Oral cholera vaccination promotes homing of IgA+ memory B cells to the large intestine and the respiratory tract.

Oral cholera vaccination is used to induce immune responses in the intestines to protect against cholera infection. However, oral vaccination may also affect immune responses in other mucosal tissues. To study this, tissue-specific homing potential and kinetics of B-cell responses were characterized after oral cholera vaccination. Healthy adult volunteers received two doses of Dukoral® and blood, saliva, nasal wash, and fecal samples were collected over time to detect vaccine-specific antibodies. Additionally, homing potential of lymphocytes to small intestine, colon, airways, skin, and periphery was measured by expression of Integrin ß1 and ß7, CCR9, CCR10, CCR7, and CLA. After vaccination, antibody responses to cholera toxin B (CTB) and Dukoral® were detected in serum and nasal wash. CTB-specific memory B cells in peripheral blood and tissue homing profiles of memory B cells peaked at day 18. IgA+ memory B cells expressed markers that enable homing to the airways and colon, while IgA- memory B cells primarily expressed small-intestine-homing markers. These data show that oral cholera vaccination has a differential effect on immune responses in various mucosal sites, including the respiratory tract.

Mental Health Medication Use Correlates with Poor Outcome After Femoroacetabular Impingement Surgery in a Military Population.

BACKGROUND: Femoroacetabular impingement is a common cause of hip pain in young adults. Several preoperative risk factors for poor outcomes with surgery have been identified; however, to our knowledge, no study has attempted to determine the effect of psychiatric comorbidity on outcomes with femoroacetabular impingement surgery. METHODS: A retrospective review was performed on active-duty patients at one institution undergoing surgery for femoroacetabular impingement over five years. Medical records were reviewed for demographic characteristics, radiographic data, and history of mental health medication use. Return-to-duty status was considered the primary outcome measure. Outcome scores obtained included modified Harris hip scores, Single Assessment Numeric Evaluation scores, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, patient satisfaction, and Veterans RAND-12 scores. Patients taking mental health medication were compared with those who were not with regard to return to duty and validated patient-reported outcome measures. RESULTS: Ninety-three patients (mean age, 32.2 years) were available for follow-up at a mean duration of 3.6 years. Of the seventeen patients discharged from service postoperatively, twelve (71%) were taking mental health medications. One-third (twenty-five) of seventy-six patients who returned to duty were taking mental health medication and this difference was significant (p < 0.006). Patients taking mental health medication had significantly poorer modified Harris hip scores (p < 0.02), WOMAC scores (p < 0.0008), and Veterans RAND-12 mental scores (p < 0.001). Antidepressant, antipsychotic, and multiple mental health medication use were all predictive of medical discharge due to hip pain. CONCLUSIONS: Psychiatric comorbidities are an important risk factor in active-duty military personnel undergoing surgery for femoroacetabular impingement. Mental health medication use is associated with poorer outcome scores and can significantly lower the possibility of returning to active-duty status.

Restoration of impaired intestinal barrier function by the hydrolysed casein diet contributes to the prevention of type 1 diabetes in the diabetes-prone BioBreeding rat.

AIMS/HYPOTHESIS: Impaired intestinal barrier function is observed in type 1 diabetes patients and animal models of the disease. Exposure to diabetogenic antigens from the intestinal milieu due to a compromised intestinal barrier is considered essential for induction of the autoimmune process leading to type 1 diabetes. Since a hydrolysed casein (HC) diet prevents autoimmune diabetes onset in diabetes-prone (DP)-BioBreeding (BB) rats, we studied the role of the HC diet on intestinal barrier function and, therefore, prevention of autoimmune diabetes onset in this animal model. METHODS: DP-BB rats were fed the HC diet from weaning onwards and monitored for autoimmune diabetes development. Intestinal permeability was assessed in vivo by lactulose-mannitol test and ex vivo by measuring transepithelial electrical resistance (TEER). Levels of serum zonulin, a physiological tight junction modulator, were measured by ELISA. Ileal mRNA expression of Myo9b, Cldn1, Cldn2 and Ocln (which encode the tight junction-related proteins myosin IXb, claudin-1, claudin-2 and occludin) and Il-10, Tgf-ß (also known as Il10 and Tgfb, respectively, which encode regulatory cytokines) was analysed by quantitative PCR. RESULTS: The HC diet reduced autoimmune diabetes by 50% in DP-BB rats. In DP-BB rats, prediabetic gut permeability negatively correlated with the moment of autoimmune diabetes onset. The improved intestinal barrier function that was induced by HC diet in DP-BB rats was visualised by decreasing lactulose:mannitol ratio, decreasing serum zonulin levels and increasing ileal TEER. The HC diet modified ileal mRNA expression of Myo9b, and Cldn1 and Cldn2, but left Ocln expression unaltered. CONCLUSIONS/INTERPRETATION: Improved intestinal barrier function might be an important intermediate in the prevention of autoimmune diabetes by the HC diet in DP-BB rats. Effects on tight junctions, ileal cytokines and zonulin production might be important mechanisms for this effect.

Prolonged exclusive breastfeeding reduces autoimmune diabetes incidence and increases regulatory T-cell frequency in bio-breeding diabetes-prone rats.

BACKGROUND: Previously, we reported that exclusive breastfeeding delayed and partially protected bio-breeding diabetes-prone (BBDP) rats from spontaneous autoimmune diabetes development. To investigate whether this protection results from modulation of the (mucosal) immune system, the present study was designed to analyse the effect of nutrition early in life on the immune status of BBDP rats. METHODS: The breastfeeding period of BBDP pups was extended or not, while allowing half of the pups to eat during that period whereas the other half received only breast milk. Cytokine profiles as well as naturally occurring regulatory T-cell frequencies were measured over time in the mesenteric lymph nodes (MLNs) and spleen. RESULTS: Prolonged exclusive breastfeeding partially protects against autoimmune diabetes development and resulted in elevated levels of natural regulatory T cells (CD4(+) CD25(+) FoxP3(+)) in MLNs and spleen directly after weaning and throughout life. Stimulation of MLN cells from rats that ingested solid food during the nursing period showed massive secretion of interferon gamma (IFN-gamma), interleukin (IL)-4 and IL-10, whereas MLN cells from exclusive breastfed rats did not. In contrast, transforming growth factor beta (TGF-ss) was secreted equally by all groups. CONCLUSIONS: Prolonged exclusive breastfeeding partially protects BBDP rats from autoimmune diabetes development. Interestingly, ingestion of solid food during the weaning period completely abolishes this protective effect. The protective effect of exclusive breastfeeding correlates with higher levels of naturally occurring regulatory T cells throughout life and low cytokine secretion at weaning.

Antibiotic treatment partially protects against type 1 diabetes in the Bio-Breeding diabetes-prone rat. Is the gut flora involved in the development of type 1 diabetes?

AIMS/HYPOTHESIS: Accumulating data suggest that the gut immune system plays a role in the development of type 1 diabetes. The intestinal flora is essential for the development of the (gut) immune system and the establishment of tolerance. It has been reported that oral administration of food and bacterial antigens early in life suppresses later development of diabetes in the Bio-Breeding diabetes-prone (BB-DP) rat. This study was designed to investigate the possible relationship between the development of diabetes and the composition of intestinal flora. MATERIALS AND METHODS: The intestinal flora of BB-DP rats, a rat model for type 1 diabetes, was characterised long before the clinical onset of diabetes by fluorescent in situ hybridisation. In a separate experiment, BB-DP rats were treated with antibiotics and the effect on diabetes incidence and level of insulitis was analysed. RESULTS: We observed a difference in bacterial composition between rats that eventually did and those that did not develop diabetes. This difference was detectable long before clinical onset of the disease. Rats that did not develop diabetes at a later age displayed a lower amount of Bacteroides sp. Modulation of the intestinal flora through antibiotic treatment decreased the incidence and delayed the onset of diabetes. A combination of antibiotic treatment and a protective hydrolysed casein diet completely prevented diabetes in the BB-DP rat. CONCLUSIONS/INTERPRETATION: Our data suggest that the intestinal flora is involved in the development of type 1 diabetes. Factors influencing composition of the intestinal flora could be a target for therapeutic intervention.

Neonatal oral administration of DiaPep277, combined with hydrolysed casein diet, protects against Type 1 diabetes in BB-DP rats. An experimental study.

AIMS/HYPOTHESIS: Environmental factors such as diet and bacterial antigens play an important role in the onset of Type 1 diabetes. Different self-antigens are suggested to play a role in the development of diabetes. Antibodies against the 60-kDa heat shock protein 60, which have a high homology to bacterial heat shock protein 65, have been found in the circulation at the onset of diabetes in humans and in pre-diabetic NOD-mice. One of the immunodominant epitopes in autoimmune diabetes is p277, a specific peptide of human heat shock protein 60 corresponding to positions 437-460. In this study we investigated whether neonatal oral administration of DiaPep277 (a synthetic peptide analogue of p277) affected the development of diabetes in the BioBreeding-Diabetes Prone (BB-DP) rat, and whether this could potentiate the effect of a protective hydrolysed casein-diet. METHODS: BB-DP rats were orally inoculated once per day with placebo or DiaPep277 at days 4, 5, 6 and 7 of life. At the age of 21 days rats were weaned on to a conventional, cereal-based diet or on to the hydrolysed casein-diet. RESULTS: The development of diabetes in animals receiving DiaPep277 in combination with the hydrolysed casein-diet was delayed by 17 days, and a relative reduction of the incidence by 64% was seen. Non-diabetic animals did not show any sign of insulitis. CONCLUSIONS/INTERPRETATION: Short-term neonatal feeding with p277 in early life, combined with diet adaptation, appears to provide a procedure to significantly reduce the development of Type 1 diabetes in later life.

Combined blockade of both micro - and kappa-opioid receptors prevents the acute orexigenic action of Agouti-related protein.

Agouti-related protein (AgRP) is an endogenous antagonist at the melanocortin 3 and 4 receptor in the hypothalamus. Central administration of AgRP produces a robust increase in food intake, and this effect can be blocked by administration of nonspecific opioid receptor antagonist. Such results implicate opioid receptors as critical to mediating the effects of AgRP. To determine which opioid receptor subtype is critical, we first determined the highest i3vt (administered into the third ventricle) dose of two specific opioid antagonists, nor-Binaltorphine or beta-funaltrexamine, that did not influence food intake on their own. Then, rats were pretreated with either of these two antagonists before i3vt AgRP and access to a high-fat diet. For neither the kappa- nor the micro -specific antagonist was there any effect to block the effects of AgRP on food intake. However, administration of both the kappa- and micro -receptor antagonists does significantly reduce the effect of AgRP. The current results implicate opioid receptors as critical downstream mediators of the potent effects of AgRP to increase food intake but indicate that either micro - or kappa-receptor activation is sufficient for AgRP's effect.

Psychological and family characteristics of adolescents with vocal cord dysfunction.

Vocal cord dysfunction (VCD) is a respiratory disorder often confused with asthma. Although previous case reports have implicated family and/or individual psychopathology in the etiology of this condition, this is the first paper to present prospective, case-control empirical data on a group of pediatric patients with VCD. A case-control methodology was employed to examine patients in terms of both family and individual functioning. Results indicate that patients with VCD were not different from asthmatic controls on measures of family functioning. However, they did experience significantly higher levels of anxiety and received a higher number of anxiety-related diagnoses such as separation anxiety and generalized anxiety disorder on a structured psychiatric interview. The nature of the relation between VCD and psychological symptoms in children is discussed. Etiologic and treatment issues are examined in the context of the findings.

Evaluation of a diagnostic approach to pediatric interstitial lung disease.

OBJECTIVE: To evaluate the value of a systematic approach to the diagnosis of pediatric interstitial lung disease (ILD). METHODS: In this descriptive, observational, prospective study, we evaluated 51 children presenting with ILD of unknown etiology during a 3-year period. Specific clinical information regarding history, physical examination, diagnostic evaluation, and final diagnosis was recorded on each patient. RESULTS: A specific diagnosis was established by history and physical examination alone in 1 patient, noninvasive tests alone in 8 others, and invasive tests, including lung biopsy, in another 26. Of the remaining patients, 8 had a suggestive diagnosis, and 8 had no specific diagnosis. CONCLUSIONS: A systematic approach to the diagnosis of pediatric ILD is useful, and not all patients need lung biopsy for diagnosis.

Vocal cord dysfunction: don't mistake it for asthma.

Vocal cord dysfunction (VCD), with its symptoms of stridor, air hunger, and chest or throat tightness, occurs primarily in active adolescents and young adults and may mimic exercise-induced asthma. Suspicions of VCD will be borne out by a mostly inspiratory stridor, abrupt onset and resolution of symptoms, an unpredictable symptom pattern, and the failure of usual asthma medications to resolve attacks. Laryngoscopy during acute symptoms is the definitive diagnostic tool. Panting can often stop an attack, and preventive treatment consists of patient education, speech therapy, and, when needed, psychological measures.

Laparoscopic fundoplication to enhance pulmonary function in children with severe reactive airway disease and gastroesophageal reflux disease.

BACKGROUND: The relationship between severe reactive airway disease (RAD) and gastroesophageal reflux disease (GERD) has been noted but the relationship is poorly understood. This study reports our experience with laparoscopic fundoplication and its effect on the pulmonary status of children with severe steroid-dependent reactive airway disease. METHODS: Fifty-six patients with severe steroid-dependent RAD and medically refractory GERD underwent laparoscopic Nissen fundoplications. Mean age was 7 years and mean weight was 20 kg. All patients had the procedure completed successfully laparoscopically with an average operative time of 62 min. Average hospital stay was 1.6 days. RESULTS: Forty-eight of 56 patients noted significant improvement in their respiratory symptoms in the first week. Fifty of 56 patients have been weaned off their oral steroids and four others have had a greater than 50% decrease in their dose. Sixteen patients had a documented increase in their FEV1 in the initial postoperative period (avg. 26%). CONCLUSION: Patients with steroid-dependent RAD and GERD refractory to medical management show improvement in their respiratory status following fundoplication and the majority can be weaned off of their oral steroids. Laparoscopic techniques allow this procedure to be performed safely even in this high-risk group of patients.

Asthma in infants and small children.

The wheezy young child is a particularly challenging patient to treat. This article focuses on a diagnostic approach and some of the treatment issues peculiar to this age group. Specifically addressed are (1) the problem of differentiating asthma from wheezy bronchitis in babies and the clinical implications of this; (2) general concepts of treating babies in whom many commonly used drugs are not FDA approved; (3) inhalation therapy, especially the use of metered-dose inhalers with spacers; (4) the standard asthma drugs and their beneficial and adverse effects, with particular reference to inhaled steroids; and (5) the nonpharmacologic management of asthma. A brief discussion of long-term outcome is also included.

Parental criticism and treatment outcome in adolescents hospitalized for severe, chronic asthma.

This pilot study investigated the relationship between parental criticism and medical treatment outcome across an inpatient hospitalization in 19 adolescents with severe, chronic asthma. Parental criticism toward their asthmatic adolescent was assessed using the Five Minute Speech Sample technique (FMSS) at the beginning of the adolescent's inpatient stay at a national asthma referral center. Those adolescents whose parents were rated as high in criticism on the FMSS were found to have greater improvement in their overall asthma severity, greater reduction in their steroid medication dose, and shorter lengths of stay in the hospital than those whose parents were rated as low in criticism. The adolescents whose parents were rated as high in criticism also showed lower compliance with their prescribed theophylline and oral steroid medication at admission than the low criticism group. These findings do not appear to be due to misdiagnosis secondary to the presence of vocal cord dysfunction or to the allergy status of the children. Clinical implications and possible causal mechanisms underlying these findings are discussed.

Pulmonary vascular disorders masquerading as interstitial lung disease.

During the acquisition of a series of 92 children with interstitial lung disease (ILD) over a 14 year period, a significant minority (8/92 or 9%) were initially diagnosed as having ILD, but were subsequently found to have a variety of arterial, venous, and/or capillary disorders that explained their initial pulmonary findings. This subgroup of patients has had a very high morbidity and mortality, with only three of eight patients currently surviving. The presentation, evaluation, and natural history of these eight children were reviewed. We developed a strategy of cardiac and pulmonary evaluation for children presenting with clinical and radiographic features of ILD that helped us to identify rapidly those with pulmonary vascular disorders.

Increased lower airways responsiveness associated with sinusitis in a rabbit model.

The association between sinusitis and asthma has been clinically recognized, but its precise nature is controversial. We studied the relationship between sinusitis and lower airways function in a rabbit model of sterile maxillary sinusitis induced by the chemotactic complement fragment C5a des arg. Animals kept in a head-up position following experimental sinusitis demonstrated a significant increase in airways responsiveness (AWR) to histamine. In contrast, animals of which the sinuses were injected with a saline diluent and in which no sinus inflammation developed had no increase in AWR. Experiments were subsequently carried out to investigate some of the potential mechanisms for these observations. A group of rabbits in which a distal site of inflammation was induced did not demonstrate increased AWR. Likewise, when sinus inflammation was established but passage of fluid to the lower airways was prevented, either by intubation or by head-down positioning, there was no change in AWR. A fourth experiment was designed to decrease complement factor activity before placing the animals in a head-up position. This led to the same degree of increased AWR. Neither the histology nor the bronchoalveolar lavage data demonstrated significant lower airways inflammation in any group. We conclude that sterile sinusitis can increase lower airways responsiveness to histamine in a rabbit model. The most likely mechanism for this effect is the postnasal dripping of cells or cell products into the lower airway. The role of a nasobronchial reflex or inflammatory mediator absorption could not be demonstrated in this model.

Clinical spectrum of chronic interstitial lung disease in children.

To describe the clinical spectrum of interstitial lung disease in children, we reviewed our experience with 48 patients during a 12-year period. Most patients initially had typical findings of restrictive lung disease and hypoxemia. Growth failure or pulmonary hypertension or both were found in more than one third. Specific diagnosis, made in 35 patients (70%), most often required invasive studies, particularly open lung biopsy. Although the diagnostic yield from open lung biopsy was high, the diagnosis of many patients remained uncertain. Many different disorders were encountered. The response to corticosteroids, bronchodilators, and chloroquine was inconsistent. Six patients died, five within 1 year after the initial evaluation. The spectrum of pediatric interstitial lung disease includes a large, heterogeneous group of rare disorders associated with high morbidity and mortality rates.

Vitamin D metabolites in adolescents and young adults with cystic fibrosis: effects of sun and season.

To assess mineral metabolism in patients with cystic fibrosis and to study the effects of season and sunlight exposure on generation of vitamin D metabolites, we quantified serum levels of calcidiol and calcitriol, other measures of bone metabolism, and radiographic bone mass in 20 adolescents and young adults with CF and 20 age-matched normal volunteers. Levels of calcidiol were lower in patients with CF than in controls and lower in Massachusetts than in Arizona in both study groups. Controls in Arizona had higher (P less than 0.05) levels of calcitriol than in Massachusetts throughout the year. All control subjects in both states had higher levels of calcitriol than did patients with CF. Patients in Massachusetts had significantly lower levels of calcitriol in winter than in summer. Summer levels of calcitriol in CF were significantly higher in Massachusetts than in Arizona; during winter, lower levels were found in Massachusetts than in Arizona. Mean bone density in patients with CF was 88% and 89% of normal American standards in Massachusetts and Arizona, respectively. These data indicate a seasonal, sunlight-related influence on levels of vitamin D metabolites in patients with CF receiving approximately 1000 IU vitamin D per day. Older patients with CF with progressively diminishing sunlight exposure may be at increased risk for development of osteopenia. The detected radiographic abnormalities of bone mineralization may also be related to malabsorptive deficiencies of calcium and phosphorus.