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.

Alcohol Induces Sensitization to Gluten in Genetically Susceptible Individuals: A Case Control Study

Background: The mechanisms of cerebellar degeneration attributed to prolonged and excessive alcohol intake remain unclear. Additional or even alternative causes of cerebellar degeneration are often overlooked in suspected cases of alcohol-related ataxia. The objectives of this study were two fold: (1) to investigate the prevalence of gluten-related serological markers in patients with alcohol-related ataxia and; (2) to compare the pattern of brain involvement on magnetic resonance imaging between patients with alcohol and gluten ataxias. Materials & Methods: Patients diagnosed with alcohol and gluten ataxias were identified from a retrospective review of patients attending a tertiary clinic. HLA genotype and serological markers of gluten-related disorders were recorded. Cerebellar volumetry, MR spectroscopy and voxel-based morphometric analyses were performed on patients and compared with matched control data. Results: Of 904 registered patients, 104 had alcohol ataxia and 159 had gluten ataxia. 61% of the alcohol ataxia group and 70% of the gluten ataxia group had HLA DQ2/DQ8 genotype compared to 30% in healthy local blood donors. 44% of patients with alcohol ataxia had antigliadin antibodies compared to 12% in the healthy local population and 10% in patients with genetically confirmed ataxias. None of the patients with alcohol ataxia and antigliadin antibodies had celiac disease compared to 40% in patients with gluten ataxia. The pattern of structural brain abnormality in patients with alcohol ataxia who had antigliadin antibodies differed from gluten ataxia and was identical to that of alcohol ataxia. Conclusions: Alcohol related cerebellar degeneration may, in genetically susceptible individuals, induce sensitization to gluten. Such sensitization may result from a primary cerebellar insult, but a more systemic effect is also possible. The duration and amount of exposure to alcohol may not be the only factors responsible for the cerebellar insult

Global overview of the management of acute cholecystitis during the COVID-19 pandemic (CHOLECOVID study)

Background: This study provides a global overview of the management of patients with acute cholecystitis during the initial phase of the COVID-19 pandemic. Methods: CHOLECOVID is an international, multicentre, observational comparative study of patients admitted to hospital with acute cholecystitis during the COVID-19 pandemic. Data on management were collected for a 2-month study interval coincident with the WHO declaration of the SARS-CoV-2 pandemic and compared with an equivalent pre-pandemic time interval. Mediation analysis examined the influence of SARS-COV-2 infection on 30-day mortality. Results: This study collected data on 9783 patients with acute cholecystitis admitted to 247 hospitals across the world. The pandemic was associated with reduced availability of surgical workforce and operating facilities globally, a significant shift to worse severity of disease, and increased use of conservative management. There was a reduction (both absolute and proportionate) in the number of patients undergoing cholecystectomy from 3095 patients (56.2 per cent) pre-pandemic to 1998 patients (46.2 per cent) during the pandemic but there was no difference in 30-day all-cause mortality after cholecystectomy comparing the pre-pandemic interval with the pandemic (13 patients (0.4 per cent) pre-pandemic to 13 patients (0.6 per cent) pandemic; P = 0.355). In mediation analysis, an admission with acute cholecystitis during the pandemic was associated with a non-significant increased risk of death (OR 1.29, 95 per cent c.i. 0.93 to 1.79, P = 0.121). Conclusion: CHOLECOVID provides a unique overview of the treatment of patients with cholecystitis across the globe during the first months of the SARS-CoV-2 pandemic. The study highlights the need for system resilience in retention of elective surgical activity. Cholecystectomy was associated with a low risk of mortality and deferral of treatment results in an increase in avoidable morbidity that represents the non-COVID cost of this pandemic

Global overview of the management of acute cholecystitis during the COVID-19 pandemic (CHOLECOVID study)

Background: This study provides a global overview of the management of patients with acute cholecystitis during the initial phase of the COVID-19 pandemic. Methods: CHOLECOVID is an international, multicentre, observational comparative study of patients admitted to hospital with acute cholecystitis during the COVID-19 pandemic. Data on management were collected for a 2-month study interval coincident with the WHO declaration of the SARS-CoV-2 pandemic and compared with an equivalent pre-pandemic time interval. Mediation analysis examined the influence of SARS-COV-2 infection on 30-day mortality. Results: This study collected data on 9783 patients with acute cholecystitis admitted to 247 hospitals across the world. The pandemic was associated with reduced availability of surgical workforce and operating facilities globally, a significant shift to worse severity of disease, and increased use of conservative management. There was a reduction (both absolute and proportionate) in the number of patients undergoing cholecystectomy from 3095 patients (56.2 per cent) pre-pandemic to 1998 patients (46.2 per cent) during the pandemic but there was no difference in 30-day all-cause mortality after cholecystectomy comparing the pre-pandemic interval with the pandemic (13 patients (0.4 per cent) pre-pandemic to 13 patients (0.6 per cent) pandemic; P = 0.355). In mediation analysis, an admission with acute cholecystitis during the pandemic was associated with a non-significant increased risk of death (OR 1.29, 95 per cent c.i. 0.93 to 1.79, P = 0.121). Conclusion: CHOLECOVID provides a unique overview of the treatment of patients with cholecystitis across the globe during the first months of the SARS-CoV-2 pandemic. The study highlights the need for system resilience in retention of elective surgical activity. Cholecystectomy was associated with a low risk of mortality and deferral of treatment results in an increase in avoidable morbidity that represents the non-COVID cost of this pandemic