The Relationship between Pathogenesis and Possible Treatments for the MASLD-Cirrhosis Spectrum.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a term that entails a broad spectrum of conditions that vary in severity. Its development is influenced by multiple factors such as environment, microbiome, comorbidities, and genetic factors. MASLD is closely related to metabolic syndrome as it is caused by an alteration in the metabolism of fatty acids due to the accumulation of lipids because of an imbalance between its absorption and elimination in the liver. Its progression to fibrosis is due to a constant flow of fatty acids through the mitochondria and the inability of the liver to slow down this metabolic load, which generates oxidative stress and lipid peroxidation, triggering cell death. The development and progression of MASLD are closely related to unhealthy lifestyle habits, and nutritional epigenetic and genetic mechanisms have also been implicated. Currently, lifestyle modification is the first-line treatment for MASLD and nonalcoholic steatohepatitis; weight loss of ≥10% produces resolution of steatohepatitis and fibrosis regression. In many patients, body weight reduction cannot be achieved; therefore, pharmacological treatment should be offered in particular populations.

Radiographic/MR Imaging Correlation of the Wrist.

In this review article, the authors discuss the imaging features of the most common pathologic conditions of the wrist by putting the emphasis on radiographic and MR imaging correlations. A topographic approach based on the 3 functional columns of the wrist (radial, central, and ulnar) serves as a framework. The pathologic conditions are classified, based on the structures involved, as fractures, ligament injuries, arthropathies, bone abnormalities, and tendinopathies. The authors describe and evaluate classic radiographic signs and explain how they correlate with MR imaging. The advantages and limitations of each technique are thoroughly discussed as well as other imaging modalities.

Role of Murine Complement Component C5 in Acute in Vivo Infection by Pathogenic Leptospira interrogans.

Leptospirosis is considered one of the most important zoonosis worldwide. The activation of the Complement System is important to control dissemination of several pathogens in the host. Only a few studies have employed murine models to investigate leptospiral infection and our aim in this work was to investigate the role of murine C5 during in vivo infection, comparing wild type C57BL/6 (B6 C5+/+) and congenic C57BL/6 (B6 C5-/-, C5 deficient) mice during the first days of infection. All animals from both groups survived for at least 8 days post-infection with pathogenic Leptospira interrogans serovar Kennewicki strain Fromm (LPF). At the third day of infection, we observed greater numbers of LPF in the liver of B6 C5-/- mice when compared to B6 C5+/+ mice. Later, on the sixth day of infection, the LPF population fell to undetectable levels in the livers of both groups of mice. On the third day, the inflammatory score was higher in the liver of B6 C5+/+ mice than in B6 C5-/- mice, and returned to normal on the sixth day of infection in both groups. No significant histopathological differences were observed in the lung, kidney and spleen from both infected B6 C5+/+ than B6 C5-/- mice. Likewise, the total number of circulating leukocytes was not affected by the absence of C5. The liver levels of IL-10 on the sixth day of infection was lower in the absence of C5 when compared to wild type mice. No significant differences were observed in the levels of several inflammatory cytokines when B6 C5+/+ and B6 C5-/- were compared. In conclusion, C5 may contribute to the direct killing of LPF in the first days of infection in C57BL/6 mice. On the other hand, other effector immune mechanisms probably compensate Complement impairment since the mice survival was not affected by the absence of C5 and its activated fragments, at least in the early stage of this infection.

Phonomyography as a non-invasive continuous monitoring technique for muscle ischemia in an experimental model of acute compartment syndrome.

BACKGROUND: In acute compartment syndrome (ACS), clinicians have difficulty diagnosing muscle ischemia provoked by increased intra-compartmental pressure in a timely and non-invasive manner. Phonomyography records the acoustic signal produced by muscle contraction. We hypothesize that alterations in muscle contraction caused by muscle ischemia can be detected with phonomyography, serving as a potential non-invasive technique in the detection of ACS. METHODS: The left hind limb of 15 Sprague-Dawley rats was submitted to a reversible ischemic model of limb injury for 30min and 1, 2, 4, 6h (3 rats in each group). The right limb served as control. Phonomyography microphones were placed over the posterior calf of both limbs and the sciatic nerve was stimulated percutaneously at 10-min intervals to evaluate muscle contraction. Histopathological analysis of muscles and nerves biopsies was performed and correlation was made between duration of injury, phonomyography output and degree of muscle and nerve necrosis. RESULTS: There was a statistically significant decrease in the phonomyography signal output in the ischemic limb that correlated with the duration of ischemia and histological findings of muscle and nerve necrosis. The phonomyography signal decrease and histological findings were respectively: 55.5% (n=15;p=0.005) with rare muscle and nerve necrosis at 30min, 65.6% (n=12;p=0.005) with 5-10% muscle necrosis at 1h, 68.4% (n=9;p=0.015) with 100% muscle necrosis and little nerve damage at 2h, 72.4% (n=6;p=0.028) with 100% muscle necrosis and severe nerve damage at 4h, and 92.8% (n=3;p=0.109) with 100% muscle necrosis and severe nerve degeneration at 6h. CONCLUSION: Changes in phonomyography signal are observed in early ischemic injury prior to the onset of nerve or muscle necrosis. Therefore, phonomyography could serve as a non-invasive technique to detect early ischemic muscle changes in acute compartment syndrome. CLINICAL RELEVANCE: The detection of abnormal muscle contraction in a timely fashion and non-invasive manner is of interest in clinical settings where the presence of ischemia is not easy to diagnose.

The Serine Protease Pic From Enteroaggregative Escherichia coli Mediates Immune Evasion by the Direct Cleavage of Complement Proteins.

Enteroaggregative and uropathogenic Escherichia coli, Shigella flexneri 2a, and the hybrid enteroaggregative/Shiga toxin-producing E. coli strain (O104:H4) are important pathogens responsible for intestinal and urinary tract infections, as well as sepsis and hemolytic uremic syndrome. They have in common the production of a serine protease called Pic. Several biological roles for Pic have been described, including protection of E. coli DH5α from complement-mediated killing. Hereby we showed that Pic significantly reduces complement activation by all 3 pathways. Pic cleaves purified C3/C3b and other proteins from the classic and lectin pathways, such as C4 and C2. Cleavage fragments of C3, C4, and C2 were also observed with HB101(pPic1) culture supernatants, and C3 cleavage sites were mapped by fluorescence resonance energy transfer peptides. Experiments using human serum as a source of complement proteins confirmed Pic proteolytic activity on these proteins. Furthermore, Pic works synergistically with the human complement regulators factor I and factor H, promoting inactivation of C3b. In the presence of both regulators, further degradation of C3 α' chain was observed. Therefore, Pic may contribute to immune evasion of E. coli and S. flexneri, favoring invasiveness and increasing the severity of the disorders caused by these pathogens.