Deficiency of invariant natural killer T cells in coeliac disease.

BACKGROUND: Immunoregulatory invariant natural killer (iNK) T cells rapidly produce interleukin (IL)-4 and other cytokines that suppress a Th1 response and are deficient in some autoimmune diseases. AIM: The aim of this study was to investigate any deficiency of iNK T cells in coeliac disease. METHODS: Blood was collected from 86 subjects with coeliac disease and from 152 healthy control subjects for investigation of Valpha24+ T cells by flow cytometry. iNK T cells were assessed by Valpha24 and alpha-galactosylceramide/CD1d tetramer markers in 23 normal controls and 13 subjects with coeliac disease. Intracellular IL-4 was measured after anti-CD3 antibody stimulation. Duodenal biopsies were obtained in a subgroup of subjects with coeliac disease and control subjects for Valpha24 mRNA expression using relative PCR and for Valpha24+ T cells by immunofluorescence. RESULTS: The mean numbers of circulating Valpha24+ T cells and iNK T cells in coeliac disease were 27% (p<0.001) and 16% (p<0.001), respectively, of levels in control subjects. After in vitro anti-CD3 stimulation, numbers of IL-4+ producing iNK T cells from subjects with coeliac disease were unchanged but increased by 21% in control subjects. In subjects with coeliac disease, Valpha24 mRNA intestinal expression was reduced to 17% (p<0.001) by relative PCR and numbers of intestinal Valpha24+ T cells were 16% (p<0.01) of levels in control subjects. CONCLUSIONS: We conclude that Valpha24+ T cells and iNK T cells are deficient in coeliac disease. We speculate that this deficiency could contribute to the failure of immunological oral tolerance that seems to underlie this disease.

Effect of breast milk and weaning on epithelial growth of the small intestine in humans.

Breast feeding and weaning are important physiologically significant luminal events that influence the growth of the small intestine in humans. A variety of factors including genetic preprogramming, systemic and local hormones, and permissive factors contribute and modulate intestinal growth. Here, we offer a view that integrates some of these factors, especially those relating to breast feeding and weaning.

Improvement in intestinal permeability precedes morphometric recovery of the small intestine in coeliac disease.

It is often difficult to assess small bowel recovery in adults with coeliac disease on a gluten-free diet (GFD). This prospective study compares changes in intestinal permeability with changes in intestinal biopsy at various intervals after commencing a GFD. Intestinal permeability was measured by lactulose/rhamnose absorption from 1 week to 24 months after commencing a GFD. Intestinal morphometry was measured by villus area, crypt length and mitotic count per crypt at diagnosis and after commencing a GFD. Median intestinal permeability values decreased from 0.47 (n = 35) at diagnosis to 0.25 (n = 17) after 1 week and to 0.16 (n = 18) after 2 months of a GFD. Rhamnose absorption improved significantly at an early stage, from 6.6% (untreated) to 15.4% at 3 months of a GFD, whereas the decrease in lactulose permeation took longer: from 3.4% (untreated) to 0.8% after 12 months of a GFD. Mean villus area (n = 29) was reduced to 16% of control values at diagnosis, and improved to a maximum of 48% after 6 months on a GFD, but did not change thereafter. Mean crypt length and mitotic count per crypt were increased by 222% and 356% respectively at diagnosis, and these parameters remained elevated at 172% and 216% above control values after 6 months of a GFD. We conclude that intestinal permeability improves within 2 months after starting a GFD, but that measurable intestinal biopsy improvement requires ingestion of a GFD for at least 3-6 months, and even then remains incomplete.

Activation of the gut-associated lymphoid tissue with expression of interleukin-2 receptors that peaks during weaning in the rat.

BACKGROUND: Weaning exposes the intestinal mucosa to food and bacterial antigens at an age when the immune system is believed to be immature and functionally defective. The purpose of this study was to investigate changes in activation and phenotype of immune cells of the gut-associated lymphoid tissue during weaning. METHODS: Litters of infant rats were studied from pre- to postweaned life. The activation status, assessed by interleukin-2 receptor (IL-2R) expression, and phenotype of cells in the gut-associated lymphoid tissue were examined by immunostaining. RESULTS: Interleukin-2 receptor expression peaked two to four-fold at midweaning (day 21) in mesenteric lymph nodes, jejunal lamina propria, Peyer's patches, and intraepithelial lymphocytes, compared with adult animals (day 70). CD45+ cells expanded in the lamina propria, epithelium, and lymphocyte-filled villi. With CD45 as the denominator, 10% to 50% of lymphocytes in the lamina propria and epithelium were alphabetaT-cell receptor (TCR)+, but the remaining cells had a null phenotype, because there were low numbers of gammadeltaTCR+ T cells, B cells, and macrophages. Natural killer cells peaked at midweaning in the lamina propria (9%) and epithelium (20%) but were less than 5% of CD45+ cells after weaning. CONCLUSIONS: Rather than being immature or functionally inactive, the gut-associated lymphoid tissue reacts appropriately during weaning with expression of IL-2R and expansion of alphabetaTCR+ T-cells.

Epithelial growth of the small intestine in human infants.

BACKGROUND: Findings in studies in rodents have suggested that epithelial growth of the small intestine is dependent on activation of the immune system. The purpose of this study was to compare changes of postnatal epithelial growth with immunologic activity in humans. METHODS: Duodenal biopsies were obtained by endoscopy from 74 infants. Villus area, crypt length, and mitotic count were measured, using a microdissection technique. Enterocyte height, intraepithelial lymphocytes and mucosal mast cells were recorded in histologic sections, and soluble interleukin-2 receptor levels were measured in sera. These data were compared with those from 77 adult control subjects. RESULTS: Mean +/- SD villus area was similar in infants compared with that in adults (0.364 +/- 0.108 mm2 vs. 0.339 +/- 0.1 mm2); but mean crypt length was 31% longer (270 +/- 56 microm vs. 206 +/- 29 microm; p < 0.0001), and mitotic count was 68% higher (4.2 +/- 2.8 vs. 2.5 +/- 1 per crypt; p < 0.0001) in infants. Enterocyte height was lower during infancy (27.0 +/- 3.4 microm vs. 30.9 +/- 4.6 microm; p < 0.0001). There was no evidence of a trophic effect on the small intestine of breast feeding compared with the effect of bottle feeding. Counts of intraepithelial lymphocytes but not mucosal mast cells were significantly less in infants. Mean soluble interleukin-2 receptor levels peaked during early infancy, compared with levels in adults (1,820 +/- 596 U/ml vs. 695 +/- 359 U/ml). CONCLUSION: These results indicate that epithelial proliferation is increased during infancy at an age when immunologic activity is high.

Thromboembolism after foot and ankle surgery. A multicenter study.

Thromboembolic disease presents a potentially fatal complication to patients undergoing orthopaedic surgery. Although the incidence after hip and knee surgery has been studied and documented, its incidence after surgery of the foot and ankle is unknown. For this reason, a prospective multicenter study was undertaken to identify patients with clinically evident thromboembolic disease to evaluate potential risk factors. Two thousand seven hundred thirty-three patients were evaluated for preoperative risk factors and postoperative thromboembolic events. There were six clinically significant thromboembolic events, including four nonfatal pulmonary emboli, after foot and ankle surgery. The incidence of deep vein thrombosis was six of 2733 (0.22%) and that of nonfatal pulmonary emboli was four of 2733 (0.15%). Factors found to correlate with an increased incidence of deep vein thrombosis were nonweightbearing status and immobilization after surgery. On the basis of these results, routine prophylaxis for thromboembolic disease after foot and ankle surgery probably is not warranted.

Roger Mann Award 1995. Capsular interposition arthroplasty for severe hallux rigidus.

Thirty patients (37 feet) with severe hallux rigidus underwent resection arthroplasty of the first metatarsophalangeal joint with our modification (reattachment of the extensor hood and extensor brevis to the flexor hallucis brevis as a capsular interposition arthroplasty, with minimal bone resection). Pain and function were significantly improved. Transfer metatarsalgia was not seen. All patients had at least 4/5 plantarflexion strength and averaged 50 degrees of dorsiflexion. In patients with severe hallux rigidus and nearly equal length of first and second metatarsals, capsular interposition arthroplasty offers a surgical option that relieves pain without sacrificing motion or strength.

Proximal metatarsal osteotomy in hallux valgus correction: a comparison of crescentic and chevron procedures.

We retrospectively evaluated the results of 50 hallux valgus reconstructions in 36 patients for moderate to severe deformities, performed by the senior author (F. M. T.). All feet were treated at the metatarsophalangeal joint with a distal soft tissue realignment. The first 25 feet were corrected proximally with a crescentic osteotomy fixed with an AO screw; these cases had an average follow-up of more than 5 years (range, 40-141 months). The second 25 feet underwent a basal osteotomy with a proximally directed chevron osteotomy; these cases had an average follow-up of 21.4 months (range, 12-33 months). The average hallux valgus correction in the crescentic osteotomy group went from 37.6 degrees to 11.4 degrees, and in the chevron osteotomy group, the hallux valgus angle was reduced from 31.3 degrees to 11.6 degrees. The intermetatarsal angle in the crescentic group was corrected from 16.2 degrees to 6 degrees, and in the chevron group the intermetatarsal angle was reduced from 15.1 degrees to 5.4 degrees. The fibular sesamoid subluxation was reduced from 92% to 24% in the crescentic group and from 88% to 18% in the chevron group. All patients were assessed using the American Orthopaedic Foot and Ankle Society scale, in which 100 points are used to compare pre- and postoperative pain, function and range of motion, shoewear comfort and activity levels, and alignment. In the crescentic group, the score improved from 46.8 points to 93.1 points; in the chevron group, the score changed from 53.4 points to 92.7 points. In all parameters studied, there were no statistically significant differences using the Student's t-test. We conclude that the two operative techniques offer equivalent results, which are excellent and predictable. The proximal chevron osteotomy is technically easier, eliminates the proximal dorsal scar, and does not require postoperative metal removal.

Treatment of established nonunions of Mitchell osteotomies.

The Mitchell distal metatarsal stepcut osteotomy for the treatment of hallux valgus is a technically demanding procedure with a high complication rate. Reported complications include metatarsal shortening with lateral metatarsalgia, partial avascular necrosis of the distal fragment, and loss of position with incomplete correction. Nonunion, however, has only rarely been reported. We describe our experience with the treatment of three nonunions of Mitchell osteotomies reconstructed using a tricortical iliac crest bone graft.

Pes planus in patients with posterior tibial tendon insufficiency: asymptomatic versus symptomatic foot.

Bilateral weightbearing anteroposterior and lateral radiographs were analyzed in 43 patients with a clinical diagnosis of posterior tibial tendon insufficiency by two independent observers. The radiographs of each patient's asymptomatic foot was considered to serve as the control for the preexistance of pes planus. The radiographs were assessed for the severity of flatfoot deformity, the degree of talonavicular coverage, the talometatarsal angle, the calcaneometatarsal angle, the cuneiform to ground height and the cuneiform to fifth metatarsal height. Interobserver correlations were assessed. Results indicated that there was a high interobserver correlation for the values measured, making these angles reproducible among observers. Strong correlations were found in the degree of severity of flatfoot deformity between the asymptomatic and symptomatic feet as well as the values used to assess pes planus (i.e., similar radiographic measurements on the opposite side). The data suggest that patients with posterior tibial tendon insufficiency often have a preexisting flatfoot. This substantiates our belief that a preexisting flexible flatfoot, although far from the determining factor, is one of several etiological factors in the development of posterior tibial tendon insufficiency.

Macrodystrophia lipomatosa of the foot: a report of three cases and literature review.

Macrodystrophia lipomatosa is a distinct clinical entity often misdiagnosed as other forms of macrodactyly. The most specific finding is an overabundance of fibrofatty tissue on the plantar aspect of the foot. Three cases, with the diagnoses made from tissue specimens, are presented in this article. The clinical, pathologic, and roentgenographic findings are discussed and a review of the literature is provided.

Clinical evaluation of the Ruiz-Mora procedure: long-term follow-up.

The Ruiz-Mora procedure has been advocated for treatment of congenital overlapping fifth toes, fifth hammertoe, and clavus deformities. This study evaluated the results of the Ruiz-Mora procedure in 12 patients with an average follow-up of more than 4 years. The data indicate the majority of patients are satisfied with the results of the procedure. Unacceptable cosmesis was the primary complaint of all dissatisfied patients. Assessment of preoperative versus postoperative symptoms indicate an improvement in symptoms as well as maintenance of stability and function. The average shortening of the toe was 12.8 mm. This presented no functional problems to the patients. Three patients had transient skin healing problems which resolved with local care. Based on this series, the Ruiz-Mora procedure is effective in dealing with the problem of the cock-up fifth hammertoe and is associated with few complications. Because of patient dissatisfaction with cosmesis, consideration should be given to showing patients postoperative photographs of the procedure before surgery and reserving this procedure for salvage of iatrogenic cock-up deformities, recalcitrant hard corns, and congenital cock-up deformities.

Chronic ankle pain caused by osteoid osteoma of the neck of the talus.

Five patients with osteoid osteomas of the talar neck were treated at the Hospital for Special Surgery between 1981 and 1992. The course of care leading to definitive diagnosis and treatment was reviewed. All five of the patients had night pain relieved by aspirin or nonsteroidal anti-inflammatory drugs. One of the five reported associated trauma. The average time from onset of symptoms to correct diagnosis was 2.5 years. Juxta-articular osteoid osteoma can cause a small spur that resembles a traction spur on the neck of the talus. Anterior ankle impingement was the most common misdiagnosis. Initial treatments included arthroscopic spur debridement or synovectomy, casting for fracture, and repeated nerve blocks for reflex sympathetic dystrophy. The five patients were cured by en bloc excision of the lesion. In the diagnosis of osteoid osteoma, a history of relief of pain with aspirin is important. Plain radiographs and a bone scan are useful. Fine cut computed tomography scanning or magnetic resonance imaging are the best studies for making a definitive diagnosis. Localization by computed tomography guided needle placement or intraoperative radionuclide scanning are recommended to find the lesion for excision. Intraoperative radiographs of the excised lesion should be used to confirm complete removal.

Postnatal changes in mucosal immune response: a physiological perspective of breast feeding and weaning.

There are profound changes of immune activity during infancy from suppression during breast feeding, activation with weaning, and later intrinsic down-regulation after weaning. Breast feeding, as well as protecting against infections, seems to have a fundamental role in modifying the immune system against certain disease states. Transforming growth factor (TGF)beta in breast milk may mediate this immunosuppressive effect. Although the infant immune system is not in an adult state, the notion that the infant immune system is immature is difficult to reconcile with evidence that most infants respond appropriately to immunization and to infections. The systemic immune system of neonates may be subject to Th2 immune deviation, while the mucosal immune system, particularly of the gastrointestinal tract and probably the respiratory tract, is up-regulated with physiological inflammation during infancy. Weaning is associated with a peak of intestinal immune activation which includes mucosal mast cells and T cells. The physiological effects of this activation are promotion of epithelial growth of the small intestine and initial activation of mechanisms leading to subsequent down-regulation of the physiological heightened immune activity. This coincides with the development of mucosal (oral) tolerance to food and bacterial antigens.

Pain in the posterior aspect of the ankle in dancers. Differential diagnosis and operative treatment.

A retrospective review was performed of the results of operative treatment of stenosing tenosynovitis of the flexor hallucis longus tendon or posterior impingement syndrome, or both, in thirty-seven dancers (forty-one operations). The average duration of follow-up was seven years (range, two to thirteen years). The results were assessed with use of a questionnaire for all patients, and a clinical evaluation was performed for twenty-one patients (twenty-two ankles). Twenty-six operations were performed for tendinitis and posterior impingement; nine, for isolated tendinitis; and six, for isolated posterior impingement syndrome. A medial incision was used in thirty-three procedures; a lateral incision, in six; an anterior and a medial incision, in one; and a lateral and a medial incision, in one. Thirty ankles had a good or excellent result; six, a fair result; and four, a poor result. (The result of the second procedure on an ankle that was operated on twice was not included.) The result was good or excellent for twenty-eight of the thirty-four ankles in professional dancers, compared with only two of the six ankles in amateur dancers.

Dependence of epithelial growth of the small intestine on T-cell activation during weaning in the rat.

BACKGROUND & AIMS: Intestinal crypt hyperplasia is associated with local T-cell activation in both clinical and experimental examples of immunologically mediated enteropathy. This suggests that T cell-derived factors may be trophic for epithelial proliferation in the intestine postnatally. The purpose of this study was to investigate T-cell activity during weaning in the rat and to investigate immune dependence of intestinal growth on T-cell activation. METHODS: The expression of interleukin-2 receptor (IL-2R) by mesenteric lymph node T cells was investigated from days 14 to 160 of life. Rats were treated with monoclonal antibodies against the IL-2R that were nonblocking (control) or blocking (experimental) from day 7, and intestinal growth was assessed at days 19, 25, and 29 of life. RESULTS: The mean +/- SEM of T cells expressing the IL-2R during weaning (days 15-28) was 6.1% +/- 0.3% compared with 3.3% +/- 0.3% at other ages (P < 0.001). The small intestine in rats treated with blocking antibody had reduced crypt length and mitotic count compared with control animals. CONCLUSIONS: Weaning is associated with activation of T cells and blockade of the IL-2R reduces intestinal growth.