Structure of RC1339/APRc from Rickettsia conorii, a retropepsin-like aspartic protease.

The crystal structures of two constructs of RC1339/APRc from Rickettsia conorii, consisting of either residues 105-231 or 110-231 followed by a His tag, have been determined in three different crystal forms. As predicted, the fold of a monomer of APRc resembles one-half of the mandatory homodimer of retroviral pepsin-like aspartic proteases (retropepsins), but the quaternary structure of the dimer of APRc differs from that of the canonical retropepsins. The observed dimer is most likely an artifact of the expression and/or crystallization conditions since it cannot support the previously reported enzymatic activity of this bacterial aspartic protease. However, the fold of the core of each monomer is very closely related to the fold of retropepsins from a variety of retroviruses and to a single domain of pepsin-like eukaryotic enzymes, and may represent a putative common ancestor of monomeric and dimeric aspartic proteases.

Hypovolemic Shock And The Need For Invasive Mechanical Ventilation On A Patient With Congenital Heart Disease.

Techniques of venoarterial-extracorporeal membrane oxygenation (VA-ECMO) have improved over the decades, with numerous applications.1 Those with reversible low cardiac output benefit most from this support.1 Case of 21-year-old male, history of congenital heart disease (severe right ventricle hypoplasia and pulmonary artery stenosis with extracardiac cavo-pulmonary shunt (Fontan surgery), and atrial septal defect). Brought to the Emergency Department due to a Mallory-Weiss syndrome, upper-endoscopy "laceration at esophagogastric junction (EGJ) with active bleeding", clips were applied. However, worsening shock, repeated melenas and hematemesis, hemoglobin drop, lactate 2.8mmol/L, and needing noradrenaline (1.21mcg/kg/min). Due to active blood loss and worsening shock, the patient was intubated to maintain airway protection. Repeated upper-endoscopy "voluminous live red clot at EGJ, 4-clips and active bleeding of mucosa between, injection of polidocanol". Despite the implemented strategy, high risk of rebleeding remained. Following invasive mechanical ventilation (IMV), sustained hypotension having to increase noradrenaline (1.52mcg/kg/min) and lactate (5.8mmol/l), despite fluid resuscitation. Echocardiogram evidenced severe ventricular dysfunction, and fixed inferior vena cava (IVC) of 20mm. The heart defect combined with positive intrathoracic pressure, contributed to the worsened shock, as Fontan circulation is dependent on low vascular resistance to maintain output2. Needing VA-ECMO and admitted to ICU, volemia optimization, adjusting ventilation to lower intrathoracic pressure and started on milrinone and sildenafil. Another upper-endoscopy showed laceration at EGJ, with placement of clips. Echocardiogram revealed "Normal left ventricle. Hypoplastic right ventricle. Mild mitral regurgitation; aortic VTi 19cm. IVC 22mm. RV/RA gradient 70mmHg. Interatrial bidirectional shunt". Favorable evolution permitted extubation, suspension of milrinone and sildenafil, followed by decannulation. With rescue ECMO, congenital heart disease are salvageable despite sudden decompensation3. This case, positive intrathoracic pressure impairs the Fontan circulation, dependent on preload and higher central venous pressure to maintain cardiac output, as the ventricle is unable to compensate increased demands2, and worsening shock.

Anti-interleukin-6 receptor antibody for the treatment of remitting seronegative symmetrical synovitis with pitting oedema: a new outlook?

We present the case of an elderly man with a small-joint polyarthritis, accompanied by pitting oedema, involving hands and feet, raising clinical suspicion of remitting seronegative symmetrical synovitis with pitting oedema (RS3PE). Treatment with corticosteroids was initiated with significant improvement, but unacceptable iatrogeny ensued, and tapering was not possible without disease flare-up. A trial of tocilizumab allowed disease activity control, slow weaning of corticosteroids and, ultimately, its suspension. RS3PE is a rare rheumatological entity, initially thought to be a variant of rheumatoid arthritis (RA), with shared traits with polymyalgia rheumatica (PMR), and other seronegative spondyloarthropathies, thereby implying a shared pathophysiological background. Elevated levels of interleukin 6 (IL-6) are found in patients with RA, have shown to mirror disease activity in PMR and have also been described in the serum and synovial fluid of patients with RS3PE. Tocilizumab, an anti-IL-6 receptor antibody, shows auspicious results in several other rare rheumatic diseases other than RA.