Protein expression studies of desmoplakin mutations in cardiomyopathy patients reveal different molecular disease mechanisms.

Mutations in the gene for desmoplakin (DSP) may cause arrhythmogenic right ventricular cardiomyopathy (ARVC) and Carvajal syndrome (CS). Desmoplakin is part of all desmosomes, which are abundantly expressed in both myocardial and epidermal tissue and serve as intercellular mechanical junctions. This study aimed to investigate protein expression in myocardial and epidermal tissue of ARVC and CS patients carrying DSP mutations in order to elucidate potential molecular disease mechanisms. Genetic investigations identified three ARVC patients carrying different heterozygous DSP mutations in addition to a homozygous DSP mutation in a CS patient. The protein expression of DSP in mutation carriers was evaluated in biopsies from myocardial and epidermal tissue by immunohistochemistry. Keratinocyte cultures were established from skin biopsies of mutation carriers and characterized by reverse transcriptase polymerase chain reaction, western blotting, and protein mass spectrometry. The results showed that the mutation carriers had abnormal DSP expression in both myocardial and epidermal tissue. The investigations revealed that the disease mechanisms varied accordingly to the specific types of DSP mutation identified and included haploinsufficiency, dominant-negative effects, or a combination hereof. Furthermore, the results suggest that the keratinocytes cultured from patients are a valuable and easily accessible resource to elucidate the effects of desmosomal gene mutations in humans.

Limited value of 99mTc depreotide single photon emission CT compared with CT for the evaluation of pulmonary lesions.

OBJECTIVES: A contrast-enhanced multidetector CT (MDCT) scan is the first choice examination when evaluating patients with suspected lung cancer. However, while the clinical focus is on CT, research focus is on molecular biological methods whereby radiolabelled pharmaceuticals are injected into participants and target malignant lung tumours. We examined whether a contrast-enhanced MDCT scan supplied with an additional non-contrast enhanced high-resolution CT scan, or a newer but more expensive (99m)Tc depreotide single photon emission CT (SPECT) scan, was the better first-choice examination for the work-up of pulmonary lesions. Furthermore, we examined whether a (99m)Tc depreotide SPECT scan was an appropriate second-choice examination for patients with indeterminate lesions. METHODS: 140 participants were included in the analysis. CT images were given a malignancy potential rating of 1, 2 or 3 with higher rating being indicative of disease. (99m)Tc depreotide SPECT images were graded either positive or negative. Histopathology and CT follow-up were used as reference standard. Sensitivity, specificity and diagnostic accuracy were calculated. RESULTS: Overall sensitivity, specificity and diagnostic accuracy of CT were 97%, 30% and 84%, respectively. Overall sensitivity, specificity and diagnostic accuracy of (99m)Tc depreotide SPECT were 94%, 58% and 76%, respectively. For indeterminate lesions sensitivity, specificity and diagnostic accuracy of (99m)Tc depreotide SPECT were 71%, 68% and 69%, respectively. CONCLUSION: Both CT and (99m)Tc depreotide SPECT made valuable contributions to the evaluation of pulmonary lesions. (99m)Tc depreotide SPECT results were not superior to CT results and did not contribute further to the diagnostic work-up. Regarding indeterminate lesions,( 99m)Tc depreotide SPECT sensitivity was too low.