MR Lymphography with a Lymphotropic T1-Type MR Contrast Agent: Gd-DTPA-PGM

A model system of a paramagnetic lymphotropic MR contrast agent (Gd-DTPA labeled polyglucose associated macrocomplex, PGM) for T¹-weighted MR imaging of lymph nodes in rats and rabbits was evaluated. Pharmacokinetic (tissue accumulation) and MR imaging data (optimal dose and timing parameters) were obtained in normal rats (n = 88) after subcutaneous (SC) injection of paramagnetic, radiolabeled [111In]Gd-DTPA-PGM. A rabbit model of lymph node metastases (n = 8) was ultimately used to demonstrate the potential of MR imaging with Gd-DTPA-PGM for nodal tumor detection. Maximum concentrations of Gd-DTPA-PGM were found in popliteal and paraaortic lymph nodes within 24 h after SC administration, and highest lymph node SNR values were obtained by MR imaging at this time point. The optimum imaging dose was 6–12 μmol Gd/kg. Tumor-lymph node contrast increased from 0.0 ± 1.2 precontrast to 19.2 ± 6.5 (spoiled gradient echo sequence, TR 50/TE 7/flip angle 60°) postcontrast and conspicuity of nodal metastases was improved. Gd-DTPA-PGM accumulates in lymph nodes after SC administration and significantly enhances lymph node signal intensity of normal animals but not metastatic lymph nodes.     

The rare coexistence of high titer inhibitor development and gastrointestinal stromal tumor in a patient with severe hemophilia: A case report

Hemophilia is a hereditary disease with impaired blood coagulation due to a genetic deficiency of blood coagulation factors. The development of inhibitors further complicates the course of the disease and management. The case is here reported of a haemophilia patient who presented with coexisting development of high titer inhibitor with Gastrointestinal Stromal Tumor (GIST) diagnosis and was admitted with upper gastrointestinal system bleeding. The patient had no prior history of inhibitor presence. During all procedures including surgery, excellent hemostasis was achieved with rFVIIa treatment and no hemorrhagic complication was observed. To the best of our knowledge, this constitutes the first reported case of GIST associated with inhibitor development in a hemophilia A patient.     

The Akt inhibitor,triciribine, ameliorates chronic hypoxia-induced vascular pruning and TGFβ-induced pulmonary fibrosis

Background and Purpose

Interstitial lung disease accounts for a group of chronic and progressive disorders associated with severe pulmonary vascular remodelling, peripheral vascular rarefaction and fibrosis, thus limiting lung function. We have previously shown that Akt is necessary for myofibroblast differentiation, a critical event in organ fibrosis. However, the contributory role of the Akt-mTOR pathway in interstitial lung disease and the therapeutic benefits of targeting Akt and mTOR remain unclear.

Experimental Approach

We investigated the role of the Akt-mTOR pathway and its downstream molecular mechanisms in chronic hypoxia- and TGFβ-induced pulmonary vascular pruning and fibrosis in mice. We also determined the therapeutic benefits of the Akt inhibitor triciribine and the mTOR inhibitor rapamycin for the treatment of pulmonary fibrosis in mice.

Key Results

Akt1^−/− mice were protected from chronic hypoxia-induced peripheral vascular pruning. In contrast, hyperactivation of Akt1 induced focal fibrosis similar to TGFβ-induced fibrosis. Pharmacological inhibition of Akt, but not the Akt substrate mTOR, inhibited hypoxia- and TGFβ-induced pulmonary vascular rarefaction and fibrosis. Mechanistically, we found that Akt1 modulates pulmonary remodelling via regulation of thrombospondin1 (TSP1) expression. Hypoxic Akt1^−/− mice lungs expressed less TSP1. Moreover, TSP1^−/− mice were resistant to adMyrAkt1-induced pulmonary fibrosis.

Conclusions and Implications

Our study identified Akt1 as a novel target for the treatment of interstitial lung disease and provides preclinical data on the potential benefits of the Akt inhibitor triciribine for the treatment of interstitial lung disease.     

How to Avoid Nontherapeutic Laparotomy in Patients With Multiple Organ Failure of Unknown Origin. The Role of CT Scan Revisited

Diagnosis of intra-abdominal diseases in critically ill patients remains a clinical challenge. Physical examination is unreliable whereas exploratory laparotomy may aggravate patient''s condition and delay further evaluation. Only a few studies have investigated the place of computed tomography (CT) on this hazardous situation. We aimed to evaluate the ability of CT to prevent unnecessary laparotomy during the management of critically ill patients. Charts of all consecutive patients who had undergone an emergency nontherapeutic laparotomy from 1996 to 2013 were retrospectively studied and patient''s demographic, clinical characteristics, and surgical findings were collected. During this period 59 patients had an unnecessary laparotomy. Fifty-one patients had at least one preoperative imaging and 36 had a CT scan. CT scans were interpreted to be normal (n = 12), with minor anomalies (n = 10), or major anomalies (pneumoperitoneum, portal venous gas/pneumatosis intestinalis, thickened gallbladder wall, and small bowel obstruction signs). Surgical exploration was performed through laparotomy (n = 55) or laparoscopy. Overall mortality was 37% with a median survival after surgery of 7 days. In univariate analysis, hospitalization in ICU before surgical exploration was the only factor related to death. In our series CT scans, objectively interpreted, helped avoid unnecessary surgical exploration in 61% of our patients.Key words: Laparotomy, Critical care, Abnormalities, Digestive system, CT scansEarly diagnosis of acute nontraumatic life-threatening intra-abdominal diseases remains a clinical challenge. In critically ill patients, pathologies such as mesenteric ischemia, intestinal perforation, pancreatitis and biliary diseases carry a high mortality rate ranging from 50% to 100%.^1,2 For these patients, physical examination can be unreliable due to deep sedation and absence of acute abdomen symptoms, and use of imaging studies may therefore be necessary to identify intra-abdominal pathologies and prevent delay in diagnosis. Also, imaging studies may help avoiding unnecessary laparotomy which can be associated with a morbidity rate up to 22%.³ Ultrasonography (US) can be performed at the bedside and is a good alternative for the diagnosis of biliary tract disease; however, it is highly operator dependent, made difficult by abdominal distension,⁴ and not effective for bowel perforation or ischemia.⁵ Computed tomography (CT) scans are increasingly used for emergency patients with acute nontraumatic abdominal pain and tenderness, however, misinterpretation or overinterpretation of CT findings are not rare.^6,7 Despite the large use of imaging procedures in the evaluation of intra-abdominal pathologies, few studies have attempted to assess their impact on the management of critically ill patients.^8,9 The aim of this observational work was to evaluate the results of preoperative imaging procedures, especially CT, in a consecutive series of nontraumatic critically ill patients who underwent nontherapeutic surgical abdominal exploration in a French university tertiary care hospital.     

Prediction of permanent pacemaker implantation after transcatheter aortic valve replacement: The role of machine learning

BACKGROUND Atrioventricular block requiring permanent pacemaker(PPM) implantation is an important complication of transcatheter aortic valve replacement(TAVR).Application of machine learning could potentially be used to predict preprocedural risk for PPM.AIM To apply machine learning to be used to predict pre-procedural risk for PPM.METHODS A retrospective study of 1200 patients who underwent TAVR(January 2014-December 2017) was performed. 964 patients without prior PPM were included for a 30-d ...     

Long-Term Clinical Outcomes of Underdosed Direct Oral Anticoagulants in Patients with Atrial Fibrillation and Atrial Flutter

BackgroundAlthough direct oral anticoagulants (DOACs) have been shown to be effective at reducing the risk of stroke in patients with atrial fibrillation/flutter (AF), they are sometimes underdosed off-label to mitigate their associated higher bleeding risk. We sought to evaluate frequency and clinical outcomes of inappropriate underdosing of DOACS in patients with AF.MethodsWe conducted a study of subjects with AF who had a clinical indication for stroke prophylaxis (with a congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischemic attack, vascular disease, age 65 to 47 years, sex category [CHA₂DS₂-VASc] of 2 or greater) and were prescribed 1 of the 4 clinically approved DOACs (apixaban, rivaroxaban, dabigatran, or edoxaban). We compared all-cause mortality, composite of stroke and systemic embolism, composite of myocardial infarction (MI), acute coronary syndromes (ACS), and coronary revascularization, and major bleeding between patients appropriately dosed and inappropriately underdosed.ResultsA total of 8125 patients met inclusion criteria, with a mean follow up of 2.2 ± 2 years. Of those, 1724 patients (21.2%) were inappropriately dosed. After adjusting for baseline variables, there was no difference in all-cause mortality, risk of stroke or systemic embolism, International Society on Thrombosis and Haemostasis (ISTH) major bleeding, or composite of myocardial infarction, acute coronary syndromes, or coronary revascularization between patients appropriately dosed and inappropriately underdosed. In subgroup analysis, only apixaban demonstrated an increased incidence all-cause mortality (hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.03-1.49) with inappropriate underdosing. There was no difference in the remaining clinical outcomes noted on subgroup analysis.ConclusionUnderdosing of DOACs did not minimize risk of bleeding, systemic embolization or all-cause mortality in patients with AF. Inappropriate underdosing with apixaban in particular was associated with increased all-cause mortality.     

Effect of infertility on quality of life of women: a validation study of the Turkish FertiQoL

The fertility quality of life (FertiQoL) measure specifically evaluates the impact of fertility problems in various life areas. The aim of this study was to examine the relationship between FertiQoL and the hospital anxiety and depression scale (HADS) in the Turkish population. All female patients who underwent various fertility treatments in our infertility clinic from May 2011 to May 2014 were approached to participate in the study and 389 completed the questionnaires. Our results showed that the four core scales of the FertiQoL measure had a Cronbach’s α value that was between 0.70 and 0.89. Two scales (anxiety and depression) of HADS both had a Cronbach’s α value of 0.80. These values present a reliable usage of FertiQoL and HADS measures (α?>?0.60). Significant negative correlations were found between the FertiQoL scales and HADS scales, ranging from ?0.27 (between relational scale of FertiQoL and anxiety scale of HADS) to ?0.65 (between mind–body scale of FertiQoL and depression scale of HADS). The results of this study provide supportive data to confirm that the Turkish version of FertiQol can accurately evaluate QoL in women who seek fertility treatment in Turkey.     

Acute renal failure associated with nonfulminant hepatitis A virus infection

Hepatitis A is usually a mild self-limiting infection of the liver. Nonfulminant acute renal failure very rarely complicates type A viral hepatitis. An unusual case, a 32-year-old female with serologically proven acute hepatitis A infection, was complicated by acute renal failure and the patient in this study is the first case associated with Cushing's disease. She recovered, and the laboratory tests returned normal one month after initial hospitalization. Although the mechanism responsible for renal failure in acute hepatitis A virus infection is still uncertain, possible causes are discussed with the review of literature.     

Downregulation of the expression of bone morphogenetic protein 7 in experimental pyelonephritis

Bone morphogenetic protein 7 (BMP 7) is a member of the transforming growth factor (TGF) beta superfamily and is involved in regeneration, repair, and development of specific tissues, for example kidney, gut, lens, and skeleton. BMP 7 has emerged as a renotrophic factor and experimental studies have shown its protective role against fibrotic processes. Tubulointerstitial changes are present in the pyelonephritic kidney which progresses to fibrosis. Renal fibrosis may lead to significant morbidity in the form of hypertension, proteinuria, and loss of renal function. The objective of this study was to investigate BMP 7 expression in experimental acute and chronic pyelonephritis models. Eighteen Wistar rats were injected with 0.1 mL solution containing E. coli ATCC 25922 10¹⁰ cfu mL^–1 into left renal medullae. Six rats were used as a sham group and were given 0.1 mL 0.9% NaCl. Pyelonephritic rats were sacrificed 24 h (group I, n=6), 1 week (group II, n=6), and 6 weeks (group III, n=6) after E. coli injection. Serum creatinine levels were analyzed. Renal tissues were studied histopathologically by use of hematoxylin and eosin and scored for diagnosis of pyelonephritis. BMP 7 expression was studied semiquantitatively by immunohistochemical staining. Acute (group I) and chronic (group II and group III) pyelonephritic histopathological changes were observed in experimental pyelonephritic groups. A gradual decrease in BMP 7 expression was observed in the tubulointerstitial and tubular area of the pyelonephritic kidneys, mildest in the acute pyelonephritic group and most severe in the chronic pyelonephritic 6th week group. A statistically significant difference was observed between tubulointerstitial BMP 7 expression by groups I and III (P=0.017) and by groups III and IV (P=0.000). Tubular BMP 7 expression was statistically significantly different between groups II and IV (P=0.009) and between groups III and IV (P=0.002). The data imply that BMP 7 has a major role in chronic pyelonephritis. Tubulointerstitial and tubular BMP 7 expression also had a significant negative correlation with fibrosis, tubular, atrophy, and vascular changes. Serum creatinine levels of the study group were all normal. We conclude that the decrease in renal BMP 7 expression in experimental chronic pyelonephritis is one of the factors responsible for fibrotic changes in persistent renal damage.