Comer Children's Hospital

Rhinosinusitis is a significant and increasing health problem which results in a large financial burden on society. This evidence based position paper describes what is known about rhinosinusitis and nasal polyps, offers evidence based recommendations on diagnosis and treatment, and considers how we can make progress with research in this area. Rhinitis and sinusitis usually coexist and are concurrent in most individuals; thus, the correct terminology is now rhinosinusitis. Rhinosinusitis (including nasal polyps) is defined as inflammation of the nose and the paranasal sinuses characterised by two or more symptoms, one of which should be either nasal blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip), +/- facial pain/pressure, +/- reduction or loss of smell; and either endoscopic signs of polyps and/or mucopurulent discharge primarily from middle meatus and/or; oedema/mucosal obstruction primarily in middle meatus, and/or CT changes showing mucosal changes within the ostiomeatal complex and/or sinuses. The paper gives different definitions for epidemiology, first line and second line treatment and for research. Furthermore the paper describes the anatomy and (patho)physiology, epidemiology and predisposing factors, inflammatory mechanisms, evidence based diagnosis, medical and surgical treatment in acute and chronic rhinosinusitis and nasal polyposis in adults and children. Evidence based schemes for diagnosis and treatment are given for the first and second line clinicians. Moreover attention is given to complications and socio-economic cost of chronic rhinosinusitis and nasal polyps. Last but not least the relation to the lower airways is discussed.

The Ehlers-Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs) characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Over the past two decades, the Villefranche Nosology, which delineated six subtypes, has been widely used as the standard for clinical diagnosis of EDS. For most of these subtypes, mutations had been identified in collagen-encoding genes, or in genes encoding collagen-modifying enzymes. Since its publication in 1998, a whole spectrum of novel EDS subtypes has been described, and mutations have been identified in an array of novel genes. The International EDS Consortium proposes a revised EDS classification, which recognizes 13 subtypes. For each of the subtypes, we propose a set of clinical criteria that are suggestive for the diagnosis. However, in view of the vast genetic heterogeneity and phenotypic variability of the EDS subtypes, and the clinical overlap between EDS subtypes, but also with other HCTDs, the definite diagnosis of all EDS subtypes, except for the hypermobile type, relies on molecular confirmation with identification of (a) causative genetic variant(s). We also revised the clinical criteria for hypermobile EDS in order to allow for a better distinction from other joint hypermobility disorders. To satisfy research needs, we also propose a pathogenetic scheme, that regroups EDS subtypes for which the causative proteins function within the same pathway. We hope that the revised International EDS Classification will serve as a new standard for the diagnosis of EDS and will provide a framework for future research purposes. © 2017 Wiley Periodicals, Inc.

BACKGROUND: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1-positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults. METHODS: We performed genomic profiling of 1725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Ph-like ALL. We examined the functional effects of fusion proteins and the efficacy of tyrosine kinase inhibitors in mouse pre-B cells and xenografts of human Ph-like ALL. RESULTS: Ph-like ALL increased in frequency from 10% among children with standard-risk ALL to 27% among young adults with ALL and was associated with a poor outcome. Kinase-activating alterations were identified in 91% of patients with Ph-like ALL; rearrangements involving ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B, TSLP, or TYK2 and sequence mutations involving FLT3, IL7R, or SH2B3 were most common. Expression of ABL1, ABL2, CSF1R, JAK2, and PDGFRB fusions resulted in cytokine-independent proliferation and activation of phosphorylated STAT5. Cell lines and human leukemic cells expressing ABL1, ABL2, CSF1R, and PDGFRB fusions were sensitive in vitro to dasatinib, EPOR and JAK2 rearrangements were sensitive to ruxolitinib, and the ETV6-NTRK3 fusion was sensitive to crizotinib. CONCLUSIONS: Ph-like ALL was found to be characterized by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors. Trials identifying Ph-like ALL are needed to assess whether adding tyrosine kinase inhibitors to current therapy will improve the survival of patients with this type of leukemia. (Funded by the American Lebanese Syrian Associated Charities and others.).

EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. no immunosuppressants IV D no nasal saline irrigation Ib, no data in single use D yes for symptomatic relief topical antibiotics no data D no anti-IL-5 no data D unclear phytotherapy no data D no decongestant topical / oral no data in single use D no mucolytics no data D no oral antihistamine in allergic patients no data D no antimycotics -topical Ia (-) ** A(-) no antimycotics -systemic Ib (-)# A(-) $ no anti leukotrienes Ib (-) A(-) no anti-IgE Ib (-) A(-) no * Some of these studies also included patients with CRS with nasal polyps. % short term antibiotics shows one positive and one negative study. Therefore recommendation C. oral antibiotic short term <4 weeks Ib(-) # A(-)* no intravenous antibiotics III(-) ## C(-) ** no # Ib (-): Ib study with a negative outcome.

Pediatric liver transplantation with reduced size donor organs (RLT) has evolved into a standard clinical procedure increasing the choices of recipients for their treatment. Nevertheless organ availability remains a major problem. The authors therefore have proposed to study the use of hepatic segments from living related donors (LRT) in a group of 20 children less than 2 years of age or weighing less than 15 kg, in whom standard indications for transplantation existed. Volunteer related donors were selected after medical and psychiatric evaluations, and the suitability of the donor's liver was established by functional and radiologic criteria. A two-stage informed consent process assured appropriate "volunteerism." Nineteen infants received LRT as first grafts and one as a second graft. Seventeen of the recipients are alive 3 to 18 months after LRT. Fifteen of 20 patients are currently at home with the original graft and normal liver function (bilirubin less than 1.5 mg/dl) after a median hospital stay of 27 days (range, 14-93 days). Four patients underwent retransplantation, in all cases due to arterial thrombosis. The overall graft survival for 20 primary LRTs is 75%, with follow-up between 3 and 18 months. A number of technical problems occurred during our initial trial, the most aggravating being vascular thrombosis. Refined approaches to vascular reconstruction should reduce the incidence of thrombosis and improve the rate of survival in future cases. The donor group for the initial 20 LRT procedures comprised 12 mothers, 7 fathers, and 1 grandmother. In addition one father and one uncle, who was an identical twin of the recipient's father, who did not qualify for anatomic reasons, were used in repeat LRT. All donors survived and are now in normal health between 3 and 18 months after LRT, having returned to all activities enjoyed before donation. The median hospital stay was 6 days (range, 5-14). Complications were minimal, and all were limited to the first three procedures, in which a full left hepatectomy was performed. After alteration of the procedure into a left lateral segmentectomy, no complications were encountered. The left lateral segmentectomy presents minimal surgical trauma to the liver and should remain the primary approach for obtaining a liver graft from a living donor. For children, transplantation of a left lateral segment from a live donor provides a new way of providing a transplant of appropriate size and with good function. The success of this program has led to the acceptance of LRT for general clinical application in the authors' institution.

RATIONALE: The overall efficacy of adenotonsillectomy (AT) in treatment of obstructive sleep apnea syndrome (OSAS) in children is unknown. Although success rates are likely lower than previously estimated, factors that promote incomplete resolution of OSAS after AT remain undefined. OBJECTIVES: To quantify the effect of demographic and clinical confounders known to impact the success of AT in treating OSAS. METHODS: A multicenter collaborative retrospective review of all nocturnal polysomnograms performed both preoperatively and postoperatively on otherwise healthy children undergoing AT for the diagnosis of OSAS was conducted at six pediatric sleep centers in the United States and two in Europe. Multivariate generalized linear modeling was used to assess contributions of specific demographic factors on the post-AT obstructive apnea-hypopnea index (AHI). MEASUREMENTS AND MAIN RESULTS: Data from 578 children (mean age, 6.9 +/- 3.8 yr) were analyzed, of which approximately 50% of included children were obese. AT resulted in a significant AHI reduction from 18.2 +/- 21.4 to 4.1 +/- 6.4/hour total sleep time (P < 0.001). Of the 578 children, only 157 (27.2%) had complete resolution of OSAS (i.e., post-AT AHI <1/h total sleep time). Age and body mass index z-score emerged as the two principal factors contributing to post-AT AHI (P < 0.001), with modest contributions by the presence of asthma and magnitude of pre-AT AHI (P < 0.05) among nonobese children. CONCLUSIONS: AT leads to significant improvements in indices of sleep-disordered breathing in children. However, residual disease is present in a large proportion of children after AT, particularly among older (>7 yr) or obese children. In addition, the presence of severe OSAS in nonobese children or of chronic asthma warrants post-AT nocturnal polysomnography, in view of the higher risk for residual OSAS.

BACKGROUND: A new form of congenital hyperinsulinism characterized by hypoglycemia and hyperammonemia was described recently. We hypothesized that this syndrome of hyperinsulinism and hyperammonemia was caused by excessive activity of glutamate dehydrogenase, which oxidizes glutamate to alpha-ketoglutarate and which is a potential regulator of insulin secretion in pancreatic beta cells and of ureagenesis in the liver. METHODS: We measured glutamate dehydrogenase activity in lymphoblasts from eight unrelated children with the hyperinsulinism-hyperammonemia syndrome: six with sporadic cases and two with familial cases. We identified mutations in the glutamate dehydrogenase gene by sequencing glutamate dehydrogenase complementary DNA prepared from lymphoblast messenger RNA. Site-directed mutagenesis was used to express the mutations in COS-7 cells. RESULTS: The sensitivity of glutamate dehydrogenase to inhibition by guanosine 5'-triphosphate was a quarter of the normal level in the patients with sporadic hyperinsulinism-hyperammonemia syndrome and half the normal level in patients with familial cases and their affected relatives, findings consistent with overactivity of the enzyme. These differences in enzyme insensitivity correlated with differences in the severity of hypoglycemia in the two groups. All eight children were heterozygous for the wild-type allele and had a mutation in the proposed allosteric domain of the enzyme. Four different mutations were identified in the six patients with sporadic cases; the two patients with familial cases shared a fifth mutation. In two clones of COS-7 cells transfected with the mutant sequence from one patient, the sensitivity of the enzyme to guanosine 5'-triphosphate was reduced, findings similar to those in the child's lymphoblasts. CONCLUSIONS: The hyperinsulinism-hyperammonemia syndrome is caused by mutations in the glutamate dehydrogenase gene that impair the control of enzyme activity.

National, longitudinal surveys from Great Britain and the United States were used to investigate the effects of divorce on children. In both studies, a subsample of children who were in two-parent families during the initial interview (at age 7 in the British data and at ages 7 to 11 in the U.S. data) were followed through the next interview (at age 11 and ages 11 to 16, respectively). At both time points in the British data, parents and teachers independently rated the children's behavior problems, and the children were given reading and mathematics achievement tests. At both time points in the U.S. data, parents rated the children's behavior problems. Children whose parents divorced or separated between the two time points were compared to children whose families remained intact. For boys, the apparent effect of separation or divorce on behavior problems and achievement at the later time point was sharply reduced by considering behavior problems, achievement levels, and family difficulties that were present at the earlier time point, before any of the families had broken up. For girls, the reduction in the apparent effect of divorce occurred to a lesser but still noticeable extent once preexisting conditions were considered.

BACKGROUND: The Gaucher Registry, the largest database of patients with Gaucher disease (GD) worldwide, was initiated to better delineate the progressive nature of the disorder and determine optimal therapy. This report describes the demographic and clinical characteristics of 1698 patients with GD before they received enzyme replacement therapy. METHODS: Physicians worldwide who treat patients with GD were invited to submit prospective and retrospective data for an ongoing registry, using standardized data collection forms, for central processing and review. RESULTS: Most patients were from the United States (45%) and Israel (17%), but patients are from 38 countries. Most (94%) had type 1 GD, fewer than 1% had type 2, and 5% had type 3. Mutant allele frequency data, available for 45% of patients, showed the most common alleles to be N370S (53%), L444P (18%), 84GG (7%), and IVS2+1 (2%). Twenty-five percent of L444P homozygotes (13 of 52 patients) had type 1 GD phenotype. Mean age at diagnosis in patients with the N370S/N370S genotype was 27.2 years (SD, 19.7 years); in L444P/L444P patients, 2. 3 years (SD, 3.2 years). Histories of bone pain and radiological bone disease were reported by 63% and 94% of patients, respectively; both were more likely in asplenic patients than in patients with spleens. Mean spleen and liver volumes were 19.8 and 2.0 multiples of normal, respectively. Anemia and thrombocytopenia were present in 64% and 56%, respectively. Thrombocytopenia was present in 13% of asplenic patients. CONCLUSIONS: The Gaucher Registry permits a comprehensive understanding of the clinical spectrum of GD because of the uniquely large sample size. The Registry will be useful in evaluating the effects of specific therapies in GD and the possible influences of environment, ethnicity, and genotype on the natural history of the disorder.

We identified a new type of staphylococcal cassette chromosome mec (SCCmec) from two community-acquired methicillin-resistant Staphylococcus aureus (MRSA) strains. The novel element, designated type IV SCCmec, had a unique combination of the class B mec gene complex and the type 2 ccr gene complex and was much smaller in size (21 to 24 kb) than previously identified SCCmec elements of hospital-acquired MRSA. Consistent with the strains' susceptibilities to various non-beta-lactam antibiotics, the type IV SCCmec was devoid of any antibiotic resistance genes other than the mecA gene.

BACKGROUND: Controversy exists as to the risk for postoperative apnea in former preterm infants. The conclusions of published studies are limited by the small number of patients. METHODS: The original data from eight prospective studies were subject to a combined analysis. Only patients having inguinal herniorrhaphy under general anesthesia were included; patients receiving caffeine, regional anesthesia, or undergoing other surgical procedures were excluded. A uniform definition for apnea was used for all patients. Eleven risk factors were examined: gestational age, postconceptual age, birth weight, history of respiratory distress syndrome, bronchopulmonary dysplasia, neonatal apnea, necrotizing enterocolitis, ongoing apnea, anemia, and use of opioids or nondepolarizing muscle relaxants. RESULTS: Two hundred fifty-five of 384 patients from eight studies at four institutions fulfilled study criteria. There was significant variation in apnea rates and the location of apnea (recovery room and postrecovery room) between institutions (P < 0.001). There was considerable variation in the duration and type of monitoring, definitions of apnea, and availability of historical information. The incidence of detected apnea was greater when continuous recording devices were used compared to standard impedance pneumography with alarms or nursing observations. Despite these limitations, it was determined that: (1) apnea was strongly and inversely related to both gestational age (P = 0.0005) and postconceptual age (P < 0.0001); (2) an associated risk factor was continuing apnea at home; (3) small-for-gestational-age infants seemed to be somewhat protected from apnea compared to appropriate- and large-for-gestational-age infants; (4) anemia was a significant risk factor, particularly for patients > 43 weeks' postconceptual age; (5) a relationship to apnea with history of necrotizing enterocolitis, neonatal apnea, respiratory distress syndrome, bronchopulmonary dysplasia, or operative use of opioids and/or muscle relaxants could not be demonstrated. CONCLUSIONS: The analysis suggests that, if it is assumed that the statistical models used are equally valid over the full range of ages considered and that the average rate of apnea reported across the studies analyzed is accurate and representative of actual rates in all institutions, the probability of apnea in nonanemic infants free of recovery-room apnea is not less than 5%, with 95% statistical confidence until postconceptual age was 48 weeks with gestational age 35 weeks. This risk is not less than 1%, with 95% statistical confidence, for that same subset of infants, until postconceptual age was 56 weeks with gestational age 32 weeks or postconceptual age was 54 weeks and gestational age 35 weeks. Older infants with apnea in the recovery room or anemia also should be admitted and monitored. The data do not allow prediction with confidence up to what age this precaution should continue to be taken for infants with anemia. The data were insufficient to allow recommendations regarding how long infants should be observed in recovery. There is additional uncertainty in the results due to the dramatically different rates of detected apnea in different institutions, which appear to be related to the use of different monitoring devices. Given the limitations of this combined analysis, each physician and institution must decide what is an acceptable risk for postoperative apnea.

RATIONALE: Considerable confusion exists regarding nomenclature, classification, and management of pediatric diffuse lung diseases due to the relative rarity and differences in the spectrum of disease between adults and young children. OBJECTIVES: A multidisciplinary working group was formed to: (1) apply consensus terminology and diagnostic criteria for disorders presenting with diffuse lung disease in infancy; and (2) describe the distribution of disease entities, clinical features, and outcome in young children who currently undergo lung biopsy in North America. METHODS: Eleven centers provided pathologic material, clinical data, and imaging from all children less than 2 years of age who underwent lung biopsy for diffuse lung disease from 1999 to 2004. MEASUREMENTS AND MAIN RESULTS: Multidisciplinary review categorized 88% of 187 cases. Disorders more prevalent in infancy, including primary developmental and lung growth abnormalities, neuroendocrine cell hyperplasia of infancy, and surfactant-dysfunction disorders, constituted the majority of cases (60%). Lung growth disorders were often unsuspected clinically and under-recognized histologically. Cases with known surfactant mutations had characteristic pathologic features. Age at biopsy and clinical presentation varied among categories. Pulmonary hypertension, presence of a primary developmental abnormality, or ABCA3 mutation was associated with high mortality, while no deaths occurred in cases of pulmonary interstitial glycogenosis, or neuroendocrine cell hyperplasia of infancy. CONCLUSIONS: This retrospective cohort study identifies a diverse spectrum of lung disorders, largely unique to young children. Application of a classification scheme grouped clinically distinct patients with variable age of biopsy and mortality. Standardized terminology and classification will enhance accurate description and diagnosis of these disorders.

OBJECTIVE: Our objective was to develop clinical practice guidelines for the evaluation and treatment of hirsutism in premenopausal women. PARTICIPANTS: The Task Force was composed of a chair, selected by the Clinical Guidelines Subcommittee (CGS) of The Endocrine Society, six additional experts, two methodologists, and a medical writer. The Task Force received no corporate funding or remuneration. EVIDENCE: Systematic reviews of available evidence were used to formulate the key treatment and prevention recommendations. We used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) group criteria to describe both the quality of evidence and the strength of recommendations. We used "recommend" for strong recommendations, and "suggest" for weak recommendations. CONSENSUS PROCESS: Consensus was guided by systematic reviews of evidence and discussions during one group meeting, several conference calls, and e-mail communications. The drafts prepared by the Task Force with the help of a medical writer were reviewed successively by The Endocrine Society's CGS, Clinical Affairs Core Committee (CACC), and Council. The version approved by the CGS and CACC was placed on The Endocrine Society's Web site for comments by members. At each stage of review, the Task Force received written comments and incorporated needed changes. CONCLUSIONS: We suggest testing for elevated androgen levels in women with moderate or severe hirsutism or hirsutism of any degree when it is sudden in onset, rapidly progressive, or associated with other abnormalities such as menstrual dysfunction, obesity, or clitoromegaly. For women with patient-important hirsutism despite cosmetic measures, we suggest either pharmacological therapy or direct hair removal methods. For pharmacological therapy, we suggest oral contraceptives for the majority of women, adding an antiandrogen after 6 months if the response is suboptimal. We recommend against antiandrogen monotherapy unless adequate contraception is used. We suggest against using insulin-lowering drugs. For women who choose hair removal therapy, we suggest laser/photoepilation.

BACKGROUND: Young men who have sex with men (YMSM) experience disparities in HIV rates and potentially in mental health, substance abuse, and exposure to violence. PURPOSE: We assessed the extent to which these psychosocial health problems had an additive effect on increasing HIV risk among YMSM. METHODS: An urban sample of 310 ethnically diverse YMSM reported on psychosocial health problems, sexual risk behaviors, and HIV status. A count of psychosocial health problems was calculated to test the additive relationship to HIV risk. RESULTS: The prevalence of psychosocial health problems varied from 23% for regular binge drinking to 34% for experiencing partner violence. Rates of sexual risk behaviors were high and 14% of YMSM reported receiving a HIV+ test result. Psychosocial health problems cooccurred, as evidenced by significant bivariate odds ratios (ORs) between 12 of the 15 associations tested. Number of psychosocial health problems significantly increased the odds of having multiple anal sex partners (OR=1.24), unprotected anal sex (OR=1.42), and an HIV-positive status (OR 1.42), after controlling for demographic factors. CONCLUSIONS: These data suggest the existence of cooccurring epidemics, or "syndemic," of health problems among YMSM. Disparities exist not only in the prevalence of HIV among YMSM but also in research to combat the epidemic within this vulnerable population. Future research is needed to identify risk and resiliency factors across the range of health disparities and develop interventions that address this syndemic.

Enteral nutrition (EN) is a valuable clinical intervention for patients of all ages in a variety of care settings. Along with its many outcome benefits come the potential for adverse effects. These safety issues are the result of clinical complications and of process-related errors. The latter can occur at any step from patient assessment, prescribing, and order review, to product selection, labeling, and administration. To maximize the benefits of EN while minimizing adverse events requires that a systematic approach of care be in place. This includes open communication, standardization, and incorporation of best practices into the EN process. This document provides recommendations based on the available evidence and expert consensus for safe practices, across each step of the process, for all those involved in caring for patients receiving EN.

BACKGROUND: Lactobacillus GG is a safe probiotic bacterium known to transiently colonize the human intestine. It has been found to be useful in treatment of several gastrointestinal conditions characterized by increased gut permeability. In the current study, the efficacy of Lactobacillus GG was investigated in children with Crohn's disease. METHODS: In this open-label pilot evaluation viewed as a necessary preliminary step for a possible subsequent randomized placebo-controlled trial, four children with mildly to moderately active Crohn's disease were given Lactobacillus GG (10(10) colony-forming units [CFU]) in enterocoated tablets twice a day for 6 months. Changes in intestinal permeability were measured by a double sugar permeability test. Clinical activity was determined by measuring the pediatric Crohn's disease activity index. RESULTS: There was a significant improvement in clinical activity 1 week after starting Lactobacillus GG, which was sustained throughout the study period. Median pediatric Crohn's disease activity index scores at 4 weeks were 73% lower than baseline. Intestinal permeability improved in an almost parallel fashion. CONCLUSIONS: Findings in this pilot study show that Lactobacillus GG may improve gut barrier function and clinical status in children with mildly to moderately active, stable Crohn's disease. Randomized, double-blind, placebo-controlled trials are warranted for a final assessment of the efficacy of Lactobacillus GG in Crohn's disease.

OBJECTIVES: We determined whether African American women's lifetime exposure to interpersonal racial discrimination is associated with pregnancy outcomes. METHODS: We performed a case-control study among 104 African American women who delivered very low birthweight (<1500 g) preterm (<37 weeks) infants and 208 African American women who delivered non-low-birthweight (>2500 g) term infants in Chicago, Ill. RESULTS: The unadjusted and adjusted odds ratio of very low birthweight infants for maternal lifetime exposure to interpersonal racism in 3 or more domains equaled 3.2 (95% confidence intervals=1.5, 6.6) and 2.6 (1.2, 5.3), respectively. This association tended to persist across maternal sociodemographic, biomedical, and behavioral characteristics. CONCLUSIONS: The lifelong accumulated experiences of racial discrimination by African American women constitute an independent risk factor for preterm delivery.

The skin locally synthesizes significant amounts of sexual hormones with intracrine or paracrine actions. The local level of each sexual steroid depends upon the expression of each of the androgen- and estrogen-synthesizing enzymes in each cell type, with sebaceous glands and sweat glands being the major contributors. Sebocytes express very little of the key enzyme, cytochrome P450c17, necessary for synthesis of the androgenic prohormones dehydroepiandrosterone and androstenedione, however, these prohormones can be converted by sebocytes and sweat glands, and probably also by dermal papilla cells, into more potent androgens like testosterone and dihydrotestosterone. Five major enzymes are involved in the activation and deactivation of androgens in skin. Androgens affect several functions of human skin, such as sebaceous gland growth and differentiation, hair growth, epidermal barrier homeostasis and wound healing. Their effects are mediated by binding to the nuclear androgen receptor. Changes of isoenzyme and/or androgen receptor levels may have important implications in the development of hyperandrogenism and the associated skin diseases such as acne, seborrhoea, hirsutism and androgenetic alopecia. On the other hand, estrogens have been implicated in skin aging, pigmentation, hair growth, sebum production and skin cancer. Estrogens exert their actions through intracellular receptors or via cell surface receptors, which activate specific second messenger signaling pathways. Recent studies suggest specific site-related distribution of ERalpha and ERbeta in human skin. In contrast, progestins play no role in the pathogenesis of skin disorders. However, they play a major role in the treatment of hirsutism and acne vulgaris, where they are prescribed as components of estrogen-progestin combination pills and as anti-androgens. These combinations enhance gonadotropin suppression of ovarian androgen production. Estrogen-progestin treatment can reduce the need for shaving by half and arrest progression of hirsutism of various etiologies, but do not necessarily reverse it. However, they reliably reduce acne. Cyproterone acetate and spironolactone are similarly effective as anti-androgens in reducing hirsutism, although there is wide variability in individual responses.

Probiotics are widely used by patients with Crohn's disease (CD) in an attempt to improve their health, but few controlled studies have been done to evaluate the efficacy of these therapies. We conducted a randomized, placebo-controlled trial of the probiotic Lactobacillus rhamnosus strain GG (LGG) to see if the addition of LGG to standard therapy prolonged remission in children with CD. Concomitant medications allowed in the study included aminosalicylates, 6-mercaptopurine, azathioprine, and low-dose alternate day corticosteroids. Seventy-five children (age range, 5-21 yr) with CD in remission were randomized to either LGG (n=39) or placebo (n=36) and followed for up to 2 years. The median time to relapse was 9.8 months in the LGG group and 11.0 months in the placebo group (P=0.24); 31% (12/39) of patients in the LGG group developed a relapse compared with 6/36 (17%) of the placebo group (P=0.18). The LGG was well tolerated, with a side effect profile comparable with placebo. This study suggests that LGG does not prolong time to relapse in children with CD when given as an adjunct to standard therapy.

We tested the hypothesis that insulin-like growth factor I (IGF-I) and insulin play a role in androgen production by rat ovarian thecal-interstitial cells. Collagenase/DNase-dispersed rat ovarian thecal-interstitial cells obtained from immature hypophysectomized Sprague-Dawley rats were cultured at a concentration of 10(6) cells/ml in serum-free medium in the presence of increasing concentrations of LH, IGF-I, or insulin. The medium was replaced every 48 h, and the androsterone concentration in the culture supernatants was used as an index of androgen production. In the absence of added hormones (control) androsterone levels were consistently less than 0.1 ng/ml. Increasing concentrations of LH stimulated androsterone synthesis in a dose-dependent manner. IGF-I, in the absence of LH, did not significantly increase androsterone levels above control values. However, when combined with 10 ng/ml LH, IGF-I increased androsterone synthesis above levels seen with LH alone in a dose-related fashion: for example, the peak androsterone levels seen with LH and 100 ng/ml (13 nM) IGF-I at 96 h of culture were significantly greater than the peak level seen with 10 ng/ml LH alone (302 +/- 71 vs. 17 +/- 7 ng/ml; P less than 0.0125). Similarly, while insulin alone did not increase androsterone synthesis above control values, androsterone concentrations were increased by insulin in combination with 10 ng/ml LH; a peak value of 240 +/- 67.7 ng/ml was observed at 96 h of culture with 100 ng/ml (18 mM) insulin (P less than 0.025 vs. LH alone) Androsterone levels were slightly less with insulin than with IGF-I, but this difference was not significant. The combination of IGF-I and insulin did not increase levels of androsterone synthesis above those observed with each hormone alone. IGF-I bound to a high affinity binding site on ovarian cell monolayer cultures with an apparent binding affinity of 1.3 x 10(-9) M. Insulin also competed for binding with radiolabeled IGF-I in a dose-dependent manner, but the affinity of insulin was approximately 500-fold less; half-maximal inhibition of [125I] IGF-I binding occurred with an insulin concentration of approximately 300 nM (or approximately 1700 ng/ml). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of thecal-interstitial cell monolayers affinity labeled with radiolabeled IGF-I in the absence and presence of unlabeled hormone revealed proteins with characteristics of type I IGF receptors. Affinity labeling to a protein of a relative molecular mass of approximately 45,000 was also noted, probably representing IGF carrier proteins synthesized by thecal-interstitial cell monolayers.(ABSTRACT TRUNCATED AT 400 WORDS)