Our understanding of autophagy and lysosomal function has been greatly enhanced by the discovery of natural product structures that can serve as chemical probes to reveal new patterns of signal ...transduction in cells. Coibamide A is a cytotoxic marine natural product that induces mTOR-independent autophagy as an adaptive stress response that precedes cell death. Autophagy-related (ATG) protein 5 (ATG5) is required for coibamide-induced autophagy but not required for coibamide-induced apoptosis. Using wild-type and autophagy-deficient mouse embryonic fibroblasts (MEFs) we demonstrate that coibamide-induced toxicity is delayed in ATG5
cells relative to ATG5
cells. Time-dependent changes in annexin V staining, membrane integrity, metabolic capacity and caspase activation indicated that MEFs with a functional autophagy pathway are more sensitive to coibamide A. This pattern could be distinguished from autophagy modulators that induce acute ER stress (thapsigargin, tunicamycin), ATP depletion (oligomycin A) or mTORC1 inhibition (rapamycin), but was shared with the Sec61 inhibitor apratoxin A. Coibamide- or apratoxin-induced cell stress was further distinguished from the action of thapsigargin by a pattern of early LC3-II accumulation in the absence of CHOP or BiP expression. Time-dependent changes in ATG5-ATG12, PARP1 and caspase-3 expression patterns were consistent with the conversion of ATG5 to a pro-death signal in response to both compounds.
The occupational hazards of working in the interventional laboratory have been inadequately studied for physicians and remain unaddressed for nonphysician personnel.
This study sought to determine ...whether the prevalence of work-related musculoskeletal pain, cancer, and other medical conditions is higher among physicians and allied staff who work in interventional laboratories compared with employees who do not.
Mayo Clinic employees who work in affiliated hospitals with interventional cardiology or interventional radiology laboratories took an electronic survey. Results were stratified on the basis of self-reported occupational exposure to procedures that involve radiation.
There were 1,543 employees (mean age 43 ± 11.3 years, 33% male) who responded to the survey (response rate of 57%), and 1,042 (67.5%) reported being involved with procedures utilizing radiation. These employees reported experiencing work-related pain more often than the control group before (54.7% vs. 44.7%; p < 0.001) and after adjustment for age, sex, body mass index, pre-existing musculoskeletal conditions, years in profession, and job description (odds ratio: 1.67; 95% confidence interval: 1.32 to 2.11; p < 0.001). Musculoskeletal pain varied significantly by job description, with the highest incidence reported by technicians (62%) and nurses (60%) followed by attending physicians (44%) and trainees (19%; p < 0.001). There was no difference in cancer prevalence between groups (9% vs. 9%; p = 0.96).
Musculoskeletal pain is more common among healthcare workers who participate in interventional procedures and is highest in nonphysician employees. The diagnosis of cancer in employees who participate in procedures that utilize radiation was not elevated when compared to controls within the same departments, although any conclusion regarding causality is limited by the cross-sectional nature of the study, as well as the low overall prevalence of malignancy in our study group.
The mandelalides are complex macrolactone natural products with distinct macrocycle motifs and a bioactivity profile that is heavily influenced by compound glycosylation. Mandelalides A and B are ...direct inhibitors of mitochondrial ATP synthase (complex V) and therefore more toxic to mammalian cells with an oxidative metabolic phenotype. To provide further insight into the pharmacology of the mandelalides, we studied the AMP-activated protein kinase (AMPK) energy stress pathway and report that mandelalide A is an indirect activator of AMPK. Wild-type mouse embryonic fibroblasts (MEFs) and representative human non-small cell lung cancer (NSCLC) cells showed statistically significant increases in phospho-AMPK (Thr172) and phospho-ACC (Ser79) in response to mandelalide A. Mandelalide L, which also harbors an A-type macrocycle, induced similar increases in phospho-AMPK (Thr172) and phospho-ACC (Ser79) in U87-MG glioblastoma cells. In contrast, MEFs co-treated with an AMPK inhibitor (dorsomorphin), AMPKα-null MEFs, or NSCLC cells lacking liver kinase B1 (LKB1) lacked this activity. Mandelalide A was significantly more cytotoxic to AMPKα-null MEFs than wild-type cells, suggesting that AMPK activation serves as a protective response to mandelalide-induced depletion of cellular ATP. However, LKB1 status alone was not predictive of the antiproliferative effects of mandelalide A against NSCLC cells. When EGFR status was considered, erlotinib and mandelalide A showed strong cytotoxic synergy in combination against erlotinib-resistant 11-18 NSCLC cells but not against erlotinib-sensitive PC-9 cells. Finally, prolonged exposures rendered mandelalide A, a potent and efficacious cytotoxin, against a panel of human glioblastoma cell types regardless of the underlying metabolic phenotype of the cell. These results add biological relevance to the mandelalide series and provide the basis for their further pre-clinical evaluation as ATP synthase inhibitors and secondary activators of AMPK.
To identify whether symptom relief and stent patency vary with use of long-term anticoagulation after stent placement for benign superior vena cava (SVC) syndrome.
Patients with benign SVC syndrome ...treated with stent placement between January 1999 and July 2017 were retrospectively identified (n = 58). Average age was 49 years (range, 24-80 y); 34 (58%) were women, and 24 (42%) were men. Average follow-up was 2.4 years (range, 0.1-11.1 y, SD 2.6). Of cases, 37 (64%) were due to a long-term line/pacemaker, and 21 (36%) were due to fibrosing mediastinitis. After stent placement, 36 (62%) patients were placed on long-term anticoagulation, and 22 (38%) were not placed on anticoagulation. Percent stenosis was evaluated on follow-up imaging by dividing smallest diameter of the stent by a normal nonstenotic segment of the stent and multiplying by 100.
Technical success was achieved in all cases. There was no significant difference in number of patients who reported a return of symptoms characteristic of benign SVC syndrome between the anticoagulated (16 of 36; 44.4%) and nonanticoagulated (11 of 22; 50%) groups (P = .68). There was no significant difference in the mean percent stenosis between the anticoagulated (40.4% ± 34.7% range, 0-100%) and nonanticoagulated (32.1% ± 29.2% range, 1.7%-100%) groups (P = .36). No significant difference was found in the time (days) between date of procedure and date of return of symptoms (anticoagulated, 735.9 d ± 1,003.1 range, 23-3,851 d; nonanticoagulated, 478 d ± 826.6 range, 28-2,922 d) (P = .49). There was no difference in primary patency between groups (P = .59). Finally, 1 patient (2.8%) in the anticoagulated group required surgical intervention, whereas none in the nonanticoagulated group required surgical intervention.
No significant difference was observed in clinical and treatment outcomes in patients who did and did not receive anticoagulation after stent placement for benign SVC syndrome. Management of benign SVC syndrome after stent placement may not require anticoagulation if confirmed by additional studies.
Quadrilateral space syndrome (QSS) arises from compression or mechanical injury to the axillary nerve or the posterior circumflex humeral artery (PCHA) as they pass through the quadrilateral space ...(QS). Quadrilateral space syndrome is an uncommon cause of paresthesia and an underdiagnosed cause of digital ischemia in overhead athletes. Quadrilateral space syndrome can present with neurogenic symptoms (pain and weakness) secondary to axillary nerve compression. In addition, repeated abduction and external rotation of the arm is felt to lead to injury of the PCHA within the QSS. This often results in PCHA thrombosis and aneurysm formation, with distal emboli. Because of relative infrequency, QSS is rarely diagnosed on evaluation of athletes with such symptoms. We report on 9 patients who presented at Mayo Clinic with QSS. Differential diagnosis, a new classification system, and the management of QSS are discussed, with a comprehensive literature review. The following search terms were used on PubMed: axillary nerve, posterior circumflex humeral artery, quadrilateral space, and quadrangular space. Articles were selected if they described patients with symptoms from axillary nerve entrapment or PCHA thrombosis, or if related screening or imaging methods were assessed. References available within the obtained articles were also pursued. There was no date or language restriction for article inclusion; 5 studies in languages besides English were reported in German, French, Spanish, Turkish, and Chinese.
ABSTRACT
Purpose
To identify whether long-term symptom relief and stent patency vary with the use of covered versus uncovered stents for the treatment of benign SVC obstruction.
Methods and Materials
...We retrospectively identified all patients with benign SVC syndrome treated to stent placement between January 2003 and December 2015 (
n
= 59). Only cases with both clinical and imaging follow-up were included (
n
= 47). In 33 (70%) of the patients, the obstruction was due to a central line or pacemaker wires, and in 14 (30%), the cause was fibrosing mediastinitis. Covered stents were placed in 17 (36%) of the patients, and 30 (64%) patients had an uncovered stent. Clinical and treatment outcomes, complications, and the percent stenosis of each stent were evaluated.
Results
Technical success was achieved in all cases at first attempt. Average clinical and imaging follow-up in years was 2.7 (range 0.1–11.1) (covered) and 1.7 (range 0.2–10.5) (uncovered), respectively. There was a significant difference (
p
= 0.044) in the number of patients who reported a return of symptoms between the covered (5/17 or 29.4%) and uncovered (18/30 or 60%) groups. There was also a significant difference (
p
= < 0.001) in the mean percent stenosis after stent placement between the covered 17.9% (range 0–100) ± 26.2 and uncovered 48.3% (range 6.8–100) ± 33.5 groups. No significant difference (
p
= 0.227) was found in the time (days) between the date of the procedure and the date of clinical follow-up where a return of symptoms was reported covered: 426.6 (range 28–1554) ± 633.9 and uncovered 778.1 (range 23–3851) ± 1066.8. One patient in the uncovered group had non-endovascular surgical intervention (innominate to right atrial bypass), while none in the covered group required surgical intervention. One major complication (SIR grade C) occurred that consisted of a pericardial hemorrhagic effusion after angioplasty that required covered stent placement. There were no procedure-related deaths.
Conclusion
Both covered and uncovered stents can be used for treating benign SVC syndrome. Covered stents, however, may be a more effective option at providing symptom relief and maintaining stent patency if validated by further studies.
Objective This study was conducted to determine the sensitivity and specificity of laser Doppler flowmetry (LDF) measurements for digital obstructive arterial disease (DOAD) using angiography as the ...reference standard and to compare the accuracy of different classical tests used to assess DOAD. Diagnosis of vascular abnormalities at the digital level is challenging. Angiography is the gold standard for assessment of DOAD but is invasive and expensive to perform. Methods We performed a retrospective analysis of consecutive patients referred at Mayo Clinic (Rochester, Minn) for upper extremity arterial assessment during a 27-month period. Finger-brachial index, skin blood flow (in arbitrary units a.u.), and skin temperature (in degrees Celsius) were recorded in each digit on the pulp at baseline and after a thermal challenge test (hand placed in a thermal box at 47.0°C for 15 minutes). Angiogram analysis was blinded and performed by a radiologist using a vascularization scale ranging from 0 (no vessel) to 4 (normal). The receiver operating characteristic curve was used to define a specific cutoff point to detect DOAD. Twenty-two patients had LDF measurements and complete angiograms. Results A total of 185 digits were analyzed because some patients had only analysis of one hand. The best area under the curve (AUC) was 0.98 (range, 0.94-0.99) for postwarming skin blood flow, with a cutoff point of ≤206 a.u. This AUC was statistically different from AUCs of all the other tests ( P < .01). Sensitivity and specificity were 93% (95% confidence interval, 85%-97%) and 96% (95% confidence interval, 90%-99%), respectively. Conclusions LDF combined with a thermal challenge is highly accurate, safe, and noninvasive means to detect DOAD.
Small studies suggest an association between abdominal aortic aneurysms (AAAs) and hernias, possibly related to connective tissue weakness. We evaluated the association between AAA and abdominal wall ...hernia (AWH), using peripheral arterial disease (PAD) patients as controls, in Olmsted County, Minnesota. In a retrospective cohort study we queried the electronic medical records for the diagnosis of AAA. The resulting data were then queried for prevalence of AWH. The same set of queries was repeated for PAD. Occurrence of AWH in the 2 groups was compared using the chi-square test. Of the 187 151 patient records queried, 939 had AAA and 3465 had PAD. Abdominal wall hernia occurred in 157 (16.7%) patients with AAA and in 343 (9.9%) patients with PAD. Abdominal wall hernia was 1.7 times more prevalent in those with AAA versus PAD (P < .0001). A history of hernia may prompt screening for AAA in some patients.
Abstract Background The occupational hazards of working in the interventional laboratory have been inadequately studied for physicians and remain unaddressed for nonphysician personnel. Objectives ...This study sought to determine whether the prevalence of work-related musculoskeletal pain, cancer, and other medical conditions is higher among physicians and allied staff who work in interventional laboratories compared with employees who do not. Methods Mayo Clinic employees who work in affiliated hospitals with interventional cardiology or interventional radiology laboratories took an electronic survey. Results were stratified on the basis of self-reported occupational exposure to procedures that involve radiation. Results There were 1,543 employees (mean age 43 ± 11.3 years, 33% male) who responded to the survey (response rate of 57%), and 1,042 (67.5%) reported being involved with procedures utilizing radiation. These employees reported experiencing work-related pain more often than the control group before (54.7% vs. 44.7%; p < 0.001) and after adjustment for age, sex, body mass index, pre-existing musculoskeletal conditions, years in profession, and job description (odds ratio: 1.67; 95% confidence interval: 1.32 to 2.11; p < 0.001). Musculoskeletal pain varied significantly by job description, with the highest incidence reported by technicians (62%) and nurses (60%) followed by attending physicians (44%) and trainees (19%; p < 0.001). There was no difference in cancer prevalence between groups (9% vs. 9%; p = 0.96). Conclusions Musculoskeletal pain is more common among healthcare workers who participate in interventional procedures and is highest in nonphysician employees. The diagnosis of cancer in employees who participate in procedures that utilize radiation was not elevated when compared to controls within the same departments, although any conclusion regarding causality is limited by the cross-sectional nature of the study, as well as the low overall prevalence of malignancy in our study group.
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