Neurotoxicity of MAO metabolites of catecholamine neurotransmitters: role in neurodegenerative diseases.

The monoamine oxidase (MAO) metabolites of norepinephrine (NE) or epinephrine (EPI) and of dopamine (DA) are 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) and 3,4-dihydroxyphenylacetaldehyde (DOPAL), respectively. The toxicity of these catecholamine (CA) MAO metabolites was predicted over 50 years ago. However, until our recent chemical synthesis of these CA aldehyde metabolites, the hypothesis about their toxicity could not be tested. The present paper reviews recent knowledge gained about these compounds. Topics to be reviewed include: chemical synthesis and properties of DOPEGAL and DOPAL; in vitro and in vivo toxicity of CA aldehydes; subcellular mechanisms of toxicity; free radical formation by DOPEGAL versus DOPAL; mechanisms of accumulation of CA aldehydes in Alzheimer's disease (AD) and Parkinson's disease (PD) and potential therapeutic targets in Alzheimer's disease and Parkinson's disease.

Squamous cell carcinoma arising from the pleura after pneumonectomy for squamous cell carcinoma of the lung.

BACKGROUND: A 67-year-old Caucasian man had a right pneumonectomy for primary bronchogenic carcinoma in 1998. He developed a bronchopleural fistula that was managed with an Eloesser procedure. His appearance 6 years later has been published previously. METHODS: We performed a case report and literature search. RESULTS: In 2008, the patient still had a bronchopleural fistula and reported a new symptom: constant right chest pain. He had experienced extensive asbestos exposure and mesothelioma was suspected. Endoscopy via the Eloesser aperture revealed innumerable tumor nodules. Biopsies of the pleura revealed multifocal, well-differentiated, squamous cell carcinoma with histology that was distinctly different from that of the original lung cancer. The tumor progressed rapidly during work-up and invaded the spine. He received palliative treatment but died 4 months after the onset of chest pain. We conducted a literature search and found 9 previous reports of epidermoid carcinoma arising from the pleura in patients with a chronically draining empyema; 5 patients had a prior pneumonectomy. CONCLUSIONS: Cancer can arise in areas of chronic inflammation such as osteomyelitis with a draining sinus, Crohn's disease, or chronic gastritis. Cases of squamous cell carcinoma arising from the pleura in patients with a chronically draining empyema cavity are extremely rare. We believe this is the sixth report in the literature of squamous cell carcinoma arising from the pleura in a patient with a chronic postpneumonectomy bronchopleural fistula. In vivo video footage of the involved pleura is available

Aggregation of alpha-synuclein by DOPAL, the monoamine oxidase metabolite of dopamine.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the selective loss of dopamine (DA) neurons and the presence of alpha-synuclein (AS) aggregates as Lewy bodies (LBs) in the remaining substantia nigra (SN) neurons. A continuing puzzle in studying PD pathogenesis is that although AS is expressed throughout the brain, LBs and selective dopaminergic cell loss lead to characteristic clinical signs of PD, suggesting that there is a link between AS aggregation and DA metabolism. One potential candidate for this link is the monoamine oxidase (MAO) metabolite of DA, 3,4-dihydroxyphenylacetaldehyde (DOPAL), as neither DA nor DA metabolites other than DOPAL are toxic to SN neurons at physiological concentrations. We tested DOPAL-induced AS aggregation in a cell-free system, in vitro in DA neuron cultures and in vivo with stereotactic injections into the SN of Sprague-Dawley rats by Western blots, fluorescent confocal microscopy and immunohistochemistry. We demonstrate that DOPAL in physiologically relevant concentrations, triggers AS aggregation in the cell-free system, and in cell cultures resulting in the formation of potentially toxic AS oligomers and aggregates. Furthermore, DOPAL injection into the SN of Sprague-Dawley rats resulted in DA neuron loss and the accumulation of high molecular weight oligomers of AS detected by Western blot. Our findings support the hypothesis that DA metabolism via DOPAL can cause both DA neuron loss and AS aggregation observed in PD.

Troponin I in patients without chest pain.

BACKGROUND: Testing for troponin has important clinical value for patients who present with typical symptoms of acute coronary syndromes (ACS) such as chest pain (CP). Much less is known about the value of troponin testing for patients who present with other symptoms of ACS (anginal equivalent symptoms). METHODS: The utilization and prognostic value of cardiac troponin I (cTnI) were evaluated at a Veterans Affairs Acute Care Facility. Clinical charts of 1184 predominantly male patients, who submitted specimens for initial cTnI testing by AxSYM, were evaluated for demographic data, cardiovascular risk factors, major diseases, and complaints at the time of testing. The endpoint was defined as all-cause death during a 200-day period after initial testing. RESULTS: Sixty-one percent of cTnI tests were ordered for patients who did not present with CP. Patients presenting with symptoms other than CP did not have significantly lower plasma cTnI than patients with CP. However, patients with symptoms other than CP were rarely diagnosed with ACS unless cTnI was >/=2 microg/L. The mortality during the follow-up period was severalfold higher among patients presenting with symptoms other than CP (CP, 6%; without CP, 22%; P <0.0001, chi(2) test). cTnI >/=0.2 microg/L provided significant additional predictive information for patients who presented with anginal equivalent symptoms such as shortness of breath or general weakness. CONCLUSION: Patients with anginal equivalent symptoms of ACS and low-positive cTnI are less often diagnosed with ACS and have a higher mortality than patients with CP.