Iontophoresis of polypeptides: effect of ethanol pretreatment of human skin

This paper explores the possibility of iontophoretically enhancing the in vitro transdermal flux of two polypeptides: leuprolide (a LHRH analogue; MW = 1209.4) and a cholecystokinin-8 analogue (CCK-8; MW = 1150.17). Control experiments at an applied voltage of 0.5 V across full-thickness human skin did not yield measurable fluxes of either polypeptide, suggesting that despite the expected iontophoretic flux enhancements, the intrinsic permeability of these polypeptides through skin may be too low to allow significant amounts of the drug to permeate. Therefore, pretreatment with ethanol (to simulate the effect of a chemical permeation enhancer) followed by iontophoresis was investigated with the aim of evaluating the potential of the enhancer plus ionophoresis as a means for controlled transdermal delivery of these polypeptides. The ethanol pretreatment dramatically increased the passive fluxes of both polypeptides, and iontophoresis produced further enhancements in their fluxes. Also, the experimental enhancement factors for leuprolide as a function of the applied voltage appeared to be generally lower than the predictions of the constant field theory. A synergism of iontophoresis with a chemical permeation enhancer may be a potential route for controlled transdermal delivery of these and other high molecular weight polypeptides.     

Potassium permanganate resistant amyloid in fine-needle aspirate of the liver

A case of primary amyloidosis, initially detected by fine-needle aspiration of the liver, is reported here. Amorphous acellular metachromatic material was seen extracellularly in between the hepatocytic cords compressing them. This material showed typical apple-green birefringence under crossed bipolars after alkaline Congo-red staining proved its amyloid nature. It was resistant to potassium permanganate pretreatment, indicating it to be of the AL type. © 1994 Wiley-Liss, Inc.     

ABri peptide associated with familial British dementia forms annular and ring-like protofibrillar structures.

Amyloid plaque deposition involves the aggregation of normally soluble proteins into insoluble amyloid fibrils (fibrillization) and proceeds through intermediates with distinct morphologies, including spherical aggregates, protofibrils, and mature fibrils. Recently, a novel annular protofibril-like intermediate with unique pore-like properties was produced by alpha-synuclein, A beta-Arctic and amylin, which are proteins associated with Parkinson's disease, Alzheimer's disease, and type-II diabetes. The observation of annular structures coupled with size selective channel-like activity by these proteins suggests that these structures may be responsible for vesicle permeability by ion-channel formation. Using atomic force spectroscopy, we report here that the ABri peptide associated with familial British dementia produces similar annular and ring-like protofibril structures during the following sequence of events: spherical aggregates (0.4-1.5 nm height)-->chain-like protofibrils (1.5-2.3 nm height)-->ring-like protofibrils and annular protofibrils (1.5-2.3 nm height). This suggests that ABri fibrillization occurs in a similar fashion to other amyloidogenic proteins and that the annular protofibrillar structures may represent a common amyloid intermediate.     

Cardiovascular risk in parents of children with extreme lipoprotein cholesterol levels: the Bogalusa Heart Study

Fasting serum lipids, lipoprotein cholesterol, and other cardiovascular disease risk factors were examined in 321 natural parents of children with low and/or high levels of beta- and pre-beta-lipoprotein cholesterol. Parents of children from low pre-beta-lipoprotein groups had elevated alpha- and lower pre-beta-lipoprotein cholesterol levels. Parents whose children had high beta-lipoprotein cholesterol levels also had high serum total and beta-lipoprotein cholesterol levels. Parents of children with high levels of both beta- and pre-beta-lipoprotein cholesterol had a high prevalence of both abnormal risk factor levels, as well as clinical evidence of early coronary artery disease (before age 50 years). These observations show that parents of children with high beta- and/or pre-beta-lipoprotein cholesterol levels have greatly enhanced risk for cardiovascular disease, and children mirror their parents' lipoprotein cholesterol levels. These observations emphasize the need for cardiovascular risk evaluation early in life, especially in high-risk families.     

Arterial wall injury and proteoglycan changes in atherosclerosis

The concept of injury as a mechanism leading to atherosclerosis has been fostered by numerous studies of initiating factors and by observation of the response of cardiovascular connective tissue, ie, cellular and extracellular matrix components. Carbohydrate-protein macromolecules of the extracellular matrix are a complex group of biologically important substances that play a crucial role in mesenchymal tissue repair following injury, a process needed to maintain arterial wall integrity. Of particular interest are the proteoglycans that enter into a variety of roles, from that of inhibiting atherosclerosis and helping to maintain fibrillar structures to that of taking part in lipid deposition in the development of atherosclerosis.     

The Emergence of Clinically Abnormal Levels of Cardiovascular Disease Risk Factor Variables Among Young Adults: The Bogalusa Heart-Study

Background. The Bogalusa Heart Study, a long-term epidemiologic investigation of the early natural history of atherosclerosis, was conducted for the first time in 1973-1974 on children from birth through the age of 14 in a biracial (black-white) population. Methods. The emergence of clinically recognizable abnormalities (obesity, hypertension, and hyperlipidemia) was studied in 1,928 young adults, ages 19-32 years, examined in the 1988-1991 survey. Results. The occurrence of morbid levels of cardiovascular disease risk factors varied by race and gender. The prevalence of severe overweight, body mass index ≥ 31.1 kg/m² for males and ≥ 32.3 kg/m² for females, was much higher for black women (20.1%) than for white women (8.7%), black men (14.0%), or white men (11.7%). The frequency of hypertension [systolic blood pressure (BP) ≥ 140 mm Hg, diastolic BP ≥ 90 mm Hg, or treatment for high BP] was greatest for black women (13.9%) versus black men (10.1%), white men (6.2%), or white women (5.0%). Approximately 9.5% of the men and 6% of the women had elevated LDL cholesterol (≥160 mg/dl), while elevated triglycerides (≥250 mg/dl) ranged from 0% in black females to 7.4% in white males. Dyslipoproteinemia related to HDL cholesterol (≤35 mg/dl) was more marked among white men (16%) compared with the other groups (approximately 4%). Correlations for risk factors in a subgroup of 1,587 individuals initially surveyed as children in 1973-1974 were examined as an indication of tracking over a 15-year period. Highly significant correlations were seen for obesity, blood pressure, and LDL cholesterol. Conclusion. Early identification of adverse levels of cardiovascular disease risk factors defined by clinical experience should help to predict and prevent future cardiovascular disease morbidity and mortality.     

Psychiatric considerations in pulmonary disease.

Lung disease is a prominent cause of morbidity and mortality worldwide. When a patient has a common lung disease, such as asthma, or a less prevalent one, such as idiopathic pulmonary fibrosis, psychiatric issues should be considered as an integral part of the care plan for each patient. There have been many studies of psychologic factors and psychiatric syndromes in various lung diseases and their treatment. In this article, the authors focus on an evidence-based approach to reviewing this clinical literature.