Loratadine as an Anti-inflammatory Agent Against Clostridium difficile Toxin B.

BACKGROUND: Clostridium difficile infection (CDI) is a debilitating nosocomial infection. C. difficile produces toxins A and B, which cause inflammation. Existing therapies have issues with recurrence, cost, and safety. We aim to discover a safe, effective, and economical nonmicrobiological therapeutic approach against CDI. METHODS: We included human primary peripheral blood mononuclear cells (PBMCs), fresh human colonic explants, and humanized HuCD34-NCG mice. Toxin A+B+ VPI 10463 and A-B+ ribotype 017 C. difficile strains were used. We used single-cell RNA profiling and high-throughput screening to find actionable toxin B-dependent pathways in PBMCs. RESULTS: Histamine 1 receptor-related drugs were found among the hit compounds that reversed toxin-mediated macrophage inflammatory protein (MIP) 1α expression in PBMCs. We identified loratadine as the safest representative antihistamine for therapeutic development. Loratadine inhibited toxin B-induced MIP-1α secretion in fresh human colonic tissues. Oral loratadine (10 mg/kg/d) maintained survival, inhibited intestinal CCl3 messenger RNA expression, and prevented vancomycin-associated recurrence in the VPI 10463-infected mice and ribotype 017-infected hamsters. Splenocytes from loratadine-treated mice conferred anti-inflammatory effects to the VPI 10463-infected T/B-cell--deficient Rag-/- mice. Oral loratadine suppressed human MIP-1α expression in monocytes/macrophages in toxin B-expressing ribotype 017-infected humanized HuCD34-NCG mice. CONCLUSIONS: Loratadine may be repurposed to optimize existing therapies against CDI.

Loratadine, a Food and Drug Administration­approved antihistamine, inhibits toxin B­mediated proinflammatory macrophage inflammatory protein 1α secretion from immune cells. Its anti-inflammatory effect ameliorates intestinal inflammation in Clostridium difficile­infected animals. Loratadine may be repurposed to optimize existing therapies.

Genistein Inhibits Clostridioides difficile Infection via Estrogen Receptors and Lysine-Deficient Protein Kinase 1.

BACKGROUND: Clostridioides difficile infection (CDI) is a debilitating nosocomial disease. Postmenopausal women may have an increased risk of CDI, suggesting estrogen influence. Soybean products contain a representative estrogenic isoflavone, genistein. METHODS: The anti-inflammatory and antiapoptotic effects of genistein were determined using primary human cells and fresh colonic tissues. The effects of oral genistein therapy among mice and hamsters were evaluated. RESULTS: Within 10 days of CDI, female c57BL/6J mice in a standard environment (regular diet) had a 50% survival rate, while those with estrogen depletion and in an isoflavone-free environment (soy-free diet) had a 25% survival rate. Oral genistein improved their 10-day survival rate to 100% on a regular diet and 75% in an isoflavone-free environment. Genistein reduced macrophage inflammatory protein-1α (MIP-1α) secretion in fresh human colonic tissues exposed to toxins. Genistein inhibited MIP-1α secretion in primary human peripheral blood mononuclear cells, abolished apoptosis and BCL-2-associated X (BAX) expression in human colonic epithelial cells, and activated lysine-deficient protein kinase 1 (WNK1) phosphorylation in both cell types. The anti-inflammatory and antiapoptotic effects of genistein were abolished by inhibiting estrogen receptors and WNK1. CONCLUSIONS: Genistein reduces CDI disease activity by inhibiting proinflammatory cytokine expression and apoptosis via the estrogen receptor/G-protein estrogen receptor/WNK1 pathways.

Extracellular vesicle secretion is tissue-dependent ex vivo and skeletal muscle myofiber extracellular vesicles reach the circulation in vivo.

Extracellular vesicles (EVs) are biomarkers and modifiers of human disease. EVs secreted by insulin-responsive tissues like skeletal muscle (SkM) and white adipose tissue (WAT) contribute to metabolic health and disease but the relative abundance of EVs from these tissues has not been directly examined. Human Protein Atlas data and directly measuring EV secretion in mouse SkM and WAT using an ex vivo tissue explant model confirmed that SkM tissue secretes more EVs than WAT. Differences in EV secretion between SkM and WAT were not due to SkM contraction but may be explained by differences in tissue metabolic capacity. We next examined how many EVs secreted from SkM tissue ex vivo and in vivo are myofiber-derived. To do this, a SkM myofiber-specific dual fluorescent reporter mouse was created. Spectral flow cytometry revealed that SkM myofibers are a major source of SkM tissue-derived EVs ex vivo and EV immunocapture indicates that ∼5% of circulating tetraspanin-positive EVs are derived from SkM myofibers in vivo. Our findings demonstrate that 1) SkM secretes more EVs than WAT, 2) many SkM tissue EVs are derived from SkM myofibers, and 3) SkM myofiber-derived EVs reach the circulation in vivo. These findings advance our understanding of EV secretion between metabolically active tissues and provide direct evidence that SkM myofibers secrete EVs that can reach the circulation in vivo.

Fourteen-year follow-up of a child with acroscyphodysplasia with emphasis on the need for multidisciplinary management: a case report.

BACKGROUND: Acroscyphodysplasia has been described as a phenotypic variant of acrodysostosis type 2 and pseudohypoparathyroidism. In acrodysostosis, skeletal features can include brachydactyly, facial hypoplasia, cone-shaped epiphyses, short stature, and advanced bone age. To date, reports on this disorder have focused on phenotypic findings, endocrine changes, and genetic variation. We present a 14-year overview of a patient, from birth to skeletal maturity, with acroscyphodysplasia, noting the significant orthopaedic challenges and the need for a multidisciplinary team, including specialists in genetics, orthopaedics, endocrinology, and otolaryngology, to optimize long-term outcomes. CASE PRESENTATION: The patient presented as a newborn with dysmorphic facial features, including severe midface hypoplasia, malar flattening, nasal stenosis, and feeding difficulties. Radiologic findings were initially subtle, and a skeletal survey performed at age 7 months was initially considered normal. Genetic evaluation revealed a variant in PDE4D and subsequent pseudohypoparathyroidism. The patient presented to the department of orthopaedics, at age 2 years 9 months with a leg length discrepancy, right knee contracture, and severely crouched gait. Radiographs demonstrated cone-shaped epiphyses of the right distal femur and proximal tibia, but no evidence of growth plate changes in the left leg. The child developed early posterior epiphyseal arrest on the right side and required multiple surgical interventions to achieve neutral extension. Her left distal femur developed late posterior physeal arrest and secondary contracture without evidence of schypho deformity, which improved with anterior screw epiphysiodesis. The child required numerous orthopaedic surgical interventions to achieve full knee extension bilaterally. At age 13 years 11 months, she was an independent ambulator with erect posture. The child underwent numerous otolaryngology procedures and will require significant ongoing care. She has moderate intellectual disability. DISCUSSION AND CONCLUSIONS: Key challenges in the management of this case included the subtle changes on initial skeletal survey and the marked asymmetry of her deformity. While cone-shaped epiphyses are a hallmark of acrodysostosis, posterior tethering/growth arrest of the posterior distal femur has not been previously reported. Correction of the secondary knee contracture was essential to improve ambulation. Children with acroscyphodysplasia require a multidisciplinary approach, including radiology, genetics, orthopaedics, otolaryngology, and endocrinology specialties.

Short-term changes in diet composition do not affect in vivo hepatic protein synthesis in rats.

Protein synthesis is critical to protein homeostasis (proteostasis), and modifications in protein synthesis influence lifespan and the development of comorbidities associated with obesity. In the present study, we examined the acute response of liver protein synthesis to either high-fat or high-sucrose diets in order to elucidate nutrient-mediated regulation of hepatic protein synthesis in the absence of body fat accumulation. Total and endoplasmic reticulum-associated protein syntheses were assessed by use of the stable isotope, deuterium oxide (2H2O), in rats provided a control diet or diets enriched in polyunsaturated fat, saturated fat, or sucrose for 2, 4, or 7 days. The three experimental diets increased hepatic triglycerides 46-91% on day 7 and fasting insulin levels 83-117% on day 7, but did not result in differences in body weight when compared with control ( n = 6/diet/time). The fraction of newly synthesized proteins in total liver lysates and microsomes was not significantly different among dietary groups ( n = 3/diet/time). To determine whether the experimental diets provoked a transcriptional response to enhance the capacity for protein synthesis, we also measured a panel of genes linked to amino acid transport, synthesis, and processing. There were no significant differences in any of the genes measured among groups. Therefore, dietary treatments that have been linked to impaired proteostasis and that promote hepatic steatosis and insulin resistance, did not result in significant changes in total or ER-associated protein synthesis in the liver over a 7-day period.

Bone densitometry in children and adolescents.

PURPOSE OF REVIEW: Abnormalities in bone health are increasingly recognized in the pediatric population. Although the methodologies for assessing bone mineral density were originally developed for adults, great strides have been made in recent years, improving their applicability to children. Understanding these technologies, their interpretation, utility, and limitations is critical when assessing a child or adolescent with a suspected abnormality in bone mineral density. RECENT FINDINGS: Improved normative databases that address some of the confounding variables in the growing and maturing child have solidified dual-energy X-ray absorptiometry as the preferred method for the assessment of bone mineral density in children. Consensus statements by expert panels now provide specific guidance to clinicians seeking to evaluate children with fractures or at risk for fractures. Although still primarily a research tool, continued development of quantitative computed tomography applications in pediatrics suggests there may be a complementary role for clinical use in the future. SUMMARY: In the child or adolescent with a significant fracture history or a potential for fractures because of an underlying cause, clinicians now have guidelines and normative data to better focus their evaluation. Likewise, researchers can use this information to improve clinical trial design and interpretation of results.

Pulmonary manifestations and prognosis of a cohort of patients with interstitial lung disease and positive to anti-Th/To autoantibodies.

INTRODUCTION: Th/To autoantibody may be relevant in evaluating patients with interstitial lung disease (ILD) because the clinical diagnosis of systemic sclerosis (SSc) may not be evident. The study's objective was to describe manifestations and evolution of pulmonary function in a cohort of ILD patients positive for Th/To autoantibodies. METHODS: ILD patients positive for anti-Th/To autoantibody were enrolled in this protocol. Baseline clinical features were registered, and survival analysis was performed to identify risk factors associated with worse survival. RESULTS: Fifty-two patients positive for anti-Th/To autoantibodies with ILD were included. Only 21% of the patients fulfilled the ACR/EULAR 2013 systemic sclerosis classification criteria, and 63.4% fulfilled the IPAF ATS/ERS 2015 criteria. Twenty-five percent of the patients died during follow-up. Respiratory failure was the principal cause of death. Twenty-nine patients (56%) were positive for other hallmark SSc autoantibodies. The most frequent HRCT pattern was nonspecific interstitial pneumonia (NISP). Survival was strongly associated to the systolic pulmonary arterial pressure (sPAP), male sex and the extent of fibrosis in HRCT; besides, patients positive for other hallmark SSc autoantibodies had worse survival compared to those positive only to anti-Th/To. Seventy-six percent of them behaved as fibrotic progressive pulmonary disease, with an absolute decline of the FVC of at least 5%. CONCLUSIONS: Only a small proportion of ILD patients positive for Th/To meet the criteria to be classified as SSc; however, most met criteria for IPAF. A high proportion of patients behave as progressive fibrotic pulmonary disease. Survival is associated with sPAP, the extent of lung disease, and the presence of other hallmark SSc autoantibodies.

Characteristics of vitamin D deficiency hypocalcemia inpatient admissions at a single tertiary center.

OBJECTIVES: Severe 25-hydroxyvitamin D (25(OH)D) deficiency can result in life-threatening presentations due to hypocalcemia leading to seizures and cardiac arrhythmias. vitamin D deficiency is a common cause of hypocalcemia and rickets in children; however, there are no recent studies on the burden of inpatient admissions in the United States. Our study aims to describe the clinical characteristics and risk factors of inpatient admissions due to severe hypocalcemia and 25(OH)D deficiency at a freestanding academic children's hospital. METHODS: A descriptive retrospective chart review was completed on all inpatient admissions from 2016 to 2021 for children 0-18 years of age with corrected calcium <8 mg/dL and 25(OH)D <10 ng/mL during admission. RESULTS: Thirty-eight patients met the inclusion criteria (74 % Black/African American). Neurological signs described in 49 %, bone abnormalities in 17 % and EKG abnormalities in 42 % of the patients. The mean calcium serum level was 6.0 mmol/L (range 5.0-7.9 mmol/L), the mean iCa 0.77 mmol/L (range 0.54-0.99 mmol/L). The mean level of 25(OH)D was 5.5 ng/mL (range 2.1-9.7 ng/mL). The median length of stay was 4.5 (range 1-59 days). CONCLUSIONS: In this retrospective observational study, risk factors identified: (1) Black/African American race (2) age less than two years (3) lack of supplementation of vitamin D and (4) dietary restrictions. Inpatient admissions are preventable through the implementation of education at the community and healthcare levels.

ADS024, a single-strain live biotherapeutic product of Bacillus velezensis alleviates dextran sulfate-mediated colitis in mice, protects human colonic epithelial cells against apoptosis, and maintains epithelial barrier function.

Epithelial cell apoptosis and compromised gut barrier function are features of inflammatory bowel disease. ADS024 is a single-strain live biotherapeutic product (LBP) of Bacillus velezensis under development for treating ulcerative colitis (UC). The cytoprotective effects of the sterile filtrate of ADS024's secreted products on UC patient-derived colonic tissues, human primary colonic epithelial cells (HPEC), and human colonic epithelial T84 cells were evaluated. ADS024 filtrate significantly inhibited apoptosis and inflammation with reduced Bcl-2 Associated X-protein (BAX) and tumor necrosis factor (TNF) mRNA expression in fresh colonic explants from UC patients. Exposure to UC patient-derived serum exosomes (UCSE) induced apoptosis with increased cleaved caspase 3 protein expression in HPECs. ADS024 filtrate diminished the UCSE-mediated apoptosis by inhibiting cleaved caspase 3. TNFα and interferon-gamma (IFNγ) damaged epithelial barrier integrity with reduced transepithelial electrical resistance (TEER). ADS024 filtrate partially attenuated the TEER reduction and restored tight junction protein 1 (TJP1) expression. Oral live ADS024 treatment reduced weight loss, disease activity, colonic mucosal injury, and colonic expression of interleukin 6 (IL-6) and TNFα in dextran sodium sulfate (DSS)-treated mice with colitis. Thus, ADS024 may protect the colonic epithelial barrier in UC via anti-inflammatory, anti-apoptotic, and tight-junction protection mechanisms.

ADS024, a Bacillus velezensis strain, protects human colonic epithelial cells against C. difficile toxin-mediated apoptosis.

Clostridioides difficile infection (CDI) causes intestinal injury. Toxin A and toxin B cause intestinal injury by inducing colonic epithelial cell apoptosis. ADS024 is a Bacillus velezensis strain in development as a single-strain live biotherapeutic product (SS-LBP) to prevent the recurrence of CDI following the completion of standard antibiotic treatment. We evaluated the protective effects of the sterile filtrate and ethyl acetate extract of conditioned media from ADS024 and DSM7 (control strain) against mucosal epithelial injury in toxin-treated human colonic tissues and apoptosis in toxin-treated human colonic epithelial cells. Ethyl acetate extracts were generated from conditioned culture media from DSM7 and ADS024. Toxin A and toxin B exposure caused epithelial injury in fresh human colonic explants. The sterile filtrate of ADS024, but not DSM7, prevented toxin B-mediated epithelial injury in fresh human colonic explants. Both sterile filtrate and ethyl acetate extract of ADS024 prevented toxin-mediated apoptosis in human colonic epithelial cells. The anti-apoptotic effects of ADS024 filtrate and ethyl acetate extract were dependent on the inhibition of caspase 3 cleavage. The sterile filtrate, but not ethyl acetate extract, of ADS024 partially degraded toxin B. ADS024 inhibits toxin B-mediated apoptosis in human colonic epithelial cells and colonic explants.

Elafin Reverses Intestinal Fibrosis by Inhibiting Cathepsin S-Mediated Protease-Activated Receptor 2.

BACKGROUND & AIMS: More than half of Crohn's disease patients develop intestinal fibrosis-induced intestinal strictures. Elafin is a human protease inhibitor that is down-regulated in the stricturing intestine of Crohn's disease patients. We investigated the efficacy of elafin in reversing intestinal fibrosis and elucidated its mechanism of action. METHODS: We developed a new method to mimic a stricturing Crohn's disease environment and induce fibrogenesis using stricturing Crohn's disease patient-derived serum exosomes to condition fresh human intestinal tissues and primary stricturing Crohn's disease patient-derived intestinal fibroblasts. Three mouse models of intestinal fibrosis, including SAMP1/YitFc mice, Salmonella-infected mice, and trinitrobenzene sulfonic acid-treated mice, were also studied. Elafin-Eudragit FS30D formulation and elafin-overexpressing construct and lentivirus were used. RESULTS: Elafin reversed collagen synthesis in human intestinal tissues and fibroblasts pretreated with Crohn's disease patient-derived serum exosomes. Proteome arrays identified cathepsin S as a novel fibroblast-derived pro-fibrogenic protease. Elafin directly suppressed cathepsin S activity to inhibit protease-activated receptor 2 activity and Zinc finger E-box-binding homeobox 1 expression, leading to reduced collagen expression in intestinal fibroblasts. Elafin overexpression reversed ileal fibrosis in SAMP1/YitFc mice, cecal fibrosis in Salmonella-infected mice, and colonic fibrosis in trinitrobenzene sulfonic acid-treated mice. Cathepsin S, protease-activated receptor 2 agonist, and zinc finger E-box-binding homeobox 1 overexpression abolished the anti-fibrogenic effect of elafin in fibroblasts and all 3 mouse models of intestinal fibrosis. Oral elafin-Eudragit FS30D treatment abolished colonic fibrosis in trinitrobenzene sulfonic acid-treated mice. CONCLUSIONS: Elafin suppresses collagen synthesis in intestinal fibroblasts via cathepsin S-dependent protease-activated receptor 2 inhibition and decreases zinc finger E-box-binding homeobox 1 expression. The reduced collagen synthesis leads to the reversal of intestinal fibrosis. Thus, modified elafin may be a therapeutic approach for intestinal fibrosis.

Lung Ultrasound Characteristics in Neonates With Positive Real Time Polymerase Chain Reaction for SARS-CoV-2 on a Tertiary Level Referral Hospital in Mexico City.

Introduction: Acute respiratory syndrome secondary to SARS-CoV-2 virus infection has been declared a pandemic since December 2019. On neonates, severe presentations are infrequent but possible. Lung ultrasound (LUS) has been shown to be useful in diagnosing lung involvement and following up patients, giving more information, and reducing exposure compared to traditional examination. Methods: LUS was performed after the diagnosis of SARS-CoV-2 infection with respiratory Real Time Polymerase Chain Reaction RT-PCR with portable equipment protected with a silicone sleeve. If hemodynamic or cardiology consultation was necessary, a prepared complete ultrasound machine was used. Ten regions were explored (anterior superior and inferior, lateral, and posterior superior and inferior, right and left), and a semiquantitative score (LUSS) was calculated. Disease severity was determined with a pediatric modified score. Results: Thirty-eight patients with positive RT-PCR were admitted, 32 (81%) of which underwent LUS. Included patients had heterogenous diagnosis and gestational ages as expected on a referral neonatal intensive care unit (NICU) (median, ICR: 36, 30-38). LUS abnormalities found were B-line interstitial pattern 90%, irregular/interrupted/thick pleural line 88%, compact B-lines 65%, small consolidations (≤5 mm) 34%, and extensive consolidations (≥5 mm) 37%. Consolidations showed posterior predominance (70%). LUSS showed a median difference between levels of disease severity and ventilatory support (Kruskal-Wallis, p = 0.001) and decreased with patient improvement (Wilcoxon signed-rank test p = 0.005). There was a positive correlation between LUSS and FiO2 needed (Spearman r = 0.72, p = 0.01). The most common recommendation to the attending team was pronation (41%) and increase in positive end expiratory pressure (34%). Five patients with comorbidities died. A significant rank difference of LUSS and FiO2 needed between survivors and non-survivors was found (Mann-Whitney U-test, p = 0.005). Conclusion: LUS patterns found were like the ones described in other series (neonatal and pediatrics). Eighty-eight percent of the studies were performed with handheld affordable equipment. While there is no specific pattern, it varies according to gestational age and baseline diagnosis LUS, which were shown to be useful in assessing lung involvement that correlated with the degree of disease severity and respiratory support.

An Open-label Study With Pirfenidone on Chronic Hypersensitivity Pneumonitis.

BACKGROUND: Chronic hypersensitivity pneumonitis (cHP) represents a severe lung disease often evolving to fibrosis with the subsequent destruction of the lung parenchyma. There are no approved therapies with confirmed efficacy to deal with this disease. METHODS: We performed an open-label, proof of concept study, to evaluate the efficacy and safety of pirfenidone added to immunosuppressive drugs on the treatment of cHP. We included 22 patients assigned to two groups: Group 1, nine patients that received prednisone plus azathioprine and Group 2, thirteen patients, received prednisone plus azathioprine and pirfenidone (ClinicalTrials.gov identifier NCT02496182). There were no significant imbalances in clinically relevant baseline characteristics between two study groups. RESULTS: After 1 year of treatment, inclusion of pirfenidone was not associated with improved forced vital capacity (primary end-point). A not significant tendency to show higher improvement of diffusion capacity of the lung for carbon monoxide (DLCO) was observed in the group receiving pirfenidone (p=0.06). Likewise, a significant improvement in the total score on the SGRQ was found in the group 2 (p=0.02) without differences in other two questionnaires related to quality of life (ATAQ-IPF and EQ-5D-3L). HRCT showed a decrease of the ground glass attenuation without changes in the fibrotic lesions and without differences between both groups. CONCLUSIONS: These findings suggest that the addition of pirfenidone to the anti-inflammatory treatment in patients with chronic HP may improve the outcome with acceptable safety profile. However, prospective randomized double-blind, placebo-controlled trials in largest cohorts are needed to validate its efficacy.

Functional diversity of T-cell subpopulations in subacute and chronic hypersensitivity pneumonitis.

RATIONALE: Hypersensitivity pneumonitis (HP) exhibits a diverse outcome. Patients with acute/subacute HP usually improve, whereas patients with chronic disease often progress to fibrosis. However, the mechanisms underlying this difference are unknown. OBJECTIVES: To examine the T-cell profile from patients with subacute HP and chronic HP. METHODS: T cells were obtained by bronchoalveolar lavage from 25 patients with subacute HP, 30 patients with chronic HP, and 8 control subjects. T-cell phenotype and functional profile were evaluated by flow cytometry, cytometric bead array, and immunohistochemistry. MEASUREMENTS AND MAIN RESULTS: Patients with chronic HP showed higher CD4+:CD8+ ratio (median, 3.05; range, 0.3-15; subacute HP: median, 1.3; range, 0.1-10; control: median, 1.3; range, 0.7-2.0; P < 0.01), and a decrease of gammadeltaT cells (median, 2.0; range, 0.5-3.4; subacute HP: median, 10; range, 4.8-17; control: median, 15; range, 5-19; P < 0.01). Patients with chronic HP exhibited an increase in the terminally differentiated memory CD4+ and CD8+ T-cell subsets compared with patients with subacute HP (P < 0.05). However, memory cells from chronic HP showed lower IFN-gamma production and decreased cytotoxic activity by CD8+ T lymphocytes. Chronic HP displayed a Th2-like phenotype with increased CXCR4 expression (median, 6%; range, 1.7-36, vs. control subjects: median, 0.7%; range, 0.2-1.4; and subacute HP: median, 2.2%; range, 0.1-5.3; P < 0.01), and decreased CXCR3 expression (median, 4.3%; range, 1.4-25%, vs. subacute HP: median, 37%; range, 4.9-78%; P < 0.01). Likewise, supernatants from antigen-specific-stimulated cells from chronic HP produced higher levels of IL-4 (80 +/- 63 pg/ml vs. 25 +/- 7 pg/ml; P < 0.01), and lower levels of IFN-gamma (3,818 +/- 1671 pg/ml vs. 100 +/- 61 pg/ml; P < 0.01) compared with subacute HP. CONCLUSIONS: Our findings indicate that patients with chronic HP lose effector T-cell function and exhibit skewing toward Th2 activity, which may be implicated in the fibrotic response that characterizes this clinical form.

Gynecologic and reproductive outcomes in fibrous dysplasia/McCune-Albright syndrome.

BACKGROUND: Autonomous ovarian activation with recurrent estrogen-producing cysts is a hallmark feature of the rare bone and endocrine disorder fibrous dysplasia/McCune-Albright syndrome. Precocious puberty in girls with McCune-Albright syndrome has been well-described, however long-term effects on gynecologic and reproductive function are unknown. Concerningly, case reports have described poor skeletal outcomes associated with pregnancy in women with fibrous dysplasia. METHODS: Thirty-nine women with fibrous dysplasia/McCune-Albright syndrome were evaluated as part of a natural history study. Clinical, radiographic, and biochemical data were reviewed. Women were contacted to obtain detailed menstrual and reproductive histories. RESULTS: Abnormal uterine bleeding affected 77% of women (30/39), and was associated with severe anemia requiring blood transfusion in 3 cases. Nine women underwent hysterectomy for management of bleeding, including 67% (6/9) at the unusually young age of less than age 35 years. Infertility affected 43% of women (9/21), including 2 women who developed primary ovarian insufficiency after undergoing surgical treatment of ovarian cysts. Of 25 spontaneous pregnancies in 14 women, 35% (8) were unplanned. Among the 14 pregnancies, pregnancy was associated with no change in bone pain in 7 subjects (53%), increased bone pain in 4 subjects (31%), and decreased bone pain in 2 subjects (15%). No additional skeletal complications were reported during pregnancies. CONCLUSIONS: Women with fibrous dysplasia/McCune-Albright syndrome report a high prevalence of gynecologic morbidity and reduced fertility. There is no clear association between pregnancy and poor skeletal outcomes in this population.

Abdominal trauma: experience of 4961 cases in Western Mexico.

INTRODUCTION: Trauma is a leading cause of morbimortality in the world. Intraabdominal compartment is the third most affected anatomical region and bleeding from this origin is difficult to identify, therefore the importance to predict possible lesions to the abdominal cavity. OBJECTIVE: To describe and analyze the sociodemographic profile and injuries found in patients with abdominal trauma in a western hospital in Mexico. METHOD: Consecutive patients included in the local registry GDL-SHOT were analyzed. RESULTS: From 4961 patients, 91.4% were men, with a mean age of 28.7 years. Regarding the mechanism of trauma, 39.7% were stab wounds, 33% blunt abdominal trauma and 27.3% gunshots. The most affected organs were: small bowel (20.9%), liver (18.2%), and colon (14.2%). The mean hospital stay was 6.95 days with a mortality of 6.74%. CONCLUSION: In Mexico, abdominal trauma represents an important cause of morbidity and mortality, especially in young patients. We found an important amount of penetrating trauma.

INTRODUCCIÓN: El trauma es una de las principales causas de morbimortalidad en el mundo. El abdomen es, en frecuencia, la tercera región anatómica más afectada, y el compartimento intraabdominal es un sitio de hemorragia difícil de identificar, por lo que cobra importancia el conocimiento de las posibles lesiones tras un traumatismo. OBJETIVOS: Describir y analizar el perfil sociodemográfico y las lesiones encontradas en pacientes con trauma abdominal en un hospital de referencia del occidente de México. MÉTODO: Se seleccionaron para su análisis los pacientes incluidos en el registro hospitalario local GDL-SHOT. RESULTADOS: De 4961 pacientes, el 91.4% fueron hombres, con un promedio de edad de 28.7 años. Respecto al mecanismo, el 39.7% correspondió a arma blanca, el 33% a trauma cerrado y el 27.3% a arma de fuego. Los órganos más afectados fueron el intestino delgado (20.9%), el hígado (18.2%) y el colon (14.2%). La estancia hospitalaria promedio fue de 6.95 días, con una mortalidad del 6.74%. CONCLUSIONES: En México, el trauma abdominal representa una causa importante de morbimortalidad, en especial en pacientes jóvenes, y predomina el mecanismo penetrante; el manejo más común es no conservador. La frecuencia de lesiones encontradas es discordante con la literatura de otros países y predominan las de vísceras huecas, probablemente por la diferencia en los mecanismos implicados.

Local and circulating microchimerism is associated with hypersensitivity pneumonitis.

RATIONALE: Hypersensitivity pneumonitis (HP) is a lymphocytic alveolitis provoked by exposure to a variety of antigens. However, the disease occurs in only a subset of exposed individuals, suggesting that additional factors may be involved. Microchimerism has been implicated in the pathogenesis of autoimmune diseases, especially in those showing increased incidence after childbearing age. OBJECTIVES: To evaluate the presence of circulating and local microchimeric cells in female patients with HP. METHODS: Male microchimerism was examined in 103 patients with HP, 30 with idiopathic pulmonary fibrosis (IPF), and 43 healthy women. All of them had given birth to at least one son, with no twin siblings, blood transfusions, or transplants. Microchimerism was examined by dot blot hybridization (peripheral blood), and by fluorescence in situ hybridization in bronchoalveolar lavage cells and lungs. MEASUREMENTS AND MAIN RESULTS: Blood microchimerism was found in 33% of the patients with HP in comparison with 10% in those with IPF (p = 0.019) and 16% in healthy women (p = 0.045). Patients with HP with microchimerism showed a significant reduction of diffusing capacity of carbon monoxide (Dl(CO); 53.5 +/- 11.9% vs. 65.2 +/- 19.7%; p = 0.02) compared with patients with HP without microchimerism. In bronchoalveolar lavage cells, microchimerism was detected in 9 of 14 patients with HP compared with 2 of 10 patients with IPF (p = 0.047). Cell sorting revealed that microchimeric cells were either macrophages or CD4+ or CD8+ T cells. Male microchimeric cells were also found in the five HP lungs examined by fluorescence in situ hybridization. CONCLUSIONS: Our findings (1) demonstrate that patients with HP exhibit increased frequency of fetal microchimerism, (2) confirm the multilineage capacity of microchimeric cells, and (3) suggest that microchimeric cells may increase the severity of the disease.

Clinical and Radiographic Gastrointestinal Abnormalities in McCune-Albright Syndrome.

Context: McCune-Albright syndrome (MAS) is a rare disorder characterized by fibrous dysplasia of bone, café-au-lait macules, and hyperfunctioning endocrinopathies. It arises from somatic gain-of-function mutations in GNAS, which encodes the cAMP-regulating protein Gαs. Somatic GNAS mutations have been reported in intraductal papillary mucinous neoplasms (IPMNs) and various gastrointestinal (GI) tumors. The clinical spectrum and prevalence of MAS-associated GI disease is not well established. Objective: Define the spectrum and prevalence of MAS-associated GI pathology in a large cohort of patients with MAS. Design: Cross-sectional study. Setting: National Institutes of Health Clinical Center and The Johns Hopkins Hospital. Methods: Fifty-four consecutive subjects with MAS (28 males; age range, 7 to 67 years) were screened with magnetic resonance cholangiopancreatography (MRCP). Results: Thirty of 54 subjects (56%) had radiographic GI abnormalities. Twenty-five (46%) of the screened subjects had IPMNs (mean age of 35.1 years). Fourteen of the 25 had IPMNs alone, and 11 had IPMNs and abnormal hepatobiliary imaging. The 30 patients with MAS-associated GI pathology had a higher prevalence of acute pancreatitis, diabetes mellitus, and skeletal disease burden of fibrous dysplasia than patients without GI disease. Conclusions: A broad spectrum of GI pathology is associated with MAS. IPMNs are common and occur at a younger age than in the general population. Patients with MAS should be considered for screening with a focused GI history and baseline MRCP. Further determination of the natural history and malignant potential of IPMNs in MAS is needed.

Acute development of Cushing syndrome in an HIV-infected child on atazanavir/ritonavir based antiretroviral therapy.

An 11-year-old male with perinatally acquired human immune deficiency virus (HIV) infection on antiretroviral regimen, which included abacavir plus lamivudine (Epzicom), didanosine, ritonavir and atazanavir presented with bilateral axillary striae, increased appetite, fatigue, facial swelling and acute weight gain. Two months prior to presentation, the patient had received a diagnostic and therapeutic intra-articular triamcinolone injection in the knee for pain relief and subsequently became progressively swollen in the face, developed striae bilaterally at the axillae, experienced increased appetite, fatigue and an 8 pound weight gain. During the endocrine workup, suspicion for adrenal insufficiency prompted 24-h urine collection for free cortisol, which was found to be undetectable (below LLQ of 1.0 µg/L). This prompted further evaluation of the hypothalamic-pituitary axis (HPA) by standard dose adrenocorticotropic hormone (ACTH) stimulation test. A 250 µg cosyntropin stimulation test was performed and confirmed HPA axis suppression. Baseline cortisol level was <1 µg/dL and stimulated cortisol level at 30 min was 3.8 µg/dL. The patient was diagnosed with iatrogenic Cushing syndrome and suppression of HPA axis secondary to the drug interaction between ritonavir (RTV) and intra-articular triamcinolone injection. Following endocrine evaluation and workup, the patient was admitted for planned orthopaedic procedure including elective left hamstring lengthening, distal femoral osteotomy and patellar tendon advancement. Taking into consideration the diagnosis of iatrogenic Cushing syndrome, at the start of the surgical procedure, 100 mg IV stress dose of hydrocortisone followed by 50 mg hydrocortisone every 8 h for 24 h was administered. Stress dosing was discontinued 24 h after the procedure. Throughout the hospitalization and upon discharge, the patient continued his ART. From initial presentation, patient has remained clinically stable throughout surgery and postoperative period. LEARNING POINTS: Drug-drug interaction between ritonavir and triamcinolone can cause Cushing syndrome.Although triamcinolone has a half-life of 3 h, an intra-articular injection may be systematically absorbed for 3 weeks after injection, and adrenal suppression may last as long as 30 days.Co-administration of ritonavir and corticosteroids may result in an increase of plasma levels of corticosteroids levels, as they are both eliminated by CYP3A metabolism, and this interaction has the potential to prolong the half-life of triamcinolone several fold.No specific guidelines are available for the management of iatrogenic Cushing syndrome secondary to ritonavir and corticosteroids.One treatment option includes replacing ritonavir with a non-protease inhibitor-based regimen.Initiating hydrocortisone replacement therapy to prevent an adrenal crisis is also an alternate option.