A phase I trial of α-interferon in combination with pentostatin in hematologic malignancies

Pentostatin, a novel inhibitor of adenosine deaminase, has shown activity in various lymphoid malignancies of both the T and B cell lineage. This agent has unique side effects and in general myelosuppression has been mild. Interferon has both antiviral and antineoplastic properties. This agent has shown activity in hairy cell leukemia, chronic granulocytic leukemia, low grade lymphoma, and myeloma. Side effects from interferon are in general dissimilar to those that have been seen with pentostatin and in particular myelosuppression has not been a major toxicity with low doses of interferon. This current trial explored the combination of pentostatin and interferon in hematologic malignancies. Fifteen patients were enrolled in this phase I trial at a fixed dose of pentostatin of 4 mg/m² biweekly and interferon at doses of 0.5, 1, 2, or 4 million units/m² of interferon. At the first three dose levels of interferon nausea and vomiting were the predominant toxicity and appeared to worsen with time on study. Fatigue also was seen at the lowest level of interferon and was severe enough to cause two individuals to discontinue the study medications. At higher dose levels of interferon, myelosuppression, nausea and vomiting, and fatigue were the predominant toxicities. One patient with hairy cell leukemia had a complete response and a second patient with T cell cutaneous lymphoma had a partial response which lasted for 6 to 7 weeks. The maximum tolerated dose of interferon with pentostatin in this patient population was four million units/m².     

Alterations in the dimensions of aortopulmonary septum in hypertensive subjects.

The neural crest origin of the aortopulmonary septum has led us to investigate the septum for a special function, and we designed the present study to assess the alteration, if any, in the dimensions of the aortopulmonary septum in hypertension. The dimensions of the aortopulmonary septum were measured by echocardiography in 36 hypertensive and 36 age- and sex-matched normotensive subjects. Echocardiographic examination included measurement of the cross-sectional area of the aortopulmonary septum with standard two-dimensional views from the parasternal windows. Standardization of this dimension with appropriate cardiac measurements such as aortic and internal left ventricular diameters was also performed to provide growth-independent estimates of septal size. The average area of the septum in the hypertensive group was 2.183 +/- 0.391 cm2, significantly lower than that in the normotensive group (2.370 +/- 0.415 cm2). There were also significant differences in the area of the aortopulmonary septum between the groups when the values were standardized with internal left ventricular diameters. In conclusion, these data confirm that the aortopulmonary septum is smaller in hypertensive than in normotensive humans. This difference might be the result of a possible function of the aortopulmonary septum in blood pressure regulation.     

Mitochondrial complex I and IV activities in leukocytes from patients with parkin mutations.

The parkin protein functions as a RING-type ubiquitin protein ligase. Considering the possibility that impaired ubiquitin-proteosomal system activity may impair antioxidant defenses and enhance oxidative stress, we have investigated the activity of mitochondrial respiratory enzymes in patients with parkin gene mutations. A significant decrease in the leukocyte complex I activity was found both in patients with parkin mutations (62.5%) and idiopathic PD (64.5%) compared with age-matched controls (P < 0.001). Complex IV activity was also decreased significantly in idiopathic PD patients (60%), but no difference was detected between controls and patients with parkin mutations.     

Effects of captopril and losartan on myocardial ischemia-reperfusion induced arrhythmias and necrosis in rats.

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 (AT (1)) receptor blockers improve ischemia-reperfusion induced arrhythmias and infarct size in several animal models. However, the effects of pretreatment with ACEIs or AT (1) receptor blockers on acute myocardial infarct size and arrhythmias are controversial. Thus, we sought to assess the comparative effects of pretreatment with ACEI captopril and AT (1)-receptor blocker losartan on myocardial infarct size and arrhythmias in a rat model of ischemia-reperfusion. We randomly assigned 92 male Wistar rats for arrhythmias ( n= 60) and necrosis ( n= 32) experiments. To produce arrhythmia, the left main coronary artery was occluded for 7 min, followed by 7 min of reperfusion and to produce necrosis, the the left main coronary artery was occluded for 30 min, followed by 120 min of reperfusion. Captopril (3 mg kg (-1)) and losartan (0.2 and 2 mg kg (-1)) were given intravenously 10 min before occlusion. Captopril reduced the incidences of ventricular fibrillation (VF) and mortality associated with irreversible VF, whereas the studied doses of losartan did not. Captopril also decreased the number of ventricular beats on reperfusion. Losartan 2 mg kg (-1) reduced both the number of ventricular premature beats and the incidence of ventricular tachycardia (VT) on reperfusion, while losartan at dose of 0.2 mg kg (-1) had no effect on these arrhythmias. Compared to the control group, both captopril and losartan reduced myocardial infarct size in the rat model of ischemia-reperfusion, but this was statistically significant for captopril only. In this experimental model, although captopril did not reduce the incidence of reperfusion-induced VT, it was more effective than the AT (1)-receptor blocker losartan at preventing mortality associated with irreversible VF and to reduce myocardial infarct size in rat model of ischemia-reperfusion.     

Impairment of lipophagy by PNPLA1 mutations causes lipid droplet accumulation in primary fibroblasts of Autosomal Recessive Congenital Ichthyosis patients

Background

Autosomal Recessive Congenital Ichthyosis (ARCI) is a group of epidermal keratinization disorders. One of the disease-associated proteins, patatin-like phospholipase domain-containing protein-1 (PNPLA1), plays a key role in the epidermal omega-O-acylceramide synthesis and localizes on the surface of lipid droplets (LDs).