Packages of Care for Dementia in Low- and Middle-Income Countries

In the fifth in a series of six articles on packages of care for mental disorders in low- and middle-income countries, Martin Prince and colleagues discuss the treatment of dementia

Recurrent Episodes of Diffuse Alveolar Hemorrhage in Systemic Sclerosis 30 Days Apart

Diffuse alveolar hemorrhage (DAH) is a life-threatening clinicopathologic condition caused by accumulation of intra-alveolar red blood cells (RBCs) after disruption of the alveolar-capillary basement membrane that is often seen as a complication of various diseases, but is rare in systemic sclerosis. A 46-year-old female with systemic sclerosis presented to the emergency department complaining of right-sided chest pain. Initially, her electrocardiogram and chest X-ray (CXR) were unremarkable; however, she progressively decompensated into acute respiratory failure resulting in intubation. Repeat CXR and computed tomography scan showed diffuse bilateral alveolar infiltrates and pleural effusions. Video bronchoscopy with bronchoalveolar lavage showed numerous RBCs, neutrophils, macrophages, and respiratory epithelial cells consistent with acute DAH. She was started on intravenous pulse-dosing Solu-Medrol 1 g daily for 5 days. One month later, the patient returned with intractable nausea and vomiting. Again, she went into acute respiratory distress with a PaO 2 of 59 while on a 10-L non-rebreather mask. CXR revealed development of alveolar infiltrates in the right lung. A bronchoscopy with bronchoalveolar lavage again showed numerous RBCs and neutrophils along with staining positive for hemosiderin-laden macrophages. Systemic sclerosis with alveolar hemorrhage is a rare occurrence; however, most cases are single episodes of hemorrhage, whereas we present a case with 2 confirmed episodes within 30 days. Its life-threatening nature makes a systemic approach and aggressive treatment crucial to decreasing morbidity and mortality—making it a diagnosis that should not be overlooked, especially in patients with nonspecific symptoms

An abyssal carbonate compensation depth overshoot in the aftermath of the Palaeocene–Eocene Thermal Maximum

During the Palaeocene–Eocene Thermal Maximum (PETM) about 56 million years ago, thousands of petagrams of carbon were released into the atmosphere and ocean in just a few thousand years, followed by gradual sequestration over approximately 200,000 years. If silicate weathering is one of the key negative feedbacks that removed this carbon, a period of seawater calcium carbonate saturation greater than pre-event levels would be expected during the event’s recovery phase. In marine sediments, this should be recorded as a temporary deepening of the depth below which no calcite is preserved — the calcite compensation depth (CCD). Previous and new sedimentary records from sites that were above the pre-PETM CCD show enhanced carbonate accumulation following the PETM. A new record from an abyssal site in the North Atlantic that lay below the pre-PETM CCD shows a period of carbonate preservation beginning about 70,000 years after the onset of the PETM, providing the first direct evidence for an over-deepening of the CCD. This record confirms an overshoot in ocean carbonate saturation during the PETM recovery. Simulations with two earth system models support scenarios for the PETM that involve a large initial carbon release followed by prolonged low-level emissions, consistent with the timing of CCD deepening in our record. Our findings indicate that sequestration of these carbon emissions was most likely the result of both globally enhanced calcite burial above the CCD and, at least in the North Atlantic, an over-deepening of the CCD

TBK1 phosphorylates mutant Huntingtin and suppresses its aggregation and toxicity in Huntington's disease models

Phosphorylation of the N-terminal domain of the huntingtin (HTT) protein has emerged as an important regulator of its localization, structure, aggregation, clearance and toxicity. However, validation of the effect of bona fide phosphorylation in vivo and assessing the therapeutic potential of targeting phosphorylation for the treatment of Huntington's disease (HD) require the identification of the enzymes that regulate HTT phosphorylation. Herein, we report the discovery and validation of a kinase, TANK-binding kinase 1 (TBK1), that efficiently phosphorylates full-length and N-terminal HTT fragments in vitro (at S13/S16), in cells (at S13) and in vivo. TBK1 expression in HD models (cells, primary neurons, and Caenorhabditis elegans) increases mutant HTT exon 1 phosphorylation and reduces its aggregation and cytotoxicity. We demonstrate that the TBK1-mediated neuroprotective effects are due to phosphorylation-dependent inhibition of mutant HTT exon 1 aggregation and an increase in autophagic clearance of mutant HTT. These findings suggest that upregulation and/or activation of TBK1 represents a viable strategy for the treatment of HD by simultaneously lowering mutant HTT levels and blocking its aggregation