Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis

Serum paraoxonase (PON1) is an esterase that is associated with high-density lipoproteins (HDLs) in the plasma; it is involved in the detoxification of organophosphate insecticides such as parathion and chlorpyrifos. PON1 may also confer protection against coronary artery disease by destroying pro-inflammatory oxidized lipids present in oxidized low-density lipoproteins (LDLs). To study the role of PON1 in vivo, we created PON1-knockout mice by gene targeting. Compared with their wild-type littermates, PON1-deficient mice were extremely sensitive to the toxic effects of chlorpyrifos oxon, the activated form of chlorpyrifos, and were more sensitive to chlorpyrifos itself. HDLs isolated from PON1-deficient mice were unable to prevent LDL oxidation in a co-cultured cell model of the artery wall, and both HDLs and LDLs isolated from PON1-knockout mice were more susceptible to oxidation by co-cultured cells than the lipoproteins from wild-type littermates. When fed on a high-fat, high-cholesterol diet, PON1-null mice were more susceptible to atherosclerosis than their wild-type littermates.     

State-dependent nickel block of a high-voltage-activated neuronal calcium channel

Effect of nickel ions (Ni2+) on noninactivating calcium channels in squid giant fiber lobe (GFL) neurons were investigated with whole cell voltage clamp. Three different effects of Ni2+ were observed to be associated with distinct Ca2+ channel activation states. 1) Nickel ions appear to stabilize closed channel states and, as a result, slow activation kinetics. 2) Nickel ions block open channels with little voltage dependence over a wide range of potentials. 3) Block of open channels by Ni2+ becomes more effective during an extended strong depolarization, and this effect is voltage dependent. Recovery from this additional inhibition occurs at intermediate voltages, consistent with the presence of two distinct types of Ni2+ block that we propose correspond to two previously identified open states of the calcium channel. These results, taken together with earlier evidence of state-dependent block by omega-agatoxin IVA, suggest that Ni2+ generates these unique effects in part by interacting differently with the external surface of the GFL calcium channel complex in ways that depend on channel activation state.     

The Impact of Biology on Risk Assessment--workshop of the National Research Council''s Board on Radiation Effects Research. July 21-22, 1997, National Academy of Sciences, Washington, DC

Cholinesterases exhibit functions apart from their esterase activity. We have demonstrated an aryl acylamidase and a zinc stimulated metallocarboxypeptidase activity in human serum butyrylcholinesterase. To establish the presence of zinc binding sites in the enzyme we examined the effect of metal chelators on its catalytic activities. The metal chelators 1,10-phenanthroline and N,N,N',N'-tetrakis (2-pyridyl methyl)ethylene diamine (TPEN) inhibited all the three catalytic activities in the enzyme. However, EDTA inhibited the peptidase activity exclusively without affecting the cholinesterase and aryl acylamidase activities. The catalytic activities were recovered upon removal of the chelator by Sephadex G-25 chromatography. Pre-treatment of the enzyme with any one of the three chelators resulted in the binding of the enzyme to a zinc-Sepharose column or to 65Zn2+. Histidine modification of the enzyme pretreated with chelators resulted in abolition of 65Zn2+ binding and zinc-Sepharose binding. Whereas the binding studies demonstrated removal of a metal from a Zn2+ binding site, attempts to remove the metal responsible for catalytic activity were unsuccessful. Atomic absorption spectroscopy indicated approximately 2.5 mol of zinc per mol of enzyme before treatment with EDTA and 1 mol zinc per mol enzyme after EDTA treatment. The results indicate that there are at least two metal binding sites on butyrycholinesterase. The presence of two HXXE...H sequences in butyrylcholinesterase supports these findings. Our studies implicate a zinc dependent metallocarboxypeptidase activity in the non-cholinergic functions of butyrylcholinesterase.     

Breast health care. A review

Breast health care was rarely acknowledged in the health and science fields prior to this century and has only begun, in recent years, to receive attention outside of pregnancy/lactation or cancer screening and treatment. Yet much health care is involved with regard to this reproductive and sexual organ. With any group of clients, practitioners of women's health care must address an assortment of breast health matters. This article offers an overview of the history of breast health care, the epidemiology of benign breast conditions and cancer, the anatomy and physiology of the breast, and breast development over the lifespan. Also presented are a review of breast assessment and examination, suggestions for routine care of the breast, and an overview of major health issues related to this reproductive organ. Health issues addressed include, among others, nodular and cystic changes, nipple discharge, breast/nipple pain, mastitis, elective alterations, and cancer. Discussion is focused on the latest approaches to optimal breast health care.     

New macrodiolide antibiotics, 11-O-monomethyl- and 11, 11'-O-dimethylelaiophylins, from Streptomyces sp. HKI-0113 and HKI-0114

Elaiophylin (1) and two new methyl derivatives, 11-O-monomethylelaiophylin (2) and 11,11'-O-dimethylelaiophylin (3), were isolated from the mycelium cake of Streptomyces strains HKI-0113 and HKI-0114. The structures of 2 and 3 were determined by mass spectrometric and NMR investigations. Compounds 2 and 3 display antimicrobial and moderate cytotoxic activities.     

Antibiotic-associated haemorrhagic colitis

Antibiotic-associated haemorrhagic colitis is an uncommon cause of bloody diarrhoea in patients taking penicillin or penicillin-related antibiotics. Symptoms of abdominal pain and bloody diarrhoea occur within 1 week of antibiotic use and resolve without specific therapy within days of discontinuing the offending antibiotic. There is an apparent increased incidence of the disease in patients of Oriental ethnicity. The pathogenesis is unknown. We present two cases of haemorrhagic colitis in patients taking penicillin-related antibiotics who presented within 4 months of each other. One of the patients was being treated for Helicobacter pylori infection. The published literature is reviewed with particular emphasis on the histology and pathogenesis of the condition.     

Wavefronts and their propagation in astigmatic optical systems

The geometry of the astigmatic wavefront is derived from the symplectic nature of linear optics. It is shown to be paraboloidal. Equations are derived that govern the propagation of such wavefronts through astigmatic systems in general and through thin lenses and across refracting interfaces and homogeneous gaps in particular. The equations allow the generalization of the concept of wavefront curvature or vergence to astigmatic systems. In particular they show how the step-along method of calculating wavefront curvature is generalized. Not only are Keating's earlier conclusions on this topic confirmed but also they are shown to hold under more general circumstances. They hold even when the system contains gradient-index elements such as the natural lens of the eye. Some of the premises used in the earlier study are shown not to be necessary: they are a consequence of symplecticity. The analysis also provides a step-along procedure for calculating wave-front direction. A numerical example in the Appendix shows the application of the step-along method to a particular separated astigmatic system: the back-vertex power of the system is determined as is the equation of the emergent wavefront for a distant object point.     

Short-term effects of inhaled albuterol on maternal and fetal circulations

Short-term circulatory effects with the maximum recommended dose of inhaled albuterol (Proventil) were studied on 12 asthmatic patients between 33 and 39 weeks' gestation. The mean maternal blood pressures and heart rates, systolic/diastolic ratios of the uterine arcuate and umbilical arteries, and fetal heart rates and aortic velocities were unaffected during the first 2 hours after dosing.     

Adrenal hypoplasia congenita with hypogonadotropic hypogonadism: evidence that DAX-1 mutations lead to combined hypothalmic and pituitary defects in gonadotropin production

Adrenal hypoplasia congenita (AHC) is an X-linked disorder that typically presents with adrenal insufficiency during infancy. Hypogonadotropic hypogonadism (HHG) has been identified as a component of this disorder in affected individuals who survive into childhood. Recently, AHC was shown to be caused by mutations in DAX-1, a protein that is structurally similar in its carboxyterminal region to orphan nuclear receptors. We studied two kindreds with clinical features of AHC and HHG. DAX-1 mutations were identified in both families. In the JW kindred, a single base deletion at nucleotide 1219 was accompanied by an additional base substitution that resulted in a frameshift mutation at codon 329 followed by premature termination. In the MH kindred, a GGAT duplication at codon 418 caused a frameshift that also resulted in truncation of DAX-1. Baseline luteinizing hormone (LIT), follicle-stimulating hormone (FSH), and free-alpha-subunit (FAS) levels were determined during 24 h of frequent (q10 min) venous sampling. In patient MH, baseline LH levels were low, but FAS levels were within the normal range. In contrast, in patient JW, the mean LH and FSH were within the normal range during baseline sampling, but LH secretion was erratic rather than showing typical pulses. FAS was apulsatile for much of the day, but a surge was seen over a 3-4-h period. Pulsatile gonadotropin releasing hormone (GnRH) (25 ng/kg) was administered every 2 h for 7 d to assess pituitary responsiveness to exogenous GnRH. MH did not exhibit a gonadotropin response to pulsatile GnRH. JW exhibited a normal response to the first pulse of GnRH, but there was no increase in FAS. In contrast to the priming effect of GnRH in GnRH-deficient patients with Kallmann syndrome, GnRH pulses caused minimal secretory responses of LH and no FAS responses in patient JW. The initial LH response in patient JW implies a deficiency in hypothalamic GnRH. On the other hand, the failure to respond to pulsatile GnRH is consistent with a pituitary defect in gonadotropin production. These two cases exemplify the phenotypic heterogeneity of AHC/HHG, and suggest that DAX-1 mutations impair gonadotropin production by acting at both the hypothalamic and pituitary levels.