Reduction of FK-506 requirements by combination with polyethylene glycol superoxide dismutase in orthotopic rat liver transplantation

Reperfusion after ischemia results in endothelial cell injury and Kupffer cell activation. Inflammatory cytokines thus released can induce major histocompatibility complex antigens and increase the immunogenecity of the graft. An orthotopic rat liver allotransplant model was used to test the hypothesis that prevention of reperfusion injury by infusion of polyethylene glycol superoxide dismutase (PEG-SOD) would result in long-term allograft survival in the presence of subthreshold immunosuppressive dosages. ACI rats were used as donors, and Lewis strain rats as recipients. Orthotopic liver transplantation was initially performed to identify a subthreshold dose of the immunosuppressant FK-506, which would be unable to extend survival longer than control untreated rats with this strain combination. After testing three intramuscular FK-506 doses of 0.04, 0.08, and 0.16 mg/kg, it was observed that an FK-506 dose of 0.04 mg/kg/day for 14 days was unable to extend survival longer than in untreated recipients. This dose of FK-506 was used in combination with PEG-SOD at doses of 1000, 3000, 10,000, or 30,000 units. Recipient animals were treated intravenously with PEG-SOD as a loading dose to facilitate tissue penetration on day 1, and beginning on the day of transplantation, every 2 days for the duration of the study. Results of histologic studies and mean survival time were compared in untreated recipients and in rats treated with PEG-SOD plus 0.04 mg/kg/day FK-506. Mean survival time was increased significantly in these animals (p < 0.007) to 40.6 ± 25.6 days as compared with either untreated rats (10.0 ± 2.7 days) or rats treated with 0.04 mg/kg FK-506 alone (13.7 ± 4.2 days). Histologic examination demonstrated a significant reduction in the cellular infiltrate in rats treated with PEG-SOD plus FK-506, as compared with recipients treated with either agent alone or left untreated. Our results therefore suggest a potential approach to reducing immunosuppression in transplantation. (J ALLERGY CLIN IMMUNOL 1995;95:1276-81.)     

Establishment and characterization of αs1-casein–specific T-cell lines from patients allergic to cow’s milk: Unexpected higher frequency of CD8 T-cell lines

To study cow’s milk allergy at the cellular level, we assessed the reactivity of peripheral blood mononuclear cells from patients allergic to cow’s milk to α_s1-casein, which is one of the major allergens in cow’s milk. Proliferation of the cells to α_s1-casein activation showed a rather weak response. Therefore to understand T-cell reactivity to α_s1-casein in more detail, we prepared α_s1-casein–specific T-cell lines from patients allergic to cow’s milk and established 26 T-cell lines. These T-cell lines could be classified into three groups by analyzing their surface marker expression: those containing predominantly CD4⁺CD8^- T cells, those containing both CD4⁺CD8^- and CD4^-CD8⁺ T cells, and those containing predominantly CD4^-CD8⁺ T cells. The CD8⁺ T cells were obtained at an unexpectedly higher frequency from the patients. These T-cell lines produced interferon-γ and IL-4. These results suggest that CD8⁺ T cells specific for α_s1-casein and CD4⁺ T cells were primed by the stimulation with α_s1-casein in patients allergic to milk and that both T cells may play a key role in the onset, progression of, or recovery from cow’s milk allergy. (J ALLERGY CLIN IMMUNOL 1996;97:1342-9.)     

Modification of T-cell receptor Vβ repertoire in response to allergen stimulation in peanut allergy

Background: Peanut is one of the most common foods causing allergic reactions and is the most common cause of fatal and near-fatal food-related anaphylaxis. Little is known of the immunologic mechanisms that underlie peanut allergy. Objectives: In this study we examined clonality of the T-cell response (TCR) to peanut in MHC class II identical, peanut allergy–discordant sibling pairs. Methods: Four sibling pairs were investigated. The TCR repertoire was analyzed before and after in vitro stimulation of PBMCs with crude peanut or PHA, as control for general/nonspecific reactivity. Eighteen TCR-Vβ families were examined by flow cytometry. Where significant differences in incidence of particular TCR-Vβ families were observed, PCR familyspecific cDNA amplification and gene scanning were performed. Results: After stimulation with peanut, no selective expansion of any TCR-Vβ subpopulation was observed with flow cytometry, in either the peanut-allergic or nonallergic siblings, with the exception of 1 peanut-allergic subject who demonstrated a significant increase of TCR-Vβ11⁺ cells (0.3%-5.9% of the total CD3⁺ cells). However, gene scanning revealed predominant single-size PCR products for TCRBV11 in all peanut-allergic subjects after peanut stimulation. TCRBV11 polyclo-nality was observed in allergic and nonallergic subjects before peanut stimulation and in nonallergic subjects after peanut stimulation. In comparison, all subjects, before and after stimulation with peanut, showed polyclonality for TCRBV2.Conclusions: Our results argue for clonal or oligoclonal TCRs to crude peanut and indicate that changes in the TCRBV11 subpopulation are restricted to peanut-allergic subjects after stimulation with crude peanut allergen. (J Allergy Clin Immunol 2001;107:1089-94.)     

Obstetrical deliveries associated with maternal malignancy in California, 1992 through 1997

OBJECTIVE: This study aims to characterize the rate of occurrence and nature of outcomes associated with obstetrical deliveries in women with malignant neoplasms among 3,168,911 women who delivered in California in 1992 through 1997. DESIGN: The study is a population-based retrospective review of infant birth and death certificates and maternal and neonatal discharge records. Cases of malignant neoplasms associated with obstetrical delivery were attributed to 1 of 3 categories, depending on the earliest documented hospital discharge diagnosis, as follows: "prenatal" if the diagnosis was first documented by hospitalization within 9 months preceding delivery, "at delivery" if the diagnosis was established from the delivery hospitalization, or "postpartum" if the diagnosis was first documented by hospitalization within 12 months after delivery. METHODS: Computer-linked infant birth and death certificates and maternal and neonatal discharge records were used to identify cases and outcomes. Cases of malignant neoplasms were identified by using International Classification of Diseases, Ninth Revision codes (140-208). Noninvasive neoplasms and carcinoma in situ neoplasms were excluded. In analysis of outcomes, the Mantel-Haenszel estimate for adjusted odds ratios was used. RESULTS: Among 3,168,911 obstetrical deliveries over the 6-year span, a total of 2247 cases of primary malignancy were identified. The observed rate of occurrence for primary malignant neoplasms was 0.71 per 1000 live singleton births. Most cases (53.3%) were first documented in the postpartum period as follows: prenatal, 587 cases (0.18 per 1000); at delivery, 462 cases (0.15 per 1000); and postpartum, 1198 cases (0.38 per 1000). The most frequently documented primary malignant neoplasms associated with obstetrical delivery were breast cancer (423 cases, 0.13 per 1000), thyroid cancer (389 cases, 0.12 per 1000), cervical cancer (266 cases, 0.08 per 1000), Hodgkin's disease (172 cases, 0.05 per 1000), and ovarian cancer (123 cases, 0.04 per 1000). Odds ratios for a variety of demographic factors identified maternal age as the most significant risk factor for development of malignant neoplasms (age greater than 40 vs 20-25, odds ratio 5.7, CI 4.6-6.9). Age-adjusted odds ratios for maternal cancer of any type suggested significantly elevated risks for cesarean delivery (odds ratio 1.4, CI 1.3-1.6), blood transfusion (odds ratio 6.2, CI 4.5-8.5), hysterectomy (odds ratio 27.4, CI 20.8-36.1), and maternal postpartum hospital stay greater than 5 days (odds ratio 30.6, CI 27.9-33.6), but not for postpartum maternal death (odds ratio 0.8, CI 0.6-1.0). Odds ratios also suggested significantly elevated risks for premature newborn (odds ratio 2.0, CI 1.8-2.2), very low birth weight (odds ratio 2.9, CI 2.2-3.8), and newborn hospital stay longer than 5 days (odds ratio 2.6, CI 2.4-3.0), but not for neonatal death (odds ratio 1.6, CI 0.8-3.1) or infant death (odds ratio 1.2, CI 0.5-3.3). However, several types of malignant neoplasms did confer significant elevations in risk for neonatal death. Hospital charges for both maternal and neonatal care were significantly elevated in the maternal malignant neoplasm group. CONCLUSION: A lower than expected occurrence rate of obstetrical delivery associated with maternal malignancy was seen when compared with previously published hospital-based reports. Malignant neoplasms associated with obstetrical delivery were most frequently first documented in the postpartum period. Maternal and neonatal morbidity were significantly increased, yet the risk of in-hospital maternal death was not significantly elevated. A significant increase in risk of neonatal death for infants of mothers with cervical cancer was found.     

Inhibition of methylprednisolone elimination in the presence of clarithromycin therapy

BACKGROUND: Macrolide antibiotics have long been used as steroid-sparing agents in patients with severe steroid-dependent asthma. Their efficacy and their propensity to potentiate glucocorticoid adverse effects have been attributed in part to their ability to delay glucocorticoid clearance. OBJECTIVE: We sought to determine whether clarithromycin, a newer macrolide antibiotic, can alter the pharmacokinetic profile of oral glucocorticoids and thereby increase the risk of steroid-induced adverse effects. METHODS: An open-label study in a paired design (before and after treatment) was conducted in a hospital-based outpatient clinic. Participants were 6 adult patients (mean age, 30 years) with mild-to-moderate asthma. Prednisone (40 mg/1.73 m2) and methylprednisolone (40 mg/1.73 m2) were given as single randomized doses on consecutive study days before and on days 8 and 9 of a clarithromycin (500 mg twice daily) course. Twelve-hour pharmacokinetic profiles with measurement of plasma methylprednisolone and prednisolone levels were taken before and after clarithromycin therapy. RESULTS: Clarithromycin therapy resulted in a 65% reduction of methylprednisolone clearance and significantly higher mean plasma methylprednisolone concentrations compared with preclarithromycin concentrations but had no significant effect on prednisolone clearance or mean prednisolone plasma concentrations. CONCLUSIONS: Clinicians must be aware of potential drug interactions that could place patients at increased risk for steroid-induced adverse effects. Such an effect has been demonstrated between clarithromycin and methylprednisolone, two drugs that may be administered concomitantly in asthma. To avoid potential steroid-enhancing effects, prednisone should be substituted for methylprednisolone during prolonged courses of clarithromycin therapy.     

Correlation of symptoms with location and severity of pelvic organ prolapse

OBJECTIVE: The purpose of this study was to compare the symptoms that are related to pelvic floor dysfunction with the location and severity of the coexisting prolapse. STUDY DESIGN: Two hundred thirty-seven consecutive patients with symptomatic pelvic organ prolapse came to Johns Hopkins Medicine during a 24-month period beginning in July 1998 and completed a symptom-specific Likert scale questionnaire that included standardized questions that were compiled from commonly used validated instruments. All questionnaires were completed by the patients before they were seen by a physician. Further evaluation included a standardized physical examination that included the International Continence Society's system for grading uterovaginal prolapse. Symptoms were categorized according to both severity and associated anatomic compartment. Symptoms that were related to urinary and anal incontinence and voiding, defecatory, sexual, and pelvic floor dysfunction were analyzed with respect to location and severity of pelvic organ prolapse with the use of the nonparametric correlation coefficient, Kendall's tau-b. RESULTS: The mean age of the women was 57.2 years (range, 23-93 years); 109 of the women (46%) had undergone hysterectomy. Overall, stage II was the most common pelvic organ prolapse (51%) that was encountered. In 77 patients (33%), anterior compartment pelvic organ prolapse predominated; 46 patients (19%) demonstrated posterior compartment prolapse, whereas 26 patients (11%) had apical prolapse. In 88 patients (37%), no single location was more severe than another. Voiding dysfunction that was characterized by urinary hesitancy, prolonged or intermittent flow, and a need to change position was associated with the increasing severity of anterior and apical pelvic organ prolapse. Pelvic pressure and discomfort along with visualization of prolapse were strongly associated with worsening stages of pelvic organ prolapse in all compartments. Defecatory dysfunction characterized by incomplete evacuation and digital manipulation was associated with worsening posterior compartment pelvic organ prolapse. Impairment of sexual relations and duration of abstinence were strongly associated with worsening pelvic organ prolapse. An inverse correlation was observed between increasing severity of pelvic organ prolapse and urinary incontinence and enuresis. CONCLUSION: Women with pelvic organ prolapse experience symptoms that do not necessarily correlate with compartment-specific defects. Increasing severity of pelvic organ prolapse is weakly to moderately associated with several specific symptoms that are related to urinary incontinence and voiding, defecatory, and sexual dysfunction.     

Transforming growth factor-β in breast milk: A potential regulator of atopic disease at an early age

Background: According to data from animal and in vitro studies, transforming growth factor-β (TGF-β) has a crucial effect on 2 essential parts of the mucosal immune system: IgA production and oral tolerance induction. Objective: We sought to ascertain whether TGF-β in breast milk is associated with specific IgA production and atopic disease in human subjects. Methods: Forty-seven infants with several atopic family members were followed during their first year of life. The concentrations of TGF-β1 and TGF-β2 in maternal colostrum, mature milk, and the infants’ sera were determined. The enzyme-linked immunospot assay was used to assess the infants’ specific IgA production in response to β-lactoglobulin, casein, gliadin, and ovalbumin. Results: At 12 months, atopic dermatitis was confirmed in 29 of 47 infants; in 11, atopic disease had begun during exclusive breast-feeding (preweaning onset), whereas in 18 the disease manifested itself after weaning (postweaning onset). The concentrations of both TGF-β1 and TGF-β2 were higher in maternal colostrum, but not in mature milk and infants’ serum, in infants with postweaning-onset atopic disease compared with those with preweaning-onset disease (P = .0008 and P = .015, respectively). The concentration of TGF-β2 was, and that of TGF-β1 tended to be, higher in the colostrum of mothers whose infants had specific IgA-secreting cells at 3 months in response to at least one of the dietary antigens tested compared with those who did not have such cells (P = .048 and P = .076, respectively). Conclusion: TGF-β in colostrum may prevent the development of atopic disease during exclusive breast-feeding and promote specific IgA production in human subjects. (J Allergy Clin Immunol 1999;1251-7.)     

Rigid versus wire fixation for mandibular advancement: Skeletal and dental changes after 5 years

The bilateral sagittal split osteotomy (BSSO) is the most common surgical procedure for the correction of mandibular retrognathism. Commonly, the proximal and distal segments are fixated together with either wire or rigid screws or plates. The purpose of this study was to compare long-term (5 years) skeletal and dental changes between wire and rigid fixation after BSSO. In this multisite, prospective, randomized clinical trial, the rigid fixation group received three 2-mm bicortical position screws, and the wire fixation group received inferior border wires and 6 weeks of skeletal maxillomandibular fixation with 24-gauge wires. Cephalometric films were obtained 2 weeks before surgery and at 1 week, 8 weeks, 6 months, 1 year, 2 years, and 5 years after surgery. Linear cephalometric changes were referenced to a cranial base coordinate system. Before surgery, both groups were comparable with respect to linear and angular measurements of craniofacial morphology. Both groups underwent similar surgical changes. Skeletal and dental movements occurred in both groups throughout the study period. Five years after surgery, the wire group had 2.2 mm (42%) of sagittal skeletal relapse, while the rigid group remained unchanged from immediately postsurgery. Surprisingly, at 5 years, both groups had similar changes in overbite and overjet. This was attributed to dental changes in the maxillary and mandibular incisors. Although rigid fixation is more stable than wire fixation for maintaining the skeletal advancement after a BSSO, the incisor changes made the resultant occlusions of the 2 groups indistinguishable.     

Predicting lower lip and chin response to mandibular advancement and genioplasty

The purposes of this retrospective study were to examine the multidimensional nature of soft tissue changes associated with mandibular advancement and genioplasty and to develop predictive models. Longitudinal lateral cephalograms of 62 nongrowing patients (27 men and 35 women) were taken in centric relation with the lips in repose within 4 weeks before surgery and at least 6 months postoperatively (median postsurgical duration was 11 months). The mandibular incisor and pogonion were advanced surgically approximately 6 mm and 11 mm, respectively. The lower lip lengthened slightly (2.5 +/- 3.8 mm), and its surface contour straightened because of thinning at labrale inferior (-2.8 +/- 2.0 mm); there was a slight thickening at the labiomental fold (1.0 +/- 2.3 mm) and a slight thinning at soft tissue pogonion (-0.8 +/- 2.2 mm). Multiple regression models (explaining from 80% to 94% and 66% to 82% of the variation for horizontal and vertical movements, respectively) showed that soft tissue response to advancement surgery depended on pretreatment tissue thickness, horizontal skeletal movement, vertical skeletal movement, and the position of the maxillary incisors. Similar amounts of variation were explained when the models were applied to an independent validation sample of 15 subjects. It was concluded that lower lip and chin response to mandibular advancement and genioplasty is multifactorial but can be accurately and reliably predicted.     

Treatment effects produced by the Twin-block appliance and the FR-2 appliance of Fränkel compared with an untreated Class II sample

This retrospective cephalometric study compares the treatment effects produced in 40 patients treated with the Twin-block appliance to those seen in a matched sample of 40 children treated with the FR-2 appliance of Fränkel and to changes undergone in 40 untreated Class II controls from The University of Michigan Elementary and Secondary School Growth Study. The average starting ages for the Twin-block, Fränkel, and control groups were 10 years 5 months, 10 years 2 months, and 9 years 11 months, respectively. The T₂ to T₁ observation period was adjusted to an average of 16 months for all groups. Significant decreases in overbite and overjet were observed at the end of treatment in the Twin-block and Fränkel groups. Compared with the untreated subjects, statistically significant increases in mandibular length were observed in both treated groups. The Twin-block patients achieved an additional 3.0 mm of mandibular length, whereas the Fränkel group increased 1.9 mm more than did the controls. No significant restriction of midfacial growth was observed in either functional appliance group relative to controls. A significant increase in lower anterior facial height was evident in both treatment groups. Vertical increase in the Twin-block patients was significantly greater than in the FR-2 group. In general, more extensive dentoalveolar adaptation was observed with the tooth-borne Twin-block appliance than with the more tissue-borne FR-2 of Fränkel. The Twin-block and FR-2 samples both showed significant retroclination and extrusion (eruption) of the maxillary incisors. The Twin-block patients also exhibited distal movement of the upper molars; however, there was no extrusion. Slight lower incisor proclination was noted in both treatment groups, and lower molar extrusion was found to be significantly greater in the Twin-block group compared with the other 2 samples. No horizontal differences were detected in the lower molars among groups. The present study suggests, therefore, that Class II correction with the Twin-block appliance is achieved through normal growth in addition to mandibular skeletal and dentoalveolar changes. Class II correction with the FR-2 is more skeletal in nature, with less dentoalveolar changes noted. (Am J Orthod Dentofacial Orthop 1999;116:597-609)