Charité Clinical Journal Club (English) by Fred Luft - 17.04.2019

The N Engl J Med image of the week concerns a 35-year-old man who presented to the emergency department with a 2-day history of abdominal pain, headache, and brown urine. He was alert and oriented to time, place, and self. He had no purpura or petechiae. Laboratory evaluation revealed a hemoglobin level of 8.6 g per deciliter (normal range, 13.7 to 17.5) and a platelet count of 6000 per cubic millimeter (normal range, 140,000 to 370,000). Levels of indirect bilirubin and lactate dehydrogenase were elevated, haptoglobin was undetectable, and the serum creatinine level was 1 mg per deciliter (88 μmol per liter; normal range, 0.6 to 1.3 mg per deciliter [57 to 115 μmol per liter]). Test results for infection with the human immunodeficiency virus were negative. A peripheral-blood smear showed numerous schistocytes. What is the diagnosis? We discuss N Engl J Med papers on thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome to remind you of ADAMTS13 and von Willebrand’s factor. Ischemic heart disease is a major cause of out-of-hospital cardiac arrest. The role of immediate coronary angiography and percutaneous coronary intervention (PCI) in the treatment of patients who have been successfully resuscitated after cardiac arrest in the absence of ST-segment elevation myocardial infarction (STEMI) remains uncertain. In a multicenter trial, invesitgators randomly assigned 552 patients who had cardiac arrest without signs of STEMI to undergo immediate coronary angiography or coronary angiography that was delayed until after neurologic recovery. All patients underwent PCI if indicated. Delay of PCI had no influence on outcomes. Prodromal Alzheimer’s disease offers an opportunity to test the effect of drugs that modify the deposition of amyloid in the brain before the onset of dementia. Verubecestat is an orally administered β-site amyloid precursor protein–cleaving enzyme 1 (BACE-1) inhibitor that blocks production of amyloid-beta (Aβ). The drug did not prevent clinical progression in a trial involving patients with mild-to-moderate dementia due to Alzheimer’s disease earlier. “Perhaps the drug should be given sooner” was the question asked here. Investigators conducted a randomized, double-blind, placebo-controlled, 104-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had memory impairment and elevated brain amyloid levels but whose condition did not meet the case definition of dementia. The primary outcome was the change from baseline to week 104 in the score on the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB; scores range from 0 to 18, with higher scores indicating worse cognition and daily function). Secondary outcomes included other assessments of cognition and daily function. BACE inhibition with verubecestat and with another BACE inhibitor, atabecestat, reported in N Engl J Med this week made matters worse rather than better. Hirschsprung’s disease, or congenital aganglionosis, is a developmental disorder of the enteric nervous system and is the most common cause of intestinal obstruction in neonates and infants. The disease has more than 80% heritability, including significant associations with rare and common sequence variants in genes related to the enteric nervous system, as well as with monogenic and chromosomal syndromes. Investigators genotyped and exome-sequenced samples from 190 patients with Hirschsprung’s disease to quantify the genetic burden in patients with this condition. We learn about eight other risk alleles. Despite current thinking in human medical genetics, most of the risk of Hirschsprung’s disease arose from a common widespread genetic susceptibility, on top of which rare coding and rarer copy-number variants exacerbated the risk. Expansions in tandem repeats are known to cause many Mendelian disorders, which mainly affect the nervous system, including Huntington's disease, various spinocerebellar ataxias, other polyglutamine diseases, Friedreich ataxia, fragile X syndrome, myoclonic epilepsy, polyalanine disorders and myotonic dystrophy. Now, we can add glutaminase deficiency to the list. The reviews are on obstructive sleep apnea and liver cancer...