Monitoring and Management of Respiratory Function in Pompe Disease: Current Perspectives.

Pompe disease (PD) is a neuromuscular disorder caused by a deficiency of acid alpha-glucosidase (GAA) - a lysosomal enzyme responsible for hydrolyzing glycogen. GAA deficiency leads to accumulation of glycogen in lysosomes, causing cellular disruption. The severity of PD is directly related to the extent of GAA deficiency - if no or minimal GAA is produced, symptoms are severe and manifest in infancy, known as infantile onset PD (IOPD). If left untreated, infants with IOPD experience muscle hypotonia and cardio-respiratory failure leading to significant morbidity and mortality in the first year of life. In contrast, late-onset PD (LOPD) patients have more GAA activity and present later in life, but also have significant respiratory function decline. Despite FDA-approved enzyme replacement therapy, respiratory insufficiency remains a major cause of morbidity and mortality, emphasizing the importance of early detection and management of respiratory complications. These complications include impaired cough and airway clearance, respiratory muscle weakness, sleep-related breathing issues, and pulmonary infections. This review aims to provide an overview of the respiratory pathology, monitoring, and management of PD patients. In addition, we discuss the impact of novel approaches and therapies on respiratory function in PD.

Adding Insult to Injury: Sleep Deficiency in Hospitalized Patients.

Sleep deficiency is a common problem in the hospital setting. Contributing factors include preexisting medical conditions, illness severity, the hospital environment, and treatment-related effects. Hospitalized patients are particularly vulnerable to the negative health effects of sleep deficiency that impact multiple organ systems. Objective sleep measurement is difficult to achieve in the hospital setting, posing a barrier to linking improvements in hospital outcomes with sleep promotion protocols. Key next steps in hospital sleep promotion include improvement in sleep measurement techniques and harmonization of study protocols and outcomes to strengthen existing evidence and facilitate data interpretation across studies.

Expanding small-molecule target space to mRNA translation regulation.

Multiple layers of regulation are in place on mRNA translation to ensure that cells respond in a fast manner to environmental cues in a tissue-specific and mRNA-selective manner. Here, we discuss mRNA translation regulatory mechanisms and potential drug-intervention targets. Taking on a new scientific rational of translation regulation and consequently a new target space, we have developed a unique discovery platform that is able to identify selective small molecule drugs that affect translation of specific proteins. This approach has enabled targeting of proteins that have been considered undruggable. Our discovery platform was repeatedly utilized to identify compounds in multiple therapeutic programs, including fibrosis, oncology, anti-virals and Huntington's disease. In fibrosis, the lead compound ANI-21 has demonstrated a tissue-specific effect in lowering the translation of Collagen-I and superior efficacy over best standard of care, in both cell and animal models, mediated by a novel mechanism of action. This program is expected to enter clinical studies within 12-18 months.

A Case of Laryngeal Tuberculosis, Endobronchial Tuberculosis and Pulmonary Tuberculosis Coexistent in an Immunocompetent Host.

Historically associated with poor prognosis seen in advanced disease, laryngeal tuberculosis (LTB) now represents only 1% of all cases of tuberculosis (TB). The incidence of LTB has decreased drastically with the introduction of anti-tubercular drugs. LTB can be primary or secondary to pulmonary tuberculosis. LTB can mimic laryngeal cancer. We present a case of primary laryngeal TB with descending tracheobronchial spread in an immunocompetent 71-year-old female who developed progressive dysphonia over several months with unintentional weight loss and non-productive cough. Non-contrast enhanced computed tomography (CT) revealed clustering of subcentimeter stellate nodules in the right upper lung field with an enlarging ground-glass opacity in the right lower lung but did not show structural abnormalities within the neck. Positron emission tomography (PET) showed pathologic fluorodeoxyglucose (FDG) uptake within the larynx and trachea with extension into the left mainstream bronchus as well as the proximal left upper and lower lobe bronchi. Diffuse standardized uptake value (SUV) was greatest in the larynx (20.5). Polymerase chain reaction (PCR) on bronchoscope sputum specimen confirmed Mycobacterium tuberculosis. Findings were consistent with primary laryngeal TB with endobronchial extension. She was started on a four-drug regimen comprising of isoniazid, rifampin, ethambutol, and pyrazinamide with a good response. Her close contacts were treated as well. This case highlights the unusual spread of primary laryngeal TB in an immunocompetent host. Early diagnosis can limit adverse complications and unnecessary exposure to healthcare workers. To our knowledge, this is the first case of primary LTB with proximal spread to the tracheobronchial and pulmonary tuberculosis.

Pneumopericardium, pneumomediastinum and air travel: A case report in a patient with Gardner syndrome.

Onboard aircraft medical emergencies are on the rise as commercial air traffic is increasing. However, thoracic injury secondary to air travel is extremely rare and, most reported injuries are cases of pneumothoraces. Spontaneous pneumomediastinum and pneumopericardium have been barely reported in the medical literature as a complication of air travel. We are reporting a case of spontaneous pneumopericardium and pneumomediastinum in a patient with Gardner's Syndrome after a flight from Central America to New York City. The patient presented with chest discomfort. He was managed conservatively with oxygen therapy as he was hemodynamically stable throughout his stay in the hospital. A thorough work up in hospital including and esophagogram and a CT scan of the chest were none revealing of the cause. However, the patient was noted to have metastatic rectal cancer with lung involvement. The patient was discharged with instructions to avoid air travel.

Outbreak of Electronic-Cigarette-Associated Acute Lipoid Pneumonia - North Carolina, July-August 2019.

On September 6, 2019, this report was posted as an MMWR Early Release on the MMWR website (https://www.cdc.gov/mmwr). Electronic cigarettes (e-cigarettes) produce an aerosol by heating a liquid that usually contains nicotine, flavorings, and other chemicals that users inhale, a behavior commonly referred to as "vaping." E-cigarettes can also be used to deliver marijuana and other drugs. In recent months, more than 200 possible cases of acute lung injury potentially associated with vaping were reported from 25 states (1). During July and August 2019, five patients were identified at two hospitals in North Carolina with acute lung injury potentially associated with e-cigarette use. Patients were adults aged 18-35 years and all experienced several days of worsening dyspnea, nausea, vomiting, abdominal discomfort and fever. All patients demonstrated tachypnea with increased work of breathing on examination, hypoxemia (pulse oximetry <90% on room air), and bilateral lung infiltrates on chest x-ray. All five patients shared a history of recent use of marijuana oils or concentrates in e-cigarettes. All of the products used were electronic vaping pens/e-cigarettes that had refillable chambers or interchangeable cartridges with tetrahydrocannabinol (THC) vaping concentrates or oils, which were all purchased on the street. Three of the patients also used nicotine-containing e-cigarettes, and two of the patients smoked marijuana or conventional cigarettes, although none used other illicit drugs. All five patients were hospitalized for hypoxemic respiratory failure; three required intensive care for acute respiratory distress syndrome, one of whom required intubation and mechanical ventilation. All of the patients survived.

Left-sided Catamenial Pneumothorax: A Rare Clinical Entity.

Catamenial pneumothorax (CP) is an extremely rare pulmonary pathology seen in women of reproductive age, typically occurring within 72 hours from the onset of menstrual bleeding. Multiple theories have been proposed to explain the etiopathogenesis of CP; however, the exact underlying mechanism remains elusive. More than 90% of reported cases in the literature describe a right-sided presentation of pneumothorax. In this case report, we describe a rare left-sided presentation of CP and discuss the current literature on underlying etiopathogenesis, diagnostics, and available therapeutic modalities for managing this rare clinical entity.

Bouveret's Syndrome: Literature Review.

It was in 1896 that Bouveret's syndrome acquired its name after the French physician Leon Bouveret, who published two case reports in Revue de Medecin. Bouveret's syndrome describes gastric outlet obstruction secondary to an impacted gallstone. The gallstone reaches the small bowel through a bilioenteric fistula as a consequence of chronic inflammation and adherence between the biliary system and the bowels which increase the intraluminal pressure and leads to secondary wall ischemia and wall perforation with gallstone passage into the bowel. Bouveret's syndrome's prevalence is highest among elderly women. Despite the rarity of Bouveret's syndrome, it can cause notable morbidity and mortality rates. We underwent a review of literature about Bouveret syndrome to increase awareness of its occurrence and potentially life-threatening complications.

A Case of Transudative Chylothorax: A Diagnostic Dilemma.

Chylothorax is a type of pleural effusion characterized by the presence of chyle in the pleural space with triglyceride levels >110 mg/dL or evidence of chylomicrons in pleural fluid. Chylous effusion is typically exudative in nature with lymphocytic predominance. Transudative chylothorax is a rare finding which has been associated with only a limited range of clinical settings. We report a case of idiopathic transudative chylothorax for which the etiological cause could not be identified despite extensive workup and it resolved spontaneously after thoracentesis.

From Bouveret's Syndrome to Gallstone Ileus: The Journey of a Migrating Stone!

Bouveret's syndrome, first described in 1896, is an unusual cause of gastric outlet obstruction secondary to large gallstone impaction in the proximal duodenum after migration through a cholecystoduodenal fistula. Stone migration has been previously described after endoscopic or surgical fragmentation. However, this is the first reported case, in our knowledge, where the stone migrated after oral contrast administration a few days after the onset of symptoms, causing a distal gallstone ileus.

Relevance of B-Lines on Lung Ultrasound in Volume Overload and Pulmonary Congestion: Clinical Correlations and Outcomes in Patients on Hemodialysis.

BACKGROUND: Volume overload in patients on hemodialysis (HD) is an independent risk factor for cardiovascular mortality. B-lines detected on lung ultrasound (BLUS) assess extravascular lung water. This raises interest in its utility for assessing volume status and cardiovascular outcomes. METHODS: End-stage renal disease patients on HD at the Island Rehab Center being older than 18 years were screened. Patients achieving their dry weight (DW) had a lung ultrasound in a supine position. Scores were classified as mild (0-14), moderate (15-30), and severe (>30) for pulmonary congestion. Patients with more than 60 were further classified as very severe. Patients were followed for cardiac events and death. RESULTS: 81 patients were recruited. 58 were males, with a mean age of 59.7 years. 44 had New York Heart Association (NYHA) class 1, 24 had class 2, and 13 had class 3. In univariate analysis, NYHA class was associated with B-line classes (<0.001) and diastolic dysfunction (0.002). In multivariate analysis, NYHA grade strongly correlated with B-line classification (0.01) but not with heart function (0.95). 71 subjects were followed for a mean duration of 1.19 years. 9 patients died and 20 had an incident cardiac event. A Kaplan-Meier survival analysis demonstrated an interval decrease in survival times in all-cause mortality and cardiac events with increased BLUS scores (p = 0.0049). Multivariate Cox regression analysis showed the independent predictive value of BLUS class for mortality and cardiac events with a heart rate of 2.98 and 7.98 in severe and very severe classes, respectively, compared to patients in the mild class (p = 0.025 and 0.013). CONCLUSION: At DW, BLUS is an independent risk factor for death and cardiovascular events in patients on HD.

Structural Basis for the Inhibitory Effects of Ubistatins in the Ubiquitin-Proteasome Pathway.

The discovery of ubistatins, small molecules that impair proteasomal degradation of proteins by directly binding to polyubiquitin, makes ubiquitin itself a potential therapeutic target. Although ubistatins have the potential for drug development and clinical applications, the lack of structural details of ubiquitin-ubistatin interactions has impeded their development. Here, we characterized a panel of new ubistatin derivatives using functional and binding assays. The structures of ubiquitin complexes with ubistatin B and hemi-ubistatin revealed direct interactions with ubiquitin's hydrophobic surface patch and the basic/polar residues surrounding it. Ubistatin B binds ubiquitin and diubiquitin tighter than a high-affinity ubiquitin receptor and shows strong preference for K48 linkages over K11 and K63. Furthermore, ubistatin B shields ubiquitin conjugates from disassembly by a range of deubiquitinases and by the 26S proteasome. Finally, ubistatin B penetrates cancer cells and alters the cellular ubiquitin landscape. These findings highlight versatile properties of ubistatins and have implications for their future development and use in targeting ubiquitin-signaling pathways.

Intercostal Artery Laceration: Rare Complication of Thoracentesis and Role of Ultrasound in Early Detection.

Hemothorax is a rare but potentially fatal postthoracentesis complication. Early clinical signs may be nonspecific resulting in diagnostic delay. A high index of suspicion is vital for early diagnosis and intervention to avoid further bleeding. Following procedure, early bedside ultrasound findings can be vital for early detection. We report a case of massive hemothorax in a 63-year-old male following therapeutic thoracentesis. Diagnosis was made following highly suggestive sonographic findings prompting thoracotomy and lacerated intercostal artery cauterization.

Fungal Bezoar: A Rare Cause of Ureteral Obstruction.

A 52-year-old male, with diabetes mellitus and alcoholic liver disease, presented to the Emergency Room for right flank pain of 3 days' duration, associated with dysuria. Physical examination revealed right flank tenderness with fever and hypotension; laboratory findings showed acute kidney injury and large blood and leucocytes in the urine. A CT abdomen and pelvis showed hydronephrosis of the right collecting system of a horseshoe kidney with air and hyperdense debris in the renal pelvis. Patient was treated for multisensitive Proteus mirabilis emphysematous pyelonephritis, and a right nephrostomy tube was inserted. Symptoms recurred in 4 weeks, and repeated urine culture grew Candida albicans and CT scan showed same high density material within the right moiety of the horseshoe kidney. Patient underwent ureteroscopy, and a white fluffy material was aspirated from the right renal pelvis. Pathology of the aspirate confirmed the presence of fungal balls. Patient was given 2 weeks of oral fluconazole. Fungal pyelonephritis is unusual and difficult to treat. Candida species is responsible for the clear majority of the cases. A fungus ball should be managed with surgical and medical therapy. This patient had an endoscopic procedure to remove the fungus ball and received fluconazole. His symptoms resolved and urine culture was done before termination of the treatment was negative.

Polyubiquitin-Photoactivatable Crosslinking Reagents for Mapping Ubiquitin Interactome Identify Rpn1 as a Proteasome Ubiquitin-Associating Subunit.

Ubiquitin (Ub) signaling is a diverse group of processes controlled by covalent attachment of small protein Ub and polyUb chains to a range of cellular protein targets. The best documented Ub signaling pathway is the one that delivers polyUb proteins to the 26S proteasome for degradation. However, studies of molecular interactions involved in this process have been hampered by the transient and hydrophobic nature of these interactions and the lack of tools to study them. Here, we develop Ub-phototrap (UbPT), a synthetic Ub variant containing a photoactivatable crosslinking side chain. Enzymatic polymerization into chains of defined lengths and linkage types provided a set of reagents that led to identification of Rpn1 as a third proteasome ubiquitin-associating subunit that coordinates docking of substrate shuttles, unloading of substrates, and anchoring of polyUb conjugates. Our work demonstrates the value of UbPT, and we expect that its future uses will help define and investigate the ubiquitin interactome.

Left Lung Torsion: Complication of Lobar Resection for an Early Stage Lung Adenocarcinoma.

Lobar torsion is a fatal but fortunately rare occurrence following lung resection. Early clinical signs and radiographic features may be nonspecific resulting in diagnostic delay. A high index of suspicion is vital for early diagnosis and intervention to avoid further parenchymal necrosis and deadly gangrene. We report a case of left lower lobe torsion in a 76-year-old female following elective upper lobectomy for underlying lung adenocarcinoma. Diagnosis was made following highly suggestive radiographic findings prompting bronchoscopy and revision thoracotomy. An emergency detorsion failed to restore lung viability and was followed by completion pneumonectomy. The patient recovered and was discharged on the seventh postoperative day.

Base-CP proteasome can serve as a platform for stepwise lid formation.

26S proteasome, a major regulatory protease in eukaryotes, consists of a 20S proteolytic core particle (CP) capped by a 19S regulatory particle (RP). The 19S RP is divisible into base and lid sub-complexes. Even within the lid, subunits have been demarcated into two modules: module 1 (Rpn5, Rpn6, Rpn8, Rpn9 and Rpn11), which interacts with both CP and base sub-complexes and module 2 (Rpn3, Rpn7, Rpn12 and Rpn15) that is attached mainly to module 1. We now show that suppression of RPN11 expression halted lid assembly yet enabled the base and 20S CP to pre-assemble and form a base-CP. A key role for Regulatory particle non-ATPase 11 (Rpn11) in bridging lid module 1 and module 2 subunits together is inferred from observing defective proteasomes in rpn11-m1, a mutant expressing a truncated form of Rpn11 and displaying mitochondrial phenotypes. An incomplete lid made up of five module 1 subunits attached to base-CP was identified in proteasomes isolated from this mutant. Re-introducing the C-terminal portion of Rpn11 enabled recruitment of missing module 2 subunits. In vitro, module 1 was reconstituted stepwise, initiated by Rpn11-Rpn8 heterodimerization. Upon recruitment of Rpn6, the module 1 intermediate was competent to lock into base-CP and reconstitute an incomplete 26S proteasome. Thus, base-CP can serve as a platform for gradual incorporation of lid, along a proteasome assembly pathway. Identification of proteasome intermediates and reconstitution of minimal functional units should clarify aspects of the inner workings of this machine and how multiple catalytic processes are synchronized within the 26S proteasome holoenzymes.

Chemical synthesis of phosphorylated ubiquitin and diubiquitin exposes positional sensitivities of e1-e2 enzymes and deubiquitinases.

Modification of ubiquitin by phosphorylation extends the signaling possibilities of this dynamic signal, as it could affect the activity of ligases and the processing of ubiquitin chains by deubiquitinases. The first chemical synthesis of phosphorylated ubiquitin and of Lys63-linked diubiquitin at the proximal, distal or both ubiquitins is reported. This enabled the examination of how such a modification alters E1-E2 activities of the ubiquitination machinery. It is found that E1 charging was not affected, while the assembly of phosphorylated ubiquitin chains was differentially inhibited with E2 enzymes tested. Moreover, this study shows that phosphorylation interferes with the recognition of linkage specific antibodies and the activities of several deubiquitinases. Notably, phosphorylation in the proximal or distal ubiquitin unit has differential effects on specific deubiquitinases. These results support a unique role of phosphorylation in the dynamics of the ubiquitin signal.

Abnormal cytoplasmic extensions associated with active αIIbß3 are probably the cause for macrothrombocytopenia in Glanzmann thrombasthenia-like syndrome.

Mutations in the ITGA2B or ITGB3 genes that encode for the αIIbß3 platelet integrin usually cause Glanzmann thrombasthenia, a severe autosomal recessive bleeding disorder characterized by absence of platelet aggregation, but normal platelet number and size. Several rare mutations cause a Glanzmann-like syndrome which manifests macrothrombocytopenia and usually displays autosomal dominant inheritance. The exact mechanism causing Glanzmann-like syndrome is unknown. One typical example of Glanzmann-like mutations causes deletion of 40 amino acids (p.647-686) in the ß3 ß-tail domain (ßTD_del) that was found in the heterozygous state in Italian and Japanese families. A second example is a missense mutation, C560R, located in the epidermal growth factor-like domain, found in the homozygous state in a French patient. Both mutations cause constitutive activation of αIIbß3, but differ in their surface expression. In the current study, we generated cultured cells expressing ß3-ßTD_del or ß3-C560R mutations along with wild-type αIIb, and examined the cells' ability to create tubulin-dependent protrusions compared to cells expressing wild-type αIIbß3. Unlike cells expressing wild-type αIIbß3, cells harboring each of the mutations exhibited abnormal cytoplasmic extensions on immobilized fibrinogen or Von Willebrand factor, which resembled extensions formed in megakaryocyte leading to proplatelets. Moreover, we showed that formation of abnormal extensions occurred also in wild-type αIIbß3 cells when activated by activating antibody. These results suggest that the active conformation of αIIbß3 can induce cytoskeletal rearrangements that lead to impaired proplatelet formation.

Disassembly of Lys11 and mixed linkage polyubiquitin conjugates provides insights into function of proteasomal deubiquitinases Rpn11 and Ubp6.

Protein homeostasis is largely dependent on proteolysis by the ubiquitin-proteasome system. Diverse polyubiquitin modifications are reported to target cellular proteins to the proteasome. At the proteasome, deubiquitination is an essential preprocessing event that contributes to degradation efficiency. We characterized the specificities of two proteasome-associated deubiquitinases (DUBs), Rpn11 and Ubp6, and explored their impact on overall proteasome DUB activity. This was accomplished by constructing a panel of well defined ubiquitin (Ub) conjugates, including homogeneous linkages of varying lengths as well as a heterogeneously modified target. Rpn11 and Ubp6 processed Lys(11) and Lys(63) linkages with comparable efficiencies that increased with chain length. In contrast, processing of Lys(48) linkages by proteasome was inversely correlated to chain length. Fluorescently labeled tetra-Ub chains revealed endo-chain preference for Ubp6 acting on Lys(48) and random action for Rpn11. Proteasomes were more efficient at deconjugating identical substrates than their constituent DUBs by roughly 2 orders of magnitude. Incorporation into proteasomes significantly enhanced enzymatic efficiency of Rpn11, due in part to alleviation of the autoinhibitory role of its C terminus. The broad specificity of Rpn11 could explain how proteasomes were more effective at disassembling a heterogeneously modified conjugate compared with homogeneous Lys(48)-linked chains. The reduced ability to disassemble homogeneous Lys(48)-linked chains longer than 4 Ub units may prolong residency time on the proteasome.