RESUMO
Bowel movement frequency (BMF) has been linked to changes in the composition of the human gut microbiome and to many chronic conditions, like metabolic disorders, neurodegenerative diseases, chronic kidney disease (CKD), and other intestinal pathologies like irritable bowel syndrome and inflammatory bowel disease. Lower BMF (constipation) can lead to compromised intestinal barrier integrity and a switch from saccharolytic to proteolytic fermentation within the microbiota, giving rise to microbially-derived toxins that may make their way into circulation and cause damage to organ systems. However, the connections between BMF, gut microbial metabolism, and the early-stage development and progression of chronic disease remain underexplored. Here, we examined the phenotypic impact of BMF variation in a cohort of generally-healthy, community dwelling adults with detailed clinical, lifestyle, and multi-omic data. We showed significant differences in microbially-derived blood plasma metabolites, gut bacterial genera, clinical chemistries, and lifestyle factors across BMF groups that have been linked to inflammation, cardiometabolic health, liver function, and CKD severity and progression. We found that the higher plasma levels of 3-indoxyl sulfate (3-IS), a microbially-derived metabolite associated with constipation, was in turn negatively associated with estimated glomerular filtration rate (eGFR), a measure of kidney function. Causal mediation analysis revealed that the effect of BMF on eGFR was significantly mediated by 3-IS. Finally, we identify self-reported diet, lifestyle, and psychological factors associated with BMF variation, which indicate several common-sense strategies for mitigating constipation and diarrhea. Overall, we suggest that aberrant BMF is an underappreciated risk factor in the development of chronic diseases, even in otherwise healthy populations.
RESUMO
Bowel movement frequency (BMF) directly impacts the gut microbiota and is linked to diseases like chronic kidney disease or dementia. In particular, prior work has shown that constipation is associated with an ecosystem-wide switch from fiber fermentation and short-chain fatty acid production to more detrimental protein fermentation and toxin production. Here, we analyze multi-omic data from generally healthy adults to see how BMF affects their molecular phenotypes, in a pre-disease context. Results show differential abundances of gut microbial genera, blood metabolites, and variation in lifestyle factors across BMF categories. These differences relate to inflammation, heart health, liver function, and kidney function. Causal mediation analysis indicates that the association between lower BMF and reduced kidney function is partially mediated by the microbially derived toxin 3-indoxyl sulfate (3-IS). This result, in a generally healthy context, suggests that the accumulation of microbiota-derived toxins associated with abnormal BMF precede organ damage and may be drivers of chronic, aging-related diseases.
Assuntos
Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/fisiologia , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Indicã/sangue , Motilidade Gastrointestinal/fisiologia , Constipação Intestinal/sangue , Constipação Intestinal/microbiologia , IdosoRESUMO
OBJECTIVES: Pediatric inpatients with inflammatory bowel disease (IBD) are rarely considered for thromboprophylaxis because of concerns about safety and underappreciation of thrombotic risk. We characterized thromboembolism (TE) in children and young adults with inflammatory bowel disease (IBD) at a single tertiary care hospital. METHODS: We performed a retrospective review of an inpatient billing database for all IBD admissions with colonic involvement and an anticoagulation database for thrombotic complications from 2006 to 2011. RESULTS: Of 532 patients admitted with IBD with colonic involvement, 10 (1.9%) had TE (9 venous, 1 arterial), 2 of whom had recurrent thrombosis. Many of the events resulted in considerable morbidity, including 4 cerebrovascular events and 2 pulmonary emboli. Established risk factors in IBD colitis inpatients with TE included: indwelling catheter (4/10), first-degree family member with TE (2/10), hereditary thrombophilia (3/10), smoking (1/10), oral contraceptive (1/5 females), and thalidomide (1/10). Additionally, most (8/10) patients had acquired thrombophilia, mostly elevation of factor VIII and anticardiolipin antibodies. Patients with IBD and TE received therapeutic anticoagulation without significantly increased bleeding. Thrombus resolution was documented in 7 cases, persistence in 2 cases and recurrence in 2 cases. CONCLUSIONS: Pediatric inpatients hospitalized with IBD with colonic involvement have increased risk of TE, including complications of pulmonary embolism, recurrence, persistence, and indefinite long-term anticoagulation. Therapeutic anticoagulation in patients with IBD with active colitis appears safe. We identified both inherited thrombophilias and acquired risk factors in patients with IBD and TE. We presently use risk stratification and recommend prophylactic anticoagulation in high-risk patients.
Assuntos
Anticoagulantes/uso terapêutico , Colite/complicações , Doenças Inflamatórias Intestinais/complicações , Embolia Pulmonar/etiologia , Tromboembolia/etiologia , Trombose/etiologia , Adolescente , Adulto , Anticorpos Anticardiolipina/sangue , Cateterismo/efeitos adversos , Cateteres de Demora/efeitos adversos , Criança , Colo/patologia , Anticoncepcionais Orais/efeitos adversos , Fator VIII/metabolismo , Feminino , Predisposição Genética para Doença , Hemorragia/etiologia , Humanos , Incidência , Masculino , Embolia Pulmonar/tratamento farmacológico , Embolia Pulmonar/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Fumar/efeitos adversos , Talidomida/efeitos adversos , Tromboembolia/tratamento farmacológico , Tromboembolia/epidemiologia , Trombofilia/complicações , Trombose/tratamento farmacológico , Trombose/epidemiologia , Adulto JovemRESUMO
Inflammatory bowel disease (IBD) is treated with a variety of immunomodulating and immunosuppressive therapies; however, for the majority of cases, these therapies are not targeted for specific disease phenotypes. Monogenic IBD with causative genetic defect is the exception and represents a disease cohort where precision therapeutics can be applied. With the advent of rapid genetic sequencing platforms, these monogenic immunodeficiencies that cause inflammatory bowel disease are increasingly being identified. This subpopulation of IBD called very early onset inflammatory bowel disease (VEO-IBD) is defined by an age of onset of less than six years of age. Twenty percent of VEO-IBDs have an identifiable monogenic defect. The culprit genes are often involved in pro-inflammatory immune pathways, which represent potential avenues for targeted pharmacologic treatments. This review will provide an overview of the current state of disease-specific targeted therapies, as well as empiric treatment for undifferentiated causes of VEO-IBD.
RESUMO
A 17-month-old female had an unwitnessed ingestion of 26 high-powered magnets, resulting in the creation of an esophagogastric fistula via the left crus of the diaphragm. This case highlights a rare injury to the stomach and esophagus caused by high-powered magnets requiring surgical intervention. Furthermore, this case report illustrates the risks that high-powered magnets pose to young children. Additionally, this case highlights the importance of maintaining a high level of suspicion for ingestion in young patients along with a multidisciplinary team to manage sequelae of injury.
RESUMO
BACKGROUND: Breast reconstruction rates continue to slowly rise in large part because of patients and physicians becoming more knowledgeable about postmastectomy options. Overall satisfaction with breast reconstruction after mastectomy has traditionally been high, only adding to the popularity of this choice. Prior research has demonstrated that race, age, and socioeconomic status are important determinants in whether a patient undergoes breast reconstruction; specifically, indigent women have a lower rate of breast reconstruction when compared to the national average. METHODS: All records of patients who received mastectomies between January 2001 and December 2009 were examined. The PubMed database was used to search for reference articles. RESULTS: Between January 2001 and December 2009, 309 patients underwent mastectomy, and 134 (43.4%) elected reconstruction. Patients in age ranges 20 to 39 and 40 to 59 were both significantly more likely to undergo reconstruction than patients older than 60 years. Disease stage was not significantly related to rates of breast reconstruction. Reconstruction rates by race and ethnicity were analyzed and demonstrated a significantly lower rate of breast reconstruction in Asian women (34%) compared with Hispanic women (48%), despite the same access to available services. CONCLUSIONS: Our data demonstrate breast reconstruction rates significantly higher than prior studies for women in this public hospital demographic, rivaling the reported numbers from dedicated cancer centers where breast reconstruction is expected to be at the highest range. Types of reconstruction were based mainly on patient choice after full discussion regarding individual options. These data suggest that patients considered to be financially indigent are more likely to have breast reconstruction when their care is delivered at a university-based public hospital where immediate and consistent patient education is practiced in a multidisciplinary setting.
Assuntos
Neoplasias da Mama/cirurgia , Mamoplastia/estatística & dados numéricos , Mastectomia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Adulto , Idoso , Feminino , Hospitais Públicos , Hospitais Universitários , Humanos , Mamoplastia/economia , Mamoplastia/métodos , Indigência Médica , Pessoas sem Cobertura de Seguro de Saúde , Pessoa de Meia-Idade , Cidade de Nova Iorque , Aceitação pelo Paciente de Cuidados de Saúde/etnologia , Estudos Retrospectivos , Fatores SocioeconômicosRESUMO
Very early onset inflammatory bowel disease (VEO-IBD) is diagnosed in children < 6 years of age, and in rare cases may be due to an identifiable monogenic cause. Recent advances in genetic testing have allowed for more accurate diagnosis, with as many as 100 genes now known to be associated with monogenic inflammatory bowel disease. These genes are involved in many immune pathways and thus may represent potential avenues for targeted precision medicine with pharmacologic treatments aimed at these. This review describes the broad classifications of monogenic disorders known to cause VEO-IBD, as well as empiric and disease-specific medical therapies. These include immune-modulating or immunosuppressant medications, nutritional therapy, surgery, and hematopoietic stem cell transplantation. We aim to provide an overview of the current state of targeted therapy for VEO-IBD.
Assuntos
Doenças Inflamatórias Intestinais , Idade de Início , Criança , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , FenótipoRESUMO
Lung cancer is the most common malignancy worldwide and is a focus for developing targeted therapies due to its refractory nature to current treatment. We identified a RNA helicase, DDX3, which is overexpressed in many cancer types including lung cancer and is associated with lower survival in lung cancer patients. We designed a first-in-class small molecule inhibitor, RK-33, which binds to DDX3 and abrogates its activity. Inhibition of DDX3 by RK-33 caused G1 cell cycle arrest, induced apoptosis, and promoted radiation sensitization in DDX3-overexpressing cells. Importantly, RK-33 in combination with radiation induced tumor regression in multiple mouse models of lung cancer. Mechanistically, loss of DDX3 function either by shRNA or by RK-33 impaired Wnt signaling through disruption of the DDX3-ß-catenin axis and inhibited non-homologous end joining-the major DNA repair pathway in mammalian somatic cells. Overall, inhibition of DDX3 by RK-33 promotes tumor regression, thus providing a compelling argument to develop DDX3 inhibitors for lung cancer therapy.