Hepatic abscess caused by trans-gastric migration of a fishbone

Background Stomach or duodenal perforation due to foreign body are usually associated with the development of a walled-off abdominal mass or abscess, and are less prone to cause systemic signs of infection. Methods and Case presentation A 65-year-old man with no comorbidities was admitted for rapid onset of abdominal discomfort, fever, and chills. An abdominal computed tomography (CT) showed an 8 cm abscess in the left lobe of the liver. The lesion was aspirated under ultrasound guidance; cultures from the abscess grew Streptococcus constellatus. Chest CT scan, colonoscopy, esophagogastroduodenoscopy, and blood cultures were negative. The patient’s clinical status rapidly improved with antibiotic therapy, but a follow-up CT scan revealed the presence of a thin, 3 cm-long radiopaque object at the site of the previous abscess. A few months later, due to symptomatic cholelithiasis, the patient underwent elective laparoscopic cholecystectomy and concurrent removal of a 3 cm-long fishbone, which was embedded into the wall of the gastric antrum and the third segment of the liver, the latter which was partially resected. Results The small gastrotomy was reapproximated with a single resorbable stitch. The post-operative course was uneventful and at 6 month follow up, the patient was asymptomatic without evidence of residual abdominal pathology. Conclusions Asymptomatic perforation of the gastric wall by an ingested foreign body can occur and be subsequently complicated by a liver abscess. A contained perforation can be successfully managed conservatively

Synthesis and pharmacological evaluation of indole derivatives as deaza analogues of potent human neutrophil elastase inhibitors

A number of N-benzoylindoles were designed and synthesized as deaza analogues of our previously reported potent and selective HNE inhibitors with an indazole scaffold. The new compounds containing substituents and functions that were most active in the previous series were active in the micromolar range (the most potent had IC(50)=3.8 µM) or inactive. These results demonstrated the importance of N-2 in the indazole nucleus. Docking studies performed on several compounds containing the same substituents but with an indole or an indazole scaffold, respectively, highlight interesting aspects concerning the molecule orientation and H-bonding interactions, which could help to explain the lower activity of this new series

Synthesis, enantioresolution and activity profile of chiral 6-methyl-2,4-disubstituted pyridazin-3(2H)-ones as potent N-formyl peptide receptor agonists.

A series of chiral pyridazin-3(2H)-ones was synthesized, separated as pure enantiomers, and evaluated for N-formyl peptide receptor (FPR) agonist activity. Characterization of the purified enantiomers using combined chiral HPLC and chiroptical studies (circular dichroism, allowed unambiguous assignment of the absolute configuration for each pair of enantiomers). Evaluation of the ability of racemic mixtures and purified enantiomers to stimulate intracellular Ca(2+) flux in FPR-transfected HL-60 cells and human neutrophils and to induce β-arrestin recruitment in FPR-transfected CHO-K1 cells showed that many enantiomers were potent agonists, inducing responses in the sub-micromolar to nanomolar range. Furthermore, FPRs exhibited enantiomer selectivity, generally preferring the R-(−)-forms over the S-(+)-enantiomers. Finally, we found that elongation of the carbon chain in the chiral center of the active compounds generally increased biological activity. Thus, these studies provide important new information regarding molecular features involved in FPR ligand preference and report the identification of a novel series of FPR agonists

Synthesis of five and six-membered N-phenylacetamido substituted heterocycles as formyl peptide receptor agonists

Formyl peptide receptors (FPRs) are G-protein-coupled receptors that play an important role in the regulation of inflammatory process and cellular dysfunction. In humans, three different isoforms are expressed (FPR1, FPR2 and FPR3). FPR2 appears to be directly involved in the resolution of inflammation (ROI), an active process carried out by specific pro-resolving mediators that modulate specific receptors. Previously, we identified 2-arylacetamido pyridazin-3(2H)-ones as FPR1- or FPR2-selective agonists, as well as a large number of mixed-agonists for the three isoforms. Here, we report a new series of 2-arylacetamido pyridazinones substituted at position 5 and their development as FPR agonists. We also synthesized a new series of 2-oxothiazolones bearing a 4-bromophenylacetamido fragment, which was fundamental for activity in the pyridazinone series. The compounds of most interest were 4a, a potent, mixed FPR agonist recognized by all three isotypes (FPR1 EC(50) = 19 nM, FPR2 EC(50) = 43 nM, FPR3 EC(50) = 40 nM), and 4b, which had potent activity and a preference for FPR2 (EC(50) = 13 nM). These novel compounds may represent valuable tools for studying FPR activation and signaling

Further studies on 2-arylacetamide pyridazin-3(2H)-ones: design, synthesis and evaluation of 4,6-disubstituted analogs as formyl peptide receptors (FPRs) agonists.

AbstractFormyl peptide receptors (FPRs) play an essential role in the regulation of endogenous inflammation and immunity. In the present studies, a large series of pyridazin-3(2H)-one derivatives bearing an arylacetamide chain at position 2 was synthesized and tested for FPR agonist activity. The pyridazin-3(2H)-one ring was confirmed to be an appropriate scaffold to support FPR agonist activity, and its modification at the 4 and 6 positions led to the identification of additional active agonists, which induced intracellular Ca2+ flux in HL-60 cells transfected with either FPR1, FPR2, or FPR3. Seven formyl peptide receptor 1 (FPR1)-specific and several mixed FPR1/FPR2 dual agonists were identified with low micromolar EC50 values. Furthermore, these agonists also activated human neutrophils, inducing intracellular Ca2+ flux and chemotaxis. Finally, molecular docking studies indicated that the most potent pyridazin-3(2H)-ones overlapped in their best docking poses with fMLF and WKYMVM peptides in the FPR1 and FPR2 ligand binding sites, respectively. Thus, pyridazinone-based compounds represent potential lead compounds for further development of selective and/or potent FPR agonists

Multiple primary tumours: incidence estimation in the presence of competing risks

<p>Abstract</p> <p>Background</p> <p>Estimating the risk of developing subsequent primary tumours in a population is difficult since the occurrence probability is conditioned to the survival probability.</p> <p>Methods</p> <p>We proposed to apply Markov models studying the transition intensities from first to second tumour with the Aalen-Johansen (AJ) estimators, as usually done in competing risk models. In a simulation study we applied the proposed method in different settings with constant or varying underlying intensities and applying age standardisation. In addition, we illustrated the method with data on breast cancer from the Piedmont Cancer Registry.</p> <p>Results</p> <p>The simulation study showed that the person-years approach led to a sensibly wider bias than the AJ estimators. The largest bias was observed assuming constantly increasing incidence rates. However, this situation is rather uncommon dealing with subsequent tumours incidence. In 9233 cases with breast cancer occurred in women resident in Turin, Italy, between 1985 and 1998 we observed a significant increased risk of 1.91 for subsequent cancer of corpus uteri, estimated with the age-standardised Aalen-Johansen incidence ratio (AJ-IR^stand), and a significant increased risk of 1.29 for cancer possibly related to the radiotherapy of breast cancer. The peak of occurrence of those cancers was observed after 8 years of follow-up.</p> <p>Conclusion</p> <p>The increased risk of a cancer of the corpus uteri, also observed in other studies, is usually interpreted as the common shared risk factors such as low parity, early menarche and late onset of menopause. We also grouped together those cancers possibly associated to a previous local radiotherapy: the cumulative risk at 14 years is still not significant, however the AJ estimators showed a significant risk peak between the eighth and the ninth year. Finally, the proposed approach has been shown to be reliable and informative under several aspects. It allowed for a correct estimation of the risk, and for investigating the time trend of the subsequent cancer occurrence.</p

Neuropsychiatric Disease Classification Using Functional Connectomics - Results of the Connectomics in NeuroImaging Transfer Learning Challenge

Large, open-source datasets, such as the Human Connectome Project and the Autism Brain Imaging Data Exchange, have spurred the development of new and increasingly powerful machine learning approaches for brain connectomics. However, one key question remains: are we capturing biologically relevant and generalizable information about the brain, or are we simply overfitting to the data? To answer this, we organized a scientific challenge, the Connectomics in NeuroImaging Transfer Learning Challenge (CNI-TLC), held in conjunction with MICCAI 2019. CNI-TLC included two classification tasks: (1) diagnosis of Attention-Deficit/Hyperactivity Disorder (ADHD) within a pre-adolescent cohort; and (2) transference of the ADHD model to a related cohort of Autism Spectrum Disorder (ASD) patients with an ADHD comorbidity. In total, 240 resting-state fMRI (rsfMRI) time series averaged according to three standard parcellation atlases, along with clinical diagnosis, were released for training and validation (120 neurotypical controls and 120 ADHD). We also provided Challenge participants with demographic information of age, sex, IQ, and handedness. The second set of 100 subjects (50 neurotypical controls, 25 ADHD, and 25 ASD with ADHD comorbidity) was used for testing. Classification methodologies were submitted in a standardized format as containerized Docker images through ChRIS, an open-source image analysis platform. Utilizing an inclusive approach, we ranked the methods based on 16 metrics: accuracy, area under the curve, F1-score, false discovery rate, false negative rate, false omission rate, false positive rate, geometric mean, informedness, markedness, Matthew’s correlation coefficient, negative predictive value, optimized precision, precision, sensitivity, and specificity. The final rank was calculated using the rank product for each participant across all measures. Furthermore, we assessed the calibration curves of each methodology. Five participants submitted their method for evaluation, with one outperforming all other methods in both ADHD and ASD classification. However, further improvements are still needed to reach the clinical translation of functional connectomics. We have kept the CNI-TLC open as a publicly available resource for developing and validating new classification methodologies in the field of connectomics

Frequency of complementary and alternative medicine utilization in hypertensive patients attending an urban tertiary care centre in Nigeria

<p>Abstract</p> <p>Background</p> <p>To study the frequency and pattern of use of complementary and alternative medicine (CAM) in patients with essential hypertension attending a tertiary hypertension clinic.</p> <p>Methods</p> <p>Two hundred and twenty-five consecutive hypertensive patients attending the hypertension clinic of the Lagos University Teaching Hospital over a 3-month period were interviewed. Socio-demographic data, duration of hypertension, clinic attendance, current blood pressure, and compliance to conventional medications was documented. CAM utilization was explored using both structured and open-ended questions.</p> <p>Results</p> <p>There were 90 (40%) male and 135 (60%) female patients with mean age ± SD overall was 55.1 ± 12.4 years. 88 (39.1%) of the respondents used CAM. Herbal products were the most commonly used CAM type. Amongst the CAM users, the most common herbal product used was garlic (69.3%). Others were native herbs (25%), ginger (23.9%), bitter leaf (<it>Vernonia amygdalina</it>) (9.1%), and aloe vera (4.5%). 2.5% used spiritual therapy. There was no difference in the clinical characteristics, socio-economic status, and blood pressure control of CAM users and non-users. Patients who utilized CAM had higher BMI compared with those who did not, but the difference was not statistically significant (mean BMI ± SD of 29.1 ± 5.6 vs 27.1 ± 5.9 kg/m²; P = 0.05).</p> <p>Conclusion</p> <p>A significant proportion of hypertensive patients attending our tertiary facility and receiving conventional treatment also use CAM therapies. Clinicians need to be aware of this practice, understand the rationale for this health-seeking behaviour, proactively enquire about their use, and counsel patients regarding the potential of some of the therapies for adverse reactions and drug interactions.</p