Effects of Antirheumatic Drugs on the Development of Experimental AA Amyloidosis in C57BL/6 Mice

Because there is no known specific effective therapy for secondary amyloidosis at the present time, the aim  of this study was to determine whether antirheumatic drugs inhibit the development of experimental AA  amyloidosis, induced in a C57BL/6 mice by injections of casein and fibrin. Monotherapy with sulfasalazine  (SSL) and diclofenac (D) and combined treatment with diclofenac and prednisolone (D/P) by using  prophylactic and therapeutic treatment protocols were investigated. The drugs were administered through  intragastric gavage 5 times a week for 5 or 6 weeks in the following doses: D - 1 mg/kg, P - 10 mg/kg,  and SSL - 100 mg/kg. Histopathological examination of splenic, kidney and hepatic tissues of mice was  performed. The amount of amyloid was assessed semi-quantitatively by polarizing microscopy after Congo Red staining. Our study indicated that no positive effect from prophylactic treatment with D could be seen on amyloid  deposition in investigated organs. Prophylactic combined treatment with D/P resulted in significant improvement  of disease symptoms and markedly reduced amyloid deposits in the spleen, kidneys, and liver (P  < 0.02-0.001). SSL therapy alone has been more successful in the prophylactic treatment of experimental  amyloidosis: the decrease of amyloid deposits was statistically significant in all investigated organs (P <  0.04 – 0.001) and the most suppression of amyloid formation in the kidneys and liver was observed (P <  0.004-0.001). In therapeutic treatment of experimental amyloidosis, combined treatment with D/P showed  the most inhibition of amyloid formation in the internal organs (P < 0.006 – 0.001). The highest suppression  (by 86.7%; P < 0.001) of amyloid deposits was observed in the liver. Treatment of mice with D alone  produced a significant reduction in amyloid deposition only in the liver (P < 0.03) and with SSL – only in  the spleen (P < 0.03). These findings suggest that D/P and SSL at relevant doses suppress amyloidogenesis and this suppression is  possibly related to the anti-inflammatory effect of antirheumatic drugs. Although these drugs cannot completely  inhibit the disease in this model, a possibility remains that they may be clinically useful in rheumatic  diseases associated with the formation of amyloidogenic derivatives.

Influence of Dextran Sulphate, Fibrin, and Ubiquitin on the Development of Casein-Induced Experimental AA Amyloidosis in C57BL/6 mice

The influence of subcutaneous injections of dextran sulphate (DS) and fibrin (F), as well as of an intraperitoneal  injection of ubiquitin (Ub), was investigated on 48 male C57BL/6 mice subjected to conventional  casein (C) induced amyloidosis. Histopathological examination of spleen and kidney tissue 3 and 5 weeks  after termination of the amyloidogenic stimulus showed that the amount of amyloid deposited (rated trace,  minimal, moderate or heavy) increased progressively with the duration of the amyloidogenic stimulus.  After 3 weeks of stimulation, 16.7% of mice injected with C had some perifollicular amyloid deposits in  the spleen while all had traces of amyloid in the kidney. Some amyloid was detected in the spleen of 33.3%  of the mice treated with C+DS and C+Ub and 83.3% treated with C+F. Half the latter group also showed  traces and half minimal amyloid deposits in their kidneys. In the other test groups, the incidence of kidney  amyloidosis was less. The most extensive tissue deposits were seen at 5 weeks postinjection (p.i.) with most in the C+F-treated  animals, all showing significantly more than the control C-treated group. Thus half the C+F-treated animals  had moderate and half heavy deposits throughout their spleens. Glomerulonephritis, kidney tubular  edema and some amyloid deposits were present in all of the animals. C+Ub resulted in a similar incidence  of amyloid accumulation in the spleen but in the kidneys 66.7% of animals had only traces of amyloid and  33.3%, minimal amyloid deposits. Amyloid was deposited in the mouse kidneys predominantly in the arterial  walls but also occurred in the basement membrane and interstitial tissues. A post-mortem examination  of the internal organs revealed splenomegaly in all the test groups and increased liver weight in the C-,  C+F-, and C+Ub-treated groups. The leukocyte count and ESR (erythrocyte sedimentation rate) were also  higher in all the experimental groups. Thus, the results indicated that F and Ub play a role in the amyloid deposition process in the experimentally  induced disorder in C57BL/6 mice and could enhance this pathological process.

Transvaginal ultrasound - noninvasive method for the prediction of response to concurrent chemoradiotherapy in cases of cervical cancer

The objective of this paper is to study the differences in tumor size, color score and Doppler indices prior, during and after the treatment with concurrent chemoradiotherapy in cases of locally advanced cervical carcinoma and to predict the response to the treatment. The study group comprised fifty-two patients with histologically confirmed invasive carcinoma of the cervix. All patients were scheduled for concurrent chemoradiotherapy and were assessed by transvaginal ultrasound before the initiation, before 4th course of chemotherapy and 3 months after the therapy. Maximum cervical tumor length, anterior-posterior diameter and width have been measured and tumor volume was calculated. Complete clinical response (CR) was defined when no residual tumor was found. Partial clinical response (PR) was determined when the tumor volume had decreased more than 50 %. Intratumoral blood flow was subjectively evaluated by Color Doppler examination, the lowest resistance index (RI) and the highest peak systolic velocity (PSV) were used for the analysis. The results of this study demonstrate that transvaginal ultrasound is a valuable non-invasive diagnostic tool for the assessment of the response to concurrent chemoradiotherapy in cases of advanced cervical cancer

Management and outcomes of gastrointestinal congenital anomalies in low, middle and high income countries: Protocol for a multicentre, international, prospective cohort study

Introduction Congenital anomalies are the fifth leading cause of death in children <5 years of age globally, contributing an estimated half a million deaths per year. Very limited literature exists from low and middle income countries (LMICs) where most of these deaths occur. The Global PaedSurg Research Collaboration aims to undertake the first multicentre, international, prospective cohort study of a selection of common congenital anomalies comparing management and outcomes between low, middle and high income countries (HICs) globally. Methods and analysis The Global PaedSurg Research Collaboration consists of surgeons, paediatricians, anaesthetists and allied healthcare professionals involved in the surgical care of children globally. Collaborators will prospectively collect observational data on consecutive patients presenting for the first time, with one of seven common congenital anomalies (oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation and Hirschsprung''s disease). Patient recruitment will be for a minimum of 1 month from October 2018 to April 2019 with a 30-day post-primary intervention follow-up period. Anonymous data will be collected on patient demographics, clinical status, interventions and outcomes using REDCap. Collaborators will complete a survey regarding the resources and facilities for neonatal and paediatric surgery at their centre. The primary outcome is all-cause in-hospital mortality. Secondary outcomes include the occurrence of postoperative complications. Chi-squared analysis will be used to compare mortality between LMICs and HICs. Multilevel, multivariate logistic regression analysis will be undertaken to identify patient-level and hospital-level factors affecting outcomes with adjustment for confounding factors. Ethics and dissemination At the host centre, this study is classified as an audit not requiring ethical approval. All participating collaborators have gained local approval in accordance with their institutional ethical regulations. Collaborators will be encouraged to present the results locally, nationally and internationally. The results will be submitted for open access publication in a peer reviewed journal

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Background: Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. // Methods: We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. // Findings: We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middle-income countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in low-income countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. // Interpretation: Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between low-income, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Correlation of sonographic characteristics and pathomorphological findings in cases of early-stage cervical cancer: preliminary results.

Objectives: To correlate the sonographic two-dimensional (2D) gray-scale features with pathological findings in early-stage invasive cervical cancer. Methods: Eighteen patients with biopsy-confirmed invasive cervical carcinoma (stages IB1 IIA according to FIGO staging) who underwent surgery were enrolled in the study. Transvaginal 2D gray-scale sonography was performed in all of them at the Hospital of Kaunas University of Medicine prior to hysterectomy. The largest diameters of tumor mass, tumor shape, tumor area, as well as the deepest cervical stromal invasion and the largest thickness of tumorfree cervical stroma in sagittal and axial planes were correlated with their pathomorphological equivalents using Pearson correlation coefficients. Toshiba NICE and Canvas X Scientific Edition software packages were employed for the analysis and correlation of sonographic and pathomorphological images. The interobserver variability was evaluated by having two blinded sonologists interpret each examination and calculating kappa statistics. The intraobserver variability was assayed in nine patients at 24-h intervals. Results: At 2D gray-scale analysis 15 patients (83%) showed detectable tumor masses. The largest diameters of the tumor mass (maximum length, depth and width) measured at sonographic and pathomorphological examinations correlated well (R = 0.87, R = 0.89 and R = 0.76, respectively). The largest tumor area measured in both sagittal and axial planes also showed a strong correlation (R = 0.78 and R = 0.84, respectively). Poor correlation was seen in the deepest cervical stromal invasion (R = 0.14). A discrepancy of more than 10% of the tumor shape in the sagittal plane seen during sonography and pathomorphological examination occurred in seven cases (47%). Conclusions: Two-dimensional gray-scale sonography is accurate in the assessment of early-stage cervical cancer. This method should be considered in all patients with early-stage cervical cancer scheduled for radical treatment

Early-stage cervical cancer: agreement between ultrasound and histopathological findings with regard to tumor size and extent of local disease

Objectives To determine the agreement between ultrasound and histological examination of the cervix in patients with early stage cervical cancer with regard to tumor size and local extent of the disease. Methods Eighteen patients with histologically proven cervical cancer Stage IB1-IIA according to traditional clinical staging (FIGO 1988) who were scheduled for radical surgery underwent a standardized transvaginal ultrasound examination. The maximum tumor length, anteroposterior tumor diameter, tumor width, tumor area, depth of cervical stroma invasion, and the minimal thickness of tumor-free cervical stroma on sagittal and transverse planes through the cervix were measured, and the local extent of the disease within the parametria and vagina were evaluated. The surgical specimens were examined using a specifically devised method of histopathological examination. The results of the ultrasound and histopathological examinations were compared. Results Limits of agreement were wide and the intra-class correlation coefficient (ICC) was low (0.51-0.58) for three of the four measurements taken to represent the minimal depth of tumor-free cervical stroma, i.e. the results of the measurements taken posteriorly and laterally. However, the limits of agreement were narrower and the ICC values were higher (0.74-0.92) for the depth of cervical stroma invasion and for the tumor size measurements. Histological examination revealed parametrial cancer infiltration in four patients, which was detected during ultrasound examination, with no false-positive results. Conclusions Transvaginal sonography is acceptably accurate for evaluation of tumor size and depth of cervical stroma invasion in clinical practice. Copyright (C) 2011 ISUOG. Published by John Wiley & Sons, Ltd