SELECTIVE ENDOSCOPY IN MANAGEMENT OF INGESTED FOREIGN BODIES OF THE UPPER GASTROINTESTINAL TRACT: IS IT SAFE?

During a four-year period, 308 patients presented following ingestion of foreign bodies. Ingestion was accidental in 272 cases (88.3%) and deliberate in the remainder. Symptoms at presentation included dysphagia, odynophagia, nausea and vomiting, chest pain and pharyngeal discomfort. Sixty-eight patients were asymptomatic. A policy of expectant management and selective endoscopy was employed. Following initial assessment 202 patients (65.6%) were discharged without treatment, 30 (9.7%) of whom were later reviewed as outpatients and did not require admission. Forty-nine patients (16%) were admitted for treatment; 27 had oesophagoscopy, five bronchoscopy and two had foreign body extraction with direct laryngoscopy. In nine patients who were endoscoped, no foreign body was identified. Twenty-seven others were referred to the otorhinolaryngology service in another hospital. There were no deaths in the group and morbidity was 1.2%. We conclude that a policy of selective endoscopy is safe and effective in the management of patients following ingestion of foreign bodies.     

Myocardial oxygen consumption in left ventricular hypertrophy and its relation to left ventricular mechanics

Alterations in left ventricular (LV) mechanics have significant effects on myocardial oxygen consumption (MV?O₂₂) as a result of changing LV pressure and dimensions. However, the effects of load alteration on MV?O₂₂ in the setting of LV hypertrophy and LV dysfunction have not been well characterized. Therefore, we examined changes in LV mechanics and MV?O₂₂ in 32 patients with varying degrees of LV hypertrophy and LV dysfunction before and after pharmacologic alteration of load. With phenylephrine or nitroglycerin-induced load alteration, changes in peak systolic meridional stress, mean systolic stress and the area of a stress-dimension loop all correlated modestly with changes in MV?O₂₂ (r = 0.66, 0.62, 0.63, respectively). However, changes in the time integral of LV ejection stress, or shortening load, were significantly correlated with changes in MV?O₂₂ (r = 0.88, p < 0.001). In particular, load reduction results in a beneficial effect on MV?O₂₂. In addition, for a given change in LV systolic pressure, changes in shortening load (38 + 3.7%) were significantly greater than changes in tension-time index (13 ± 1.4%), thus providing a sensitive marker of alteration of mechanical load.We conclude that physiologic alterations in mechanical load in normal persons as well as patients with LV hypertrophy are reflected in significant changes in the time integral of LV ejection stress. These changes in shortening load, mediated by changing LV pressure and dimension, are significantly related to changes in MV?O₂₂.     

A SAMHD1 mutation associated with Aicardi–Goutières syndrome uncouples the ability of SAMHD1 to restrict HIV‐1 from its ability to downmodulate type I interferon in humans

Mutations in the human SAMHD1 gene are known to correlate with the development of the Aicardi–Goutières syndrome (AGS), which is an inflammatory encephalopathy that exhibits neurological dysfunction characterized by increased production of type I interferon (IFN); this evidence has led to the concept that the SAMHD1 protein negatively regulates the type I IFN response. Additionally, the SAMHD1 protein has been shown to prevent efficient HIV‐1 infection of macrophages, dendritic cells, and resting CD4+ T cells. To gain insights on the SAMHD1 molecular determinants that are responsible for the deregulated production of type I IFN, we explored the biochemical, cellular, and antiviral properties of human SAMHD1 mutants known to correlate with the development of AGS. Most of the studied SAMHD1 AGS mutants exhibit defects in the ability to oligomerize, decrease the levels of cellular deoxynucleotide triphosphates in human cells, localize exclusively to the nucleus, and restrict HIV‐1 infection. At least half of the tested variants preserved the ability to be degraded by the lentiviral protein Vpx, and all of them interacted with RNA. Our investigations revealed that the SAMHD1 AGS variant p.G209S preserve all tested biochemical, cellular, and antiviral properties, suggesting that this residue is a determinant for the ability of SAMHD1 to negatively regulate the type I IFN response in human patients with AGS. Overall, our work genetically separated the ability of SAMHD1 to negatively regulate the type I IFN response from its ability to restrict HIV‐1.     

Targeting Gonadotropin-releasing Hormone Receptor Inhibits the Early Step of Ovarian Cancer Metastasis by Modulating Tumor-mesothelial Adhesion

Ovarian cancer has a clear predilection to metastasize to the peritoneum, which represents one of the most important prognostic factors of poor clinical outcome. Gonadotropin-releasing hormone (GnRH) receptor is significantly overexpressed during the malignant progression of human ovarian cancer. Here, using lentiviral-based small interfering RNA (siRNA) technology to downregulate GnRH receptor in metastatic ovarian cancer cells, we show that GnRH receptor is an important mediator of ovarian cancer peritoneal metastasis. GnRH receptor downregulation dramatically attenuated their adhesion to the peritoneal mesothelium. By inhibiting the expression of GnRH receptor, we showed decreased expression of α2β1 and α5β1 integrin and adhesion to specific extracellular matrix (ECM) proteins. This was also associated with a reduction of P-cadherin. Furthermore, adhesion of ovarian cancer cells to different ECMs and the mesothelium were abrogated in response to β1 integrin and P-cadherin reduction, confirming that the effects were β1 integrin- and P-cadherin–specific. Using a mouse model of human ovarian cancer metastasis, we found that the inhibition of GnRH receptor, β1 integrin, and P-cadherin significantly attenuated tumor growth, ascites formation, and the number of metastatic implants. These results define a new role for GnRH receptor in early metastasis and offer the possibility of novel therapeutic targets.