Multiple adaptive mechanisms to chronic liver disease revealed at early stages of liver carcinogenesis in the Mdr2-knockout mice Cancer Res 66

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EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy

Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0–49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease

A 26-week pregnant, 34-year-old patient who presented with right lower quadrant pain.

Axial T2 weighted image (A) shows a swollen right kidney with marked hypointense lesions in the parenchyma (arrow) and a small amount of peri-nephric free fluid (arrowhead). Coronal fat saturated T2 weighted image (B) shows hypointense lesions in the right kidney’s parenchyma (arrow) and a small amount of peri-nephric free fluid (arrowhead). Findings are consistent with acute pyelonephritis.</p

Flow chart depicting MRI diagnosis.

This study’s aim is to describe the imaging findings in pregnant patients undergoing emergent MRI for suspected acute appendicitis, and the various alternative diagnoses seen on those MRI scans. This is a single center retrospective analysis in which we assessed the imaging, clinical and pathological data for all consecutive pregnant patients who underwent emergent MRI for suspected acute appendicitis between April 2013 and June 2021. Out of 167 patients, 35 patients (20.9%) were diagnosed with acute appendicitis on MRI. Thirty patients (18%) were diagnosed with an alternative diagnosis on MRI: 17/30 (56.7%) patients had a gynecological source of abdominal pain (e.g. ectopic pregnancy, red degeneration of a leiomyoma); 8 patients (26.7%) had urological findings such as pyelonephritis; and 6 patients (20%) had gastrointestinal diagnoses (e.g. abdominal wall hernia or inflammatory bowel disease). Our conclusions are that MRI is a good diagnostic tool in the pregnant patient, not only in diagnosing acute appendicitis, but also in providing information on alternative diagnoses to acute abdominal pain. Our findings show the various differential diagnoses on emergent MRI in pregnant patients with suspected acute appendicitis, which may assist clinicians and radiologists is patient assessment and imaging utilization.</div

Ultrasound findings prior to MRI.

This study’s aim is to describe the imaging findings in pregnant patients undergoing emergent MRI for suspected acute appendicitis, and the various alternative diagnoses seen on those MRI scans. This is a single center retrospective analysis in which we assessed the imaging, clinical and pathological data for all consecutive pregnant patients who underwent emergent MRI for suspected acute appendicitis between April 2013 and June 2021. Out of 167 patients, 35 patients (20.9%) were diagnosed with acute appendicitis on MRI. Thirty patients (18%) were diagnosed with an alternative diagnosis on MRI: 17/30 (56.7%) patients had a gynecological source of abdominal pain (e.g. ectopic pregnancy, red degeneration of a leiomyoma); 8 patients (26.7%) had urological findings such as pyelonephritis; and 6 patients (20%) had gastrointestinal diagnoses (e.g. abdominal wall hernia or inflammatory bowel disease). Our conclusions are that MRI is a good diagnostic tool in the pregnant patient, not only in diagnosing acute appendicitis, but also in providing information on alternative diagnoses to acute abdominal pain. Our findings show the various differential diagnoses on emergent MRI in pregnant patients with suspected acute appendicitis, which may assist clinicians and radiologists is patient assessment and imaging utilization.</div

41-year-old patient, 19 weeks pregnant, who presented with right lower quadrant pain.

Axial fat saturated T1 weighted image shows hyperintense fluid at the posterior border of the right rectus abdominis muscle (arrows). This finding is consistent with rectus sheath hematoma.</p

Pathologies found on MRI.

This study’s aim is to describe the imaging findings in pregnant patients undergoing emergent MRI for suspected acute appendicitis, and the various alternative diagnoses seen on those MRI scans. This is a single center retrospective analysis in which we assessed the imaging, clinical and pathological data for all consecutive pregnant patients who underwent emergent MRI for suspected acute appendicitis between April 2013 and June 2021. Out of 167 patients, 35 patients (20.9%) were diagnosed with acute appendicitis on MRI. Thirty patients (18%) were diagnosed with an alternative diagnosis on MRI: 17/30 (56.7%) patients had a gynecological source of abdominal pain (e.g. ectopic pregnancy, red degeneration of a leiomyoma); 8 patients (26.7%) had urological findings such as pyelonephritis; and 6 patients (20%) had gastrointestinal diagnoses (e.g. abdominal wall hernia or inflammatory bowel disease). Our conclusions are that MRI is a good diagnostic tool in the pregnant patient, not only in diagnosing acute appendicitis, but also in providing information on alternative diagnoses to acute abdominal pain. Our findings show the various differential diagnoses on emergent MRI in pregnant patients with suspected acute appendicitis, which may assist clinicians and radiologists is patient assessment and imaging utilization.</div

Patient demographics.

This study’s aim is to describe the imaging findings in pregnant patients undergoing emergent MRI for suspected acute appendicitis, and the various alternative diagnoses seen on those MRI scans. This is a single center retrospective analysis in which we assessed the imaging, clinical and pathological data for all consecutive pregnant patients who underwent emergent MRI for suspected acute appendicitis between April 2013 and June 2021. Out of 167 patients, 35 patients (20.9%) were diagnosed with acute appendicitis on MRI. Thirty patients (18%) were diagnosed with an alternative diagnosis on MRI: 17/30 (56.7%) patients had a gynecological source of abdominal pain (e.g. ectopic pregnancy, red degeneration of a leiomyoma); 8 patients (26.7%) had urological findings such as pyelonephritis; and 6 patients (20%) had gastrointestinal diagnoses (e.g. abdominal wall hernia or inflammatory bowel disease). Our conclusions are that MRI is a good diagnostic tool in the pregnant patient, not only in diagnosing acute appendicitis, but also in providing information on alternative diagnoses to acute abdominal pain. Our findings show the various differential diagnoses on emergent MRI in pregnant patients with suspected acute appendicitis, which may assist clinicians and radiologists is patient assessment and imaging utilization.</div