A case series describing common radiographic and pathologic patterns of hard metal pneumoconiosis.

INTRODUCTION: Hard metal pneumoconiosis is a rare but serious disease of the lungs associated with inhalational exposure to tungsten or cobalt dust. Little is known about the radiologic and pathologic characteristics of this disease and the efficacy of treating with immunosuppression. OBJECTIVE: We describe the largest cohort of patients with hard metal pneumoconiosis in the literature, including radiographic and pathologic patterns as well as treatment options. METHODS: We retrospectively identified patients from the University of Pittsburgh pathology registry between the years of 1985 and 2016. Experts in chest radiology and pulmonary pathology reviewed the cases for radiologic and pathologic patterns. RESULTS: We identified 23 patients with a pathologic pattern of hard metal pneumoconiosis. The most common radiographic findings were ground glass opacities (93%) and small nodules (64%). Of 20 surgical biopsies, 17 (85%) showed features of giant cell interstitial pneumonia. Most patients received systemic corticosteroids and/or steroid-sparing immunosuppression. CONCLUSIONS: Hard metal pneumoconiosis is characterized predominately by radiographic ground glass opacities and giant cell interstitial pneumonia on histopathology. Systemic corticosteroids and steroid-sparing immunosuppression are common treatment options.

De-ubiquitinating enzyme, USP11, promotes transforming growth factor ß-1 signaling through stabilization of transforming growth factor ß receptor II.

The transforming growth factor ß-1 (TGFß-1) signaling pathway plays a central role in the pathogenesis of pulmonary fibrosis. Two TGFß-1 receptors, TßRI and TßRII, mediate this pathway. TßRI protein stability, as mediated by the ubiquitin/de-ubiquitination system, has been well studied; however, the molecular regulation of TßRII still remains unclear. Here we reveal that a de-ubiquitinating enzyme, USP11, promotes TGFß-1 signaling through de-ubiquitination and stabilization of TßRII. We elucidate the role that mitoxantrone (MTX), an USP11 inhibitor, has in the attenuation of TGFß-1 signaling. Inhibition or downregulation of USP11 results in increases in TßRII ubiquitination and reduction of TßRII stability. Subsequently, TGFß-1 signaling is greatly attenuated, as shown by the decreases in phosphorylation of SMAD2/3 levels as well as that of fibronectin (FN) and smooth muscle actin (SMA). Overexpression of USP11 reduces TßRII ubiquitination and increases TßRII stabilization, thereby elevating phosphorylation of SMAD2/3 and the ultimate expression of FN and SMA. Further, elevated expression of USP11 and TßRII were detected in lung tissues from bleomycin-challenged mice and IPF patients. Therefore, USP11 may contribute to the pathogenesis of pulmonary fibrosis by stabilization of TßRII and promotion of TGFß-1 signaling. This study provides mechanistic evidence for development of USP11 inhibitors as potential antifibrotic drugs for pulmonary fibrosis.

Thioridazine improves affective symptoms in schizophrenic patients.

Consenting schizophrenic patients ranging in age from 18 to 63 years were withdrawn from antipsychotics for at least 1 week and randomly assigned to receive identical capsules of thioridazine (n = 13), molindone (n = 10), or haloperidol (n = 12) for a minimum of 6 weeks. Compared with the molindone- and haloperidol-treated patients, the thioridazine-treated patients were significantly improved over time as measured by Brief Psychiatric Rating Scale (BPRS) and Hamilton Rating Scale for Depression (HAM-D) total scores. Improvement in BPRS scores was due largely to improvement in symptoms of anxiety and depression. Subjects did not differ significantly on other measures, with the important exception of weight. On average, molindone patients lost 5 pounds over the 6 weeks of treatment, whereas thioridazine patients gained 6 pounds. Haloperidol-treated patients had no significant weight changes.