reference yardstick for nasolabial appearance rating was established and linked to the original Asher-McDade method as well as the single examples in a previously published yardstick for patients with CUCLP. Pilot testing using the yardstick improved reliabilities. CONCLUSIONS: Use of an expanded nasolabial yardstick of reference photographs representative of the range of possibilities of each of the five Asher-McDade categories is now available to see if reliability of these ratings can be improved.

The Americleft Project: A Comparison of Short- and Longer-Term Secondary Alveolar Bone Graft Outcomes in Two Centers Using the Standardized Way to Assess Grafts Scale.

OBJECTIVE: To compare length of follow-up and cleft site dental management on bone graft ratings from two centers. DESIGN: Blind retrospective analysis of cleft site radiographs and chart reviews for determination of cleft-site lateral incisor management. PATIENTS: A total of 78 consecutively grafted patients with complete clefts from two major cleft/craniofacial centers (43 from Center 1 and 35 from Center 2). INTERVENTIONS: Secondary iliac crest alveolar bone grafting, at a mean age of 9 years 9 months (Center 1: 9 years 7 months; Center 2: 10 years 0 month). MAIN OUTCOME MEASURES: The Americleft Standardized Way to Assess Grafts scale from 0 (failed graft) to 6 (ideal) was used to rate graft outcome at two time points (T1, T2). Average T1 was 11 years 1 month of age, 1 year 3 months postgraft. Average T2 was 17 years 11 months of age, 8 years 0 months postgraft. Six trained and calibrated raters scored each radiograph twice. Reliability was calculated at T1 and T2 using weighted kappa. A paired Wilcoxon signed rank test (P < .05) tested T1 and T2 differences for each center. A Kruskal-Wallis test was used to determine the significance of differences between centers at T1 and T2. Correlation tested whether T1 ratings predicted T2. Linear regression determined possible factors that might contribute to graft rating changes over time. RESULTS: Reliability was good at T1 and T2 (interrater = .713 and .701, respectively; intrarater = .790 and .805, respectively). Center 1 scores were significantly better than those from Center 2 at both T1 (5.21 versus 3.29) and T2 (5.18 versus 3.44). There was no statistical difference between T1 and T2 scores for either center; although, there was a greater chance of bone graft score improving with completion of canine eruption and substitution for missing lateral incisors. CONCLUSIONS: Short-term ratings of graft outcomes identified significant differences between centers that persisted over time. Dental cleft-site management influenced final graft outcome.

Quantitative 3D maxillary arch evaluation of two different infant managements for unilateral cleft lip and palate.

OBJECTIVE: A two-institution retrospective study was undertaken to determine whether two different prepalatoplasty protocols quantitatively affect maxillary arch morphology in infants with complete unilateral cleft lip and palate (UCLP). DESIGN: Serial maxillary dental casts, obtained at regular intervals through the first 18 months of life from preintervention until palatoplasty were evaluated quantitatively using computer-assisted three-dimensional digitization and analysis for three populations: institution 1 (protocol 1), institution 2 (protocol 2), and unaffected individuals (neither cleft nor treatment). Sequential UCLP patients from institution 1 were matched for age and initial alveolar cleft width, sex and cleft side having been demonstrated to be nonsignificant, with UCLP patients from institution 2 and to unaffected individuals for age for the analysis. SETTING: Both treatment institutions are well-established regional interdisciplinary cleft centers. Institution 1 is located in a tertiary, academic children's hospital in a metropolis within a primarily agrarian region of the Midwest; institution 2 is a freestanding private clinic located in a small city within a primarily agrarian region of an eastern state; the unaffected population is a historic archive acquired in the 1930s. Data acquisition (model digitization) and computer processing were performed at institution 1. PATIENTS: Eighty-five casts of 28 infants from institution 1, 106 casts of 31 infants from institution 2, and 68 casts of 29 unaffected infants were analyzed. All infants had alginate impressions taken prior to intervention and at several additional 6-month intervals after that, consistent with each institution's treatment protocol. INTERVENTIONS: At institution 1, patients with UCLP underwent lip adhesion and placement of a passive alveolar molding plate at 7 weeks of age, definitive cheiloplasty at 7 months of age, and one-stage palatoplasty at 14 months of age. At institution 2, patients with UCLP underwent definitive cheiloplasty at 3 months of age, had no maxillary orthopedics, and had vomer flap hard palate repair at 12 months of age and soft palate repair at 18 months of age. MAIN OUTCOME MEASURES: The outcome measures included directly digitized (cleft segment and hemialveolar ridge lengths) and derived (alveolar base width, alveolar cleft gap, maxillary frenum-alveolar base perpendicular angle, and rates of change over time of digitized cleft segment and hemialveolar ridge lengths) features. The data were assessed by comparing simple linear regression lines and an unpaired, two-tailed t test. RESULTS: Prior to initiating therapy, there were no statistically significant differences between the two populations with clefts. However, both populations with clefts differed significantly from unaffected individuals (p < .001), with increased maxillary base widths and larger perpendicular/frenum angles. At the time of palatoplasty, the two populations with clefts had statistically significant differences between them in the maxillary base width (p < .01) and the cleft gap distance (p < .05). The base width of institution 1 did not differ significantly from that of widths of unaffected children, and that of institution 2 was significantly less, although the latter had already received first-stage palate repair. Alveolar segment growth rates were similar for the greater and lesser segments, respectively, and the left side hemialveolus of both groups. The growth rate for the noncleft side hemialveolus of institution 2 exceeded (p < .05) that of both institution 1 and unaffected patients. CONCLUSION: Two different regimens for the initial management of UCLP can significantly affect maxillary alveolar arch growth with respect to the treatment used and in comparison with unaffected controls.

Confirmation of linkage of Van der Woude syndrome to chromosome 1q32: evidence of association with STR alleles suggests possible unique origin of the disease mutation.

Van der Woude syndrome (VWS) is an autosomal dominant craniofacial disorder with high penetrance and variable expression. Its clinical features are variably expressed, but include cleft lip and/or cleft palate, lip pits and hypodontia. All VWS families studied to date map the disease gene to a < 2 cM region of chromosome 1q32, with no evidence of locus heterogeneity. The aim of this study is to refine the localization of the VWS gene and to further assess possible heterogeneity. We analyzed four multiplex VWS families. All available members were clinically assessed and genotyped for 19 short tandem repeat markers on chromosome 1 in the VWS candidate gene region. We performed two-point and multipoint limit of detection (LOD) score analyses using a high penetrance autosomal dominant model. All families showed positive LOD scores without any recombination in the candidate region. The largest two-point LOD score was 5.87. Our assay method for short tandem repeat (STR) markers provided highly accurate size estimation of marker allele fragment sizes, and therefore enabled us to determine the specific alleles segregating with the VWS gene in each of our four families. We observed a striking pattern of STR allele sharing at several closely linked loci among our four Caucasian VWS families recruited at three different locations in the US. These results suggest the possibility of a unique origin for a mutation responsible for many or most cases of VWS.

Maxillary growth in patients with clefts following secondary alveolar bone grafting.

OBJECTIVE: This investigation evaluated the effects of secondary alveolar bone grafting on subsequent maxillary growth in cleft patients. DESIGN: This was a retrospective longitudinal cephalometric study. Nineteen patients who had received secondary alveolar bone grafts were matched to a control sample by sex, cleft, availability of longitudinal records, and presurgical cranial base dimensions and growth direction. All patients had at least two lateral cephalometric radiographs before surgery and two radiographs after surgery. SETTING: The records were obtained from the Longitudinal Growth Study of the Lancaster (Pennsylvania) Cleft Palate Clinic. INTERVENTIONS: All patients had received similar primary surgical procedures by the same surgeon, no orthopedics, and similar mixed-dentition orthodontics. Secondary alveolar bone grafting was the only surgical intervention different between the two groups. MAIN OUTCOME MEASURES: Six measures of maxillary sagittal and vertical growth were taken from 235 radiographs. Slopes of the regression lines for each growth dimension were compared between groups both pre- and postsurgically. RESULTS: There were no significant between-group differences in maxillary sagittal or vertical growth following the grafting procedure. Anterior maxillary vertical growth rates decreased in the grafted group when their pre- and postsurgical rates were compared. Several growth trends in the postsurgical period were found to be continuations of the rates documented presurgically and unrelated to the grafting procedure. CONCLUSIONS: When evaluated longitudinally, maxillary growth in patients having received secondary alveolar bone grafting did not differ from a group of matched controls.

Lack of an association between a dopamine-4 receptor polymorphism and attention-deficit/hyperactivity disorder: genetic and brain morphometric analyses.

Although the etiology of attention-deficit/hyperactivity disorder (ADHD) is likely multifactorial, family, adoption, and twin studies suggest that genetic factors contribute significantly. Polymorphisms of the dopamine 4 receptor (DRD4) affect receptor binding, and one allele with seven tandem repeats in exon 3 (DRD4*7R) has been associated with ADHD. We examined this putative association in 41 children with severe ADHD and 56 healthy controls who were group matched for ethnicity and sex. The frequency of the DRD4*7R allele did not vary by diagnosis (0.220 vs 0.205 in patients and controls, respectively). Behavioral and brain anatomic MRI measures, previously found to discriminate patients from controls, did not differ significantly between subjects having and those lacking a DRD4*7R allele. These data do not support the reported association between DRD4*7R and the behavioral or brain morphometric phenotype associated with ADHD.

Comparison of 2-D calculations from periapical and occlusal radiographs versus 3-D calculations from CAT scans in determining bone support for cleft-adjacent teeth following early alveolar bone grafts.

OBJECTIVE: This investigation was conducted to determine the agreement between three-dimensional (3-D) calculations from CAT scans and two-dimensional (2-D) calculations from standard dental radiographs in evaluating bone support for cleft-adjacent teeth after primary bone grafting. DESIGN: This retrospective study utilized CAT scans and dental radiographs taken of the alveolar cleft in patients an average of 11 years after primary bone grafting. SETTING: The subjects were patients treated by the Cleft Palate Team at Children's Memorial Hospital and Loyola University Medical Center, Chicago, Illinois. PATIENTS: Fourteen UCLP patients (9 males, 5 females) agreed to participate in this study by undergoing CAT scan assessment of their alveolar cleft sites. They also had to have periapical or occlusal radiographs of the grafted cleft site taken within 6 months of the CAT scan. INTERVENTIONS: All patients underwent primary lip repair, placement of a passive palatal plate, primary alveolar bone grafting (mean age 6.4 months), and palatoplasty before 1 year of age. Major tooth movement through final orthodontics was completed by the time of the radiographic assessment. MAIN OUTCOME MEASURES: CAT scan sections were reformatted and reconstructed to three-dimensionally calculate the percentage of root covered by bone support for the 15 teeth adjacent to the graft cleft sites. Dental radiographs of the same teeth were also traced and digitized. Percentages of root supported by bone were also established using the dental radiographs by dividing the amount of root covered by bone, by the anatomic root length. RESULTS: A paired, two-sample t test revealed no significant differences between the two methods of assessment, while linear regression showed a statistically significant correlation between the CAT scan assessment and the percentages found on the radiographs. CONCLUSIONS: Routine dental radiographs were able to estimate the total 3-D bone support for the roots of cleft adjacent teeth as determined by CAT scan to a statistically significant degree when groups where compared. The clinical significance for evaluation of individual cases was less impressive with a wide range of variability and a level of agreement that required acceptance of differences up to 25%.

Inhibition of superantigen-induced proinflammatory cytokine production and inflammatory arthritis in MRL-lpr/lpr mice by a transcriptional inhibitor of TNF-alpha.

We have used fas-defective MRL-lpr/lpr mice to study the effects of the staphylococcal enterotoxin superantigens on the development of autoimmune, inflammatory joint disease in animals that are susceptible to the development of rheumatoid arthritis-like disease. We show that systematic administration by a single i.p. injection of staphylococcal enterotoxin B (SEB; 10 micrograms/mouse) caused a mild, inflammatory arthritis +30 days postchallenge in the knee joints of young (< 2-mo-old) MRL-lpr/lpr mice, but not aged-matched MRL +/+ mice. In aged (> 8-mo-old) MRL-lpr/lpr mice, but not in aged MRL +/+ mice, SEB caused a severe, inflammatory arthritis, as assessed histologically, and systemic autoimmune disease, including glomerulonephritis and autoantibody production. Furthermore, in aged MRL-lpr/lpr mice, SEB but not heat-denatured SEB caused acute weight loss and elevated levels of serum proinflammatory cytokines. Compared with highly purified peritoneal macrophages obtained from either aged MRL +/+, young MRL-lpr/lpr, or young MRL +/+, peritoneal macrophages obtained from aged MRL-lpr/lpr mice constitutively expressed 2- to 10-fold greater levels of TNF-alpha, IL-1 beta, IL-6, and IL-10, and produced elevated amounts of these cytokines when treated in vitro with SEB. SEB-challenged aged MRL-lpr/lpr mice treated with anti-TNF mAb (100 micrograms/mouse; every other day), anti-V beta 8 TCR mAb (250 micrograms/mouse; every other day), or orally with the novel TNF-alpha inhibitor MDL 201,449A (9-[(1R, 3R)-trans-cyclopentan-3-ol] adenine; 25 mg/kg/day) exhibited reduced inflammatory arthritis, autoantibody formation, and serum TNF-alpha levels, but not IL-10 levels, after +30 days of treatment. These data suggest that SEB is an extremely potent macrophage-activating factor in vitro and in vivo, enhancing several aspects of autoimmune disease in MRL-lpr/lpr mice, and that anti-TNF therapies may have potential use in inflammatory arthritis.

Effect of cuspid positioning in the cleft at the time of secondary alveolar bone grafting on eventual graft success.

This investigation was to determine the relationship between the success of secondary alveolar bone grafting and the position of the permanent cuspid relative to the cleft at the time of grafting. In this retrospective study utilizing periapical radiographs take on cleft patients to evaluate bone grafting results, the subjects were patients treated at the Lancaster Cleft Palate Clinic, a private institution specializing in the care of cleft patients. Sixty-seven patients (20 BCLP; 47 UCLP) were selected for this study based on availability of quality radiographs and a minimum of 6-month post-surgical follow-up. All patients underwent alveolar bone grafting (mean age, 10 years 7 months). Presurgical radiographs were taken within 3 months of the operation. Post-surgical radiographs were taken to evaluate the outcome of grafting (mean follow-up, 2 years 10 months). Radiographs were traced and digitized on a total of 86 cleft sites. Presurgically, a ratio was used to determine the amount of cuspid crown emerged through the alveolus into the cleft site relative to the anatomic cuspid-crown length. Post-surgically, ratios of bone support for the teeth mesial and distal to the cleft were established by dividing the amount of root covered by bone by the anatomic root length. Ratios expressing the height of alveolar crest relative to the cementoenamel junction (CEJ) of adjacent teeth and amount of alveolar notching relative to the mesial tooth root length were also evaluated. Linear regressions of each of the five ratios of graft outcome on the cuspid-eruption ratio were done. No significant correlations could be found between final graft success and the amount of cuspid crown exposed in the cleft at the time of grafting. Cuspid position could not be shown to be a significant factor in determining graft success.

Comparison of facial form in primary alveolar bone-grafted and nongrafted unilateral cleft lip and palate patients: intercenter retrospective study.

The purpose of this study was to describe and compare posttreatment craniofacial morphology in samples of complete unilateral cleft lip and palate (CUCLP) patients treated at two leading clinics: The Children's Memorial Hospital Cleft Palate Clinic, Chicago, Illinois, and the Lancaster Cleft Palate Clinic, Lancaster, Pennsylvania. These centers have well-defined treatment protocols that allow the long-term effects on craniofacial form of the following treatment regimes to be contrasted: (1) Chicago--primary alveolar bone grafting, with definitive lip repair at age 4 to 6 months and hard and soft palate repair at 6 to 12 months; and (2) Lancaster--definitive triangular-flap lip repair at 3 months of age, followed by staged surgeries of the hard and soft palates, both completed by 18 months of age, but without primary alveolar bone grafting. Although the Lancaster center now performs secondary alveolar bone grafting, the majority of the patients studied here were treated before this procedure became part of their protocol. Patients were eligible for inclusion if they had no other congenital anomalies and no previous orthodontic treatment. A sample of 43 (24 male, 19 female) CUCLP patients was obtained from the Chicago Center, each of which was then matched to a nongrafted Lancaster CUCLP patient. The matching criteria were age, sex, and sella-nasion distance (to control, at least in part, for size differences). Lateral cephalometric radiographs of these 86 CUCLP patients were traced, digitized, and analyzed. Additionally, all linear data were adjusted to a standard magnification of 8% because the cephalograms from each center featured different enlargements. The Chicago and Lancaster samples had mean posttreatment ages of 10.32 years (SD = 1.96) and 10.40 years (SD = 2.18), respectively. The grafted Chicago group had faces that were on average less maxillary protrusive compared with the nongrafted Lancaster sample; it appeared, however, that the mandible compensated for the maxillary position by downward and backward rotation. As a result, a similar maxillomandibular relationship was noted in both groups, although, in the Chicago group, the lower anterior facial height increased.

Cleft width and secondary alveolar bone graft success.

Fifty-six cleft sites were reviewed prior to alveolar bone grafting and subsequently evaluated for graft success using study models, periapical and occlusal radiographs from the Lancaster Cleft Palate Clinic. All patients in this sample had presurgical orthodontics to expand and align the maxillary arch prior to alveolar bone grafting. Ninety-five percent of the grafts were done using iliac crest, the remaining 5% were cranial grafts. The alveolar bone grafting technique used was as described by Boyne and Sands (1972, 1976). Cleft width was measured on a radiograph taken no more than 1 month preoperatively, following the completion of all orthodontic expansion. Cleft width was determined by inspection at its narrowest point. A distortion correction was attempted by determining the ratio of the radiographic width of the maxillary central incisor adjacent to the cleft compared with the actual width of this tooth measured on study models. The radiographic cleft width was then multiplied by this factor to approximate true cleft width. Alveolar contour was measured at least 6 months postoperatively using ratios of actual bone heights measured at the mesial, middle, and distal margin of the previous cleft compared with root length of adjacent teeth. This was to eliminate the radiographic distortion factors of foreshortening and elongation. Regression analysis was carried out to see if there was a correlation between preoperative cleft width and eventual success of the graft as measured on postsurgical radiographs. The success rate for achieving a bony bridge across the cleft was 91%.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of velopharyngeal growth patterns between cleft lip and/or palate patients requiring or not requiring pharyngeal flap surgery.

This investigation compares the patterns of velopharyngeal growth in cleft lip and/or palate patients. Those who had velopharyngeal competence and acceptable speech are compared with those who presented with velopharyngeal incompetence requiring pharyngeal flap surgery or prosthesis later. Lateral cephalograms of 30 cleft palate only (CPO), 35 unilateral cleft lip and palate (UCLP), and 20 bilateral cleft lip and palate (BCLP) children of the Lancaster Cleft Palate Clinic were studied. These records were taken at 6 month intervals during the first 2 postnatal years and annually thereafter up to 6 years of age. Soft tissue landmark points in the velopharyngeal region were digitized. Length and thickness of the soft palate and height and depth of the nasopharynx were measured. Evaluation of the growth curves of these four cephalometric variables indicated only two significant differences between children who later required pharyngeal flap surgery and those who did not. These differences were found in the growth in length of the soft palate of the CPO group and in the growth in depth of the nasopharynx of the BCLP group. Based on the present cephalometric data, it is impossible to predict at an early age those cleft lip and/or palate patients who will later require pharyngeal flaps.

Effect of the carbocyclic nucleoside analogue MDL 201,112 on inhibition of interferon-gamma-induced priming of Lewis (LEW/N) rat macrophages for enhanced respiratory burst and MHC class II Ia+ antigen expression.

The effects of the carbocyclic nucleoside MDL 201,112 and the purine nucleoside adenosine on the interferon-gamma (IFN-gamma)-induced priming of macrophages (m phi s) for the respiratory burst and major histocompatibility class II (MHC class II) Ia+ antigen expression were compared. Priming of purified, peritoneal m phi s from Lewis (LEW/N) rats for 18 h with recombinant rat IFN-gamma (rRaIFN-gamma) in the presence of either adenosine (100 microM) or MDL 201,112 (10 microM) resulted in a fourfold decrease in superoxide anion (O2-) production after stimulation with opsonized zymosan. Both agents were effective even when added 2 or 4 h after rRaIFN-gamma treatment. Peritoneal m phi s from LEW/N rats stimulated with LPS/rRaIFN-gamma were observed to secrete immunoreactive and bioactive TNF-alpha over 18 h in vitro and this cytokine could be dose-dependently inhibited by MDL 201,112. MDL 201,112 did not bind to classical A1 or A2 receptors on rat brain homogenates. Physiological levels of adenosine deaminase, or treatment with the nucleoside transport inhibitor dipyridamole, reversed the effects of adenosine; however, these agents at physiological concentrations had little or no effect on the inhibition of O2- release mediated by MDL 201,112. Furthermore, incubation of LEW/N m phi s for 18 h in vitro with rRaIFN-gamma resulted in significant enhancement of MHC class II Ia+ antigen expression, and these levels could be blocked by nearly 50% by either MDL 201,112 (10 microM) or adenosine (100 microM). MDL 201,112 and adenosine were also effective in decreasing m phi opsonized zymosan-stimulated O2- levels and MHC class II Ia+ antigen expression in vivo. The effects of MDL 201,112 on the down-regulation of heat-killed M. tuberculosis-activated LEW/N m phi MHC class II Ia+ antigen expression in vitro appear to be mediated by a novel pathway, because there was no rank order of potency of ADO A1 or A2 agonist/antagonists (CCPA, NECA, XAC, or CPT) in our in vitro system. In summary, our data provide compelling evidence that immunoregulatory carbocyclic nucleoside analogues such as MDL 201,112 or adenosine appear to regulate LEW/N rat m phi activation through novel molecular mechanisms and may have important therapeutic implications for acute and chronic inflammatory diseases.

T cell influence on superantigen-induced arthritis in MRL-lpr/lpr mice.

OBJECTIVE: To define the influence of the T cell receptor (TCR) and the lpr autoimmune gene on the induction and progression of superantigen-induced arthritis in V beta 8 transgenic MRL-lpr/lpr mice. METHODS: The time to onset and the extent of synovial hyperplasia after the induction of arthritis by intraarticular injection of staphylococcal enterotoxin B (SEB) were compared in mice having T cells that bear the V beta 8 transgene alone (V beta 8 TCR transgenic MRL-+/+), the lpr gene without the V beta 8 gene (nontransgenic MRL-lpr/lpr), both the V beta 8 gene and the lpr gene (V beta 8 transgenic MRL-lpr/lpr), or neither gene (nontransgenic MRL-+/+). Synovial hyperplasia was compared in SEB-injected V beta 8 transgenic MRL-lpr/lpr mice after treatment with cyclosporin A (CSA), anti-V beta 8 and anti-CD4 monoclonal antibodies, and in V beta 8 transgenic MRL-lpr/lpr mice after injection of a non-V beta 8-reactive superantigen, staphylococcal enterotoxin A (SEA). RESULTS: At day 30, increased synovial cells were observed in all SEB-treated mice, but the increase was greatest in the V beta 8 transgenic MRL-lpr/lpr mice. T cell involvement was indicated by the inability of either heat-denatured SEB or SEA to induce severe arthritis, the reduction in the severity of the arthritis on systemic treatment with CSA or anti-V beta 8, and the correlation of synovial hyperplasia with in vitro SEB reactivity of T cells. CONCLUSION: These observations suggest that superantigens can induce chronic arthritis and that the induction and progression of the arthritis requires an underlying T cell defect in anergy induction in addition to exposure to the superantigen.

Evaluation of maxillary dental arch form in unilateral clefts of lip, alveolus, and palate from one month to four years.

This study evaluated the early changes of maxillary alveolar arches of operated unilateral cleft lip and palate patients. Dental casts were available at four age increments. Triangular flap cheiloplasty was carried out at an early age. Two-stage palatoplasty by vomer flap and soft palate closure took place later. Prior to lip repair, the alveolar arches were classified according to the relationship between greater and lesser segments. Almost a quarter had overlap of the alveolar segments with no contact between the alveolar ridges at the cleft site; some had no overlap with contact of the alveolar segments in the cleft region; almost a quarter had both overlap of the alveolar segments and contact; and almost half had no overlap of the segments and the alveolar ridges were not in contact at the cleft site. After lip repair, the arch relationships were examined and the percentage of patients in each of the four groups indicated a moulding effect of lip repair on the alveolar segments. This moulding effect caused the alveolar segments in most patients to be in contact at the cleft site. Most of these also had segment overlap. All patients were re-examined shortly after palatal repair. The trend for segment overlap and contact continued after palate surgery. However, when all patients were seen at age 4, percentages of patients in each group indicated that previous overlap of segments improved to a more desirable nonoverlapped relationship in approximately half of the patients. The other half continued to demonstrate arch collapse, in excess of what would be considered ideal ridge relationship.

Glucagon-producing pancreatic endocrine tumors in two dogs with superficial necrolytic dermatitis.

A newly recognized disease in dogs, ulcerative dermatosis associated with diabetes mellitus (diabetic dermatopathy), was diagnosed in 2 dogs with pancreatic endocrine tumors that had immunohistologic evidence of glucagon production. Dogs developed diabetes mellitus in the later stages of the illness, months after the skin disease was first observed. Liver disease was identified and characterized by high serum alkaline phosphatase and alanine transaminase activities. Clinically, erythema and crusting involved the footpads, the face, perioral and genital skin, and ventrum. Histologically, skin lesions were intercellular and intracellular edema and necrosis of the upper half of the epidermis and diffuse parakeratosis. Clinically and histologically, skin lesions closely resembled necrolytic migratory erythema of people, a skin disease that usually is associated with a glucagon-secreting pancreatic endocrine tumor and diabetes mellitus (glucagonoma syndrome): The morphologically descriptive term, superficial necrolytic dermatitis, was preferred over the previously proposed names hepatocutaneous syndrome and diabetic dermatopathy, which each connote only a single feature of the disease.

Effects of chlorine dioxide on the developing rat brain.

Male and female Long-Evans rat pups, exposed to an oral dose of 14 mg chlorine dioxide (CIO2)/kg/d (postnatal d 1-20), were examined for effects on brain development and for changes in thyroid activity. Body weight reductions were observed on postnatal (pn) d 11, 21, and 35. Forebrain weight and protein content were decreased on pnd 21 and 35, as were the DNA content on d 35 and the number of dendritic spines on cerebral cortical pyramidal cells, a marker for synapse formation. Otherwise, cell proliferation in the forebrain, cerebellum, and olfactory bulbs was normal, as were migration and aggregation of neuronal cells in three areas of the cerebral cortex. Histopathology of the forebrain, cerebellum, and brainstem showed no gross lesions, loss of myelin, or change in the cells staining positive for Nissl substance. Serum T3 and T4 levels, as well as hepatic mitochondrial alpha-glycerophosphate dehydrogenase activity, were unchanged by CIO2 treatment. The results indicated that CIO2 may have central neurotoxic potential. No underlying antithyroid activity was evident.

Enhancement of murine hepatocarcinogenesis by all-trans-retinoic acid and two synthetic retinamides.

Although retinoids have significant chemopreventive activity in many in vivo carcinogenesis models, their influence on experimental hepatocarcinogenesis has received only limited study. The present experiment was designed to determine the effects of three retinoids on hepatocarcinogenesis induced in female B6D2F1 mice by diethylnitrosamine (DEN). Beginning 1 week after a single i.p. dose of 0, 50 or 100 mg DEN per kg body wt, groups of 35 mice received dietary supplements of (per kg diet): 0.1 mmol all-trans-retinoic acid (RA), 0.5 or 1.0 mmol all-trans-ethyl retinamide (ER), 0.5 or 1.0 mmol 13-cis-ethyl retinamide (13-cis-ER), or vehicle only. In mice treated with 100 mg DEN/kg, all three retinoids significantly increased the incidence of liver tumors (benign + malignant) from the level seen in dietary controls; significant increases in the incidence of hepatocellular carcinoma were seen in groups fed ER. At the lower DEN dose, all three retinoids significantly increased the incidence of total liver tumors and of hepatocellular carcinomas. In mice not treated with DEN, liver tumors were seen only in mice fed ER or 13-cis-ER at 1.0 mmol/kg diet. These data indicate that RA, ER and 13-cis-ER can promote liver carcinogenesis in mice when administered at doses that inhibit cancer induction in other tissues. Because chronic exposure to many retinoids results in the deposition and accumulation of both parent compound and metabolites in the liver, these results should suggest caution in the design of clinical chemoprevention trials with this class of compounds.