David Perlman

Translation factor eIF4E rescues cells from Myc-dependent apoptosis by inhibiting cytochrome c release.

Eukaryotic translation initiation factor 4E (eIF4E) markedly reduces cellular susceptibility to apoptosis. However, the mechanism by which the translation apparatus operates on the cellular apoptotic machinery remains uncertain. Here we show that eIF4E-mediated rescue from Myc-dependent apoptosis is accompanied by inhibition of mitochondrial cytochrome crelease. Experiments achieving gain and loss of function demonstrate that eIF4E-mediated rescue is governed by pretranslational and translational activation of bcl-x as well as by additional intermediates acting directly on, or upstream of, the mitochondria. Thus, our data trace a pathway controlling apoptotic susceptibility that begins with the activity state of the protein synthesis machinery and leads to interdiction of the apoptotic program at the mitochondrial checkpoint.

Apoptosis resistance downstream of eIF4E: posttranscriptional activation of an anti-apoptotic transcript carrying a consensus hairpin structure

Aberrant activation of the translation initiation machinery is a common property of malignant cells, and is essential for breast carcinoma cells to manifest a malignant phenotype. How does sustained activation of the rate limiting step in protein synthesis so fundamentally alter a cell? In this report, we test the post transcriptional operon theory as a possible mechanism, employing a model system in which apoptosis resistance is conferred on NIH 3T3 cells by ectopic expression of eIF4E. We show (i) there is a set of 255 transcripts that manifest an increase in translational efficiency during eIF4E-mediated escape from apoptosis; (ii) there is a novel prototype 55 nt RNA consensus hairpin structure that is overrepresented in the 5′-untranslated region of translationally activated transcripts; (iii) the identified consensus hairpin structure is sufficient to target a reporter mRNA for translational activation under pro-apoptotic stress, but only when eIF4E is deregulated; and (iv) that osteopontin, one of the translationally activated transcripts harboring the identified consensus hairpin structure functions as one mediator of the apoptosis resistance seen in our model. Our findings offer genome-wide insights into the mechanism of eIF4E-mediated apoptosis resistance and provide a paradigm for the systematic study of posttranscriptional control in normal biology and disease.

Structural and phylogenetic analysis of the chicken ventricular myosin heavy chain rod

SummaryWe have isolated and characterized five overlapping clones that encompass 3.2 kb and encode a part of the short subfragment 2, the hinge, and the light meromyosin regions of the myosin heavy chain rod as well as 143 bp of the 3′ untranslated portion of the mRNA. Northern blot analysis showed expression of this mRNA mainly in ventricular muscle of the adult chicken heart, with trace levels detected in the atrium. Transient expression was seen in skeletal muscle during development and in regenerating skeletal muscle following freeze injury. To our knowledge, this is the first report of an avian ventricular myosin heavy chain sequence. Phylogenetic analysis indicated that this isoform is a distant homolog of other ventricular and skeletal muscle myosin heavy chains and represents a distinct member of the multigene family of sarcomeric myosin heavy chains. The ventricular myosin heavy chain of the chicken is either paralogous to its counterpart in other vertebrates or has diverged at a significantly higher rate.

Adalimumab induced pulmonary sarcoid reaction.

Sarcoidosis is a multisystem granulomatous inflammatory disease of unknown etiology. There is evidence that Tumor Necrosis Factor alpha (TNF-α) antagonists are useful in the treatment of advanced or refractory disease. However, sarcoidosis-like reaction has been reported with TNF-α blockade in other inflammatory conditions. Here we report a case of sarcoid-like reaction in a patient with psoriatic arthritis shortly after initiation of adalimumab therapy. Stopping adalimumab and systemic anti-inflammatory therapy with corticosteroids resulted in resolution of pulmonary symptoms and chest radiographic findings. Though TNF-α plays a critical role in pathogenesis of sarcoidosis, the development of sarcoid reaction with TNF-α blockade is paradoxical and the mechanism of this response remains unknown. TNF-α induced sarcoid-reaction could involve multiple organs. Its development with one agent does not preclude therapy with other TNF-α blockers.

Estimates of restrictive ventilatory defect in the mining industry. Considerations for epidemiological investigations: a cross-sectional study

Objectives (1) To assess the impact of American Thoracic Society and European Respiratory Society (ATS/ERS) ‘acceptability’ and ‘usability’ criteria for spirometry on the estimates of restrictive ventilatory defect in a population of taconite miners. (2) To compare estimates of restrictive ventilatory defect with three different pulmonary function tests (spirometry, alveolar volume (VA) and diffusing capacity (DL,CO)). (3) To assess the role of population characteristics on these estimates. Design Cross-sectional study. Setting Current and former workers in six current taconite mining operations of northeastern Minnesota were surveyed. Participants We attempted to enrol 3313 participants. Of these, 1353 responded while 1188 current and former workers fully participated in the survey and 1084 performed complete pulmonary function testing and were assessed. Primary and secondary outcome measures We applied ATS/ERS acceptability criteria for all tests and categorised participants into groups according to whether they fully met, partially met or did not meet acceptability criteria for spirometry. Obstruction and restriction were defined utilising the lower limit of normal for all tests. When using VA, restriction was identified after excluding obstruction. Results Only 519 (47.9%) tests fully met ATS/ERS spirometry acceptability criteria. Within this group, 5% had obstruction and 6%, restriction on spirometry. In contrast, among all participants (N=1084), 16.8% had obstruction, while 4.5% had restriction. VA showed similar results in all groups after obstruction was excluded. Impaired gas transfer (reduced DL,CO) was identified in less than 50% of restriction identified by either spirometry or VA. Body mass index (BMI) was significantly related to spirometric restriction in all groups. Conclusions Population estimates of restriction using spirometry or VA varied by spirometric acceptability criteria. Other factors identified as important considerations in the estimation of restrictive ventilatory defect included increased BMI and gas transfer impairment in a relatively smaller proportion of those with spirometric restriction. These insights are important when interpreting population-based physiological data in occupational settings.

Cognitive function in idiopathic pulmonary fibrosis

The purpose of this study was to investigate whether there is evidence that individuals with severe idiopathic pulmonary fibrosis (IPF) have cognitive deficits when compared to individuals with healthy lungs. Participants completed five neuropsychological tests: Trail Making Test (TMT) A and B, Stroop Color Word Test (1, 2, 3), Hopkins Verbal Learning Test, Boston Naming Test, and Grooved Pegboard Test, additionally, the short form-36 and Beck Depression Index. Twelve participants (7 male, mean age 69.3, 9.4 years) comprised the severe IPF group defined by a diffusion capacity for carbon monoxide (DLCO) <30%. Thirty-four patients (22 male, mean age 63.2, 9.6 years) comprised the mild-to-moderate group with a DLCO >30%. Participating spouses (n = 15, 4 male) served as the control group and had a mean age of 66.0, 10.8 years. Controlling for gender and age, the severe group had a significantly longer mean TMT B time (69.4, 135.9 seconds) than the mild group and the control group (86.7 seconds vs 83.2 seconds; p = 0.004 and 0.008 respectively), suggesting inferior performance on tasks requiring speed divided attention. In addition, the severe group had a significantly lower number of correctly identified colors in the Stroop 3 test (22.4 vs 30.6 vs 38.6; p < 0.001), suggesting slower processing speeds when requiring suppression of a familiar response. Participants with severe IPF had worse cognitive function than mild IPF or control subjects. Further research is needed to explain these findings and to develop interventions tailored to address these deficits.

Pleural abnormalities and exposure to elongate mineral particles in Minnesota iron ore (taconite) workers

BACKGROUND Iron ore (taconite) mining and processing are an important industry in northern Minnesota and western Michigan. Concerns around exposures have centered largely on exposure to non-asbestiform amphibole elongate mineral particles (EMPs) found in the eastern portion of the Minnesota iron range. METHODS A cross sectional survey was undertaken of current and former taconite workers and spouses along with a detailed exposure assessment. Participants provided an occupational history and had a chest radiograph performed. RESULTS A total of 1188 workers participated. Potential exposures to non-amphibole EMPs were evident across multiple jobs in all active mines. Pleural abnormalities were found in 16.8% of workers. There was an association of pleural abnormalities with cumulative EMP exposure that was not specific to the eastern portion of the range. CONCLUSION There was evidence of a mild to moderate increase in pleural abnormalities in this population of miners, associated with geographically non-specific cumulative EMP exposure.

Air in the left ventricle: An unusual case of Endocarditis

Figure 1. Noncontrast thoracic computerized tomography demonstrated air in the left ventricle. A 59-year-old woman who had recently returned from a trip to Laos presented to the emergency department with decreased appetite, altered mentation, and abdominal pain. Four days before admission, she developed vomiting and nonbloody diarrhea. She was intubated in the emergency department mainly for airway protection and admitted to the intensive care unit. Her medical history included poorly controlled diabetes mellitus and gastroesophageal reflux disease. Physical examination revealed a 2/6 systolic murmur and diffuse abdominal tenderness. Computed tomography of the chest and abdomen showed air in the left ventricle (Figure 1) and within the renal collecting system bilaterally (Figure 2). Blood and urine cultures were positive for gram-negative rods, which were later identified as Citrobacter koseri. The organism was resistant to ampicillin but otherwise was pansensitive. The patient initially was treated with meropenem, which was changed later to ceftriaxone based on culture sensitivity results. Transesophageal echocardiography showed an increased echogenic density of the anterior papillary muscle, with multiple small mobile pockets presumed to be secondary to “gas gangrene” of the myocardial tissue and an echo-dense vegetation in the anterior and posterior mitral leaflets (Figure 3). Transesophageal echocardiography also showed a flail anterior mitral leaflet with severe mitral regurgitation and severe pulmonary hypertension. Magnetic resonance imaging of the brain revealed multiple infarcts compatible with an embolic process. The patient subsequently underwent urgent mitral valve replacement with papillary muscle biopsy and culture. Papillary muscle cultures confirmed C. koseri infection. The postoperative course was complicated by cardiogenic shock, which required multiple vasoactive medications, endophthalmitis, and acute kidney injury, which required continuous renal replacement therapy. The patient’s condition slowly improved, and she ultimately had complete recovery of kidney function. At the time of transfer to a long-term acute care hospital, she continued to have mild cognitive deficits, residual leftsided weakness, and dysphagia. This case has been previously reported in the form of an abstract (1). Citrobacter species, which belong to the Enterobacteriaceae family, are environmental organisms commonly found in soil, water, and the intestinal tracts of animals and humans. Although Citrobacter infections typically occur in hospital settings in patients with multiple comorbidities, they are seldom found in the general population (2). C. koseri is frequently associated with neonatal meningitis and brain abscesses. Both of these conditions have high mortality rates (3). In adults, infections are reported mainly in immunocompromised individuals, although these infections can affect immunocompetent individuals (4). Endocarditis caused by C. koseri is extremely rare. To our knowledge, there are only four previous cases of endocarditis due to C. koseri reported in the English literature. The current case demonstrates a unique example of a gas-forming infection secondary to C. koseri presenting as

Considerations for lung transplantation in patients with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive and ultimately fatal disease. Currently, there is no proven effective therapy, and lung transplantation is the only intervention associated with prolonged survival. However, outcomes after lung transplantation are worse for IPF than for other frequent indications such as chronic obstructive pulmonary disease and cystic fibrosis. IPF is one of the most frequent indications for lung transplantation. Available lungs are a scarce resource; therefore, the selection criteria are very important to optimize outcomes after lung transplantation. The optimal procedure (single vs. bilateral lung transplantation) in IPF is not clear and should be determined on a case-by-case basis. IPF patients are often critically ill with advanced respiratory failure requiring high levels of support before transplant, and there are several technical surgical challenges specific to IPF. IPF patients have worse survival after lung transplant, at least in part due to early mortality, but it remains a mainstay of therapy given the lack of effective alternatives.

Acute exacerbation of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disorder and ultimately fatal disease. Acute exacerbation of IPF (AE-IPF) is defined as a rapid deterioration with new radiographic opacities in patients with IPF with no identifiable cause such as infection, pulmonary embolism, or heart failure. Reported incidence of this disease entity is highly variable and the etiology is unknown. Research into the pathobiology of this process has implicated possible causes including microaspirations and occult viral infection. AE-IPF manifests histopathologically as diffuse alveolar damage and can have features of organizing pneumonia in the later phase. High-resolution computed tomography of the chest demonstrates new ground-glass opacities and can have prognostic value based on the pattern and extent of opacities. The mortality of this condition is very high and currently there is no proven effective treatment other than lung transplantation. AE-IPF is a major cause of morbidity and mortality in patients with IPF and further research is needed to elucidate the pathobiology and develop effective treatments.