Risk of congenital malformations associated with proximity to hazardous waste sites.

Concern about environmental pollutants has increased; however, it remains unclear whether chronic exposures to toxic chemicals in the environment occur at doses sufficient to produce adverse health effects in humans. To date, community studies have not adequately addressed this question. In this study, the authors linked two existing data bases of the New York State Department of Health to evaluate the relation between congenital malformations and residential proximity to hazardous waste sites in New York State. A total of 9,313 newborns with congenital malformations and 17,802 healthy controls living in proximity to 590 hazardous waste sites in 1983 and 1984 were evaluated. After the authors controlled for several possible confounding factors, results indicated that maternal proximity to hazardous waste sites may carry a small additional risk of bearing children with congenital malformations (odds ratio (OR) = 1.12, 95% confidence interval (Cl) 1.06-1.18). Higher malformation rates were associated with both a higher exposure risk (no exposure risk: OR = 1.00; low exposure risk: OR = 1.09, 95% Cl 1.04-1.15; high exposure risk: OR = 1.63, 95% Cl 1.34-1.99) and documentation of off-site chemical leaks (not exposed: OR = 1.00; exposed, but no leaks at site: OR = 1.08, 95% Cl 1.02-1.15; exposed, and leaks found at site: OR = 1.17, 95% Cl 1.08-1.27). The increased rates detected may be important in terms of their public health implications. Further research is necessary to strengthen causal inferences regarding the teratogenicity, of waste site exposure.     

Physicochemical classification of organisms

The hypervariable residues that compose the major part of proteins’ surfaces are generally considered outside evolutionary control. Yet, these “nonconserved” residues determine the outcome of stochastic encounters in crowded cells. It has recently become apparent that these encounters are not as random as one might imagine, but carefully orchestrated by the intracellular electrostatics to optimize protein diffusion, interactivity, and partner search. The most influential factor here is the protein surface-charge density, which takes different optimal values across organisms with different intracellular conditions. In this study, we examine how far the net-charge density and other physicochemical properties of proteomes will take us in terms of distinguishing organisms in general. The results show that these global proteome properties not only follow the established taxonomical hierarchy, but also provide clues to functional adaptation. In many cases, the proteome–property divergence is even resolved at species level. Accordingly, the variable parts of the genes are not as free to drift as they seem in sequence alignment, but present a complementary tool for functional, taxonomic, and evolutionary assignment.

Recent studies of live cells reveal that cytosolic crowding imposes some unique functional challenges that have previously been unconsidered. Essentially, the cytosolic proteins are not just sterically obstructive, but also interact electrostatically with one another through repulsive and attractive forces (1). These diffusive interactions are commonly referred to as “quinary interactions” (2), and their effect on the proteins largely exceeds that predicted from simplistic hard-sphere crowding models (3). The most dramatic effect of altering the quinary interactions is observed for the protein motions. A protein that normally diffuses relatively freely in the cytosolic compartment can be changed to get stuck to the intracellular surrounding by a single surface mutation (4). The principal determinant behind this effect is the protein-surface charge (4, 5). To maintain the cytosolic components suitably fluid, most biological macromolecules, like proteins, nucleic acids, and membranes, carry repulsive net-negative charge, and complete loss of this repulsion will naturally promote aggregation and functional arrest (1). However, the role of the protein charge has turned out to be more subtle than that: It modulates in detail the functional protein–protein encounters (1, 5–8). Because the strength and duration of these dynamic encounters need to be kept within certain limits for the cell to function optimally, the protein-charge decoration itself has been suggested to be under biological control (1, 4, 9–11). This very idea challenges the notion that the composition of the variable protein surfaces drifts freely and adds another dimension to protein evolution and organism fitness (12). Attention then shifts from the relatively small and highly conserved binding interfaces and active sites visible in crystal structures to the least-conserved parts of the protein surfaces exposed to the cytosolic surrounding. Proteome-wide studies of Escherichia coli confirm that there is indeed a systematic bias toward negative charge density and show also that not any negative charge density is acceptable: Proteins distribute around a moderately negative value, away from which few deviations are observed (1, 13) (Fig. 1). Similar results are obtained from measurements of isoelectric points, leading to the conclusion that the majority of soluble proteins are acidic and that the degree of this acidity varies across organisms (14–17). Classical examples are the proteomes of some halophilic archaea, with net-charge densities 10 times more negative than observed for most other organisms (18–23). Together, these findings show that the variable protein surfaces contain previously unrecognized evolutionary cues, which can be captured in terms of specific sets of physicochemical properties. The question is then whether organism identity can be deduced from physicochemical observables alone. To explore this possibility, we map here the divergence of proteome properties across organisms against the established taxonomic classification and demonstrate that the resolving power is indeed remarkably high. The results show that distinct clustering and separations of proteome properties not only follow taxonomic divisions, but also reflect their adaptation to various biotopes and functional specializations. Given that the data cover ∼18,000 organisms in all kingdoms of life, we focus below on a few representative examples of divergent optimizations and refer the specialist readers to our proteome explorer website for more specific analysis (https://proteome-explorer.herokuapp.com/).Open in a separate windowFig. 1.Outline of approach. (A) The UniProt Proteomes of Archaea, Bacteria, and Eukaryota were sampled and the physicochemical properties of each of their proteins calculated (Methods). From this dataset, containing ∼10,000 proteomes, any species can be further analyzed with respect to its detailed protein properties. (B) The distributions of protein MW and protein NCD for the proteomes of H. salinarum, E. coli, and H. sapiens. (C) Plot of the average MW and NCD values, derived from the protein distributions in B. This two-dimensional representation shows clear separation of the three species. Corresponding plots can be obtained for all UniProt Proteomes and, similarly, for all NCBI Assemblies (Methods; SI Appendix, Fig. S1; and Fig. 2). (D–F) Generally, the protein-surface charge of individual proteins follows closely that of the proteome average (SI Appendix, Fig. S19). Shown are surface charge potentials in vacuum (red for negative and blue for positive) of ribonucleotide reductase orthologs in H. salinarum (UniProt {"type":"entrez-protein","attrs":{"text":"Q9HMU3","term_id":"74568776","term_text":"Q9HMU3"}}Q9HMU3 modeled on PDB 5im3), E. coli (PDB 2xap), and H. sapiens (PDB 3hnc).     

PREFERENCES FOR THE NORMATIVE BASIS OF HEALTH CARE PRIORITY SETTING: SOME EVIDENCE FROM TWO COUNTRIES

The present paper concerns the criteria people would prefer for prioritising health programmes. It differs from most empirical studies as subjects were not asked about their personal preferences for programmes per se. Rather, they were asked about the principles that should guide the choice of programmes. Four different principles were framed as arguments for alternative programmes. The results from population surveys in Australia and Norway suggest that people are least supportive of the principle that decision makers should follow the stated preferences of the public. Rather, respondents expressed more support for decisions based upon health maximisation, equality and urgency. Copyright © 2012 John Wiley & Sons, Ltd.     

Acupuncture and transcutaneous electric nerve stimulation in the treatment of pain associated with chronic pancreatitis. A randomized study

In 23 patients with pancreatitis, daily pain for at least 3 months, and no abuse of alcohol, the pain-relieving effect of electroacupuncture (13 patients) or transcutaneous electric nerve stimulation (TENS) (16 patients) was studied. In two prospective studies with a cross-over design, active acupuncture was compared with sham acupuncture, and TENS of the segmental points of the pancreas with sham treatment. Neither electroacupuncture nor TENS brought about pain relief that could substitute for or supplement medical treatment.     

Benzodiazepine/gamma-aminobutyric acid receptor deficit in the midbrain of the seizure-susceptible gerbil.

The density of benzodiazepine/gamma-aminobutyric acid receptor binding sites was lower in the midbrain of seizure-susceptible gerbils compared to control seizure-resistant gerbils. Binding of [3H]diazepam to high-affinity brain-specific sites in membrane homogenates of gerbil brain showed a 20-30% lower binding in midbrain (but not other regions) in adult seizure-susceptible gerbils than in controls. This binding deficit was localized by tissue slice autoradiography with [3H]flunitrazepam to the substantia nigra and mesencephalic periaqueductal gray regions, while higher binding was observed in the interpeduncular nucleus. These differences were also seen in animals sacrificed immediately after a seizure. A parallel deficit of [3H]bicuculline methochloride binding to low-affinity gamma-aminobutyric acid receptors also was seen in the same midbrain regions. Scatchard plot analysis showed that the benzodiazepine binding deficit in the nigra was due to a lower number of binding sites with not significant difference in affinity. Lower [3H]flunitrazepam binding was likewise seen in younger animals (29% lower at 30 days of age, 38% at 60 days, and 21% at 90 days), indicating that the midbrain receptor deficit is present in the seizure-susceptible gerbil prior to the age of onset of seizures at 50-100 days. Therefore, these changes are not likely to result from seizures but reflect genetically determined biochemical differences that could play a role in the expression of seizure susceptibility. The deficit in midbrain benzodiazepine/gamma-aminobutyric acid receptors in the seizure-susceptible gerbil would be consistent with the hypothesis that a deficit of gamma-aminobutyric acid-mediated inhibition might contribute to some kinds of epilepsy.     

In vivo studies of intestinal carnitine absorption in rats

We have studied small intestinal absorption of carnitine in vivo using a combination of segmental perfusion techniques and bolus intraluminal injection. We found evidence of a partially saturable absorption process (with Km values of 1035 and 1267 microM for jejunum and ileum calculated for the saturable component) that appeared to be separate from the imino acid transport system. Absorption was characterized by slow mucosal uptake, prolonged mucosal retention, and a very slow mucosal exit process with blood levels of [3H] carnitine still rising 8 h after intraluminal administration. We have also demonstrated the presence of carnitine acetyltransferase in intestinal mucosa and have shown that the intestine forms significant amounts of acetylcarnitine from exogenous carnitine.     

Cystatin C as a marker for glomerular filtration rate in pediatric patients

Cystatin C is a non-glycated 13-kilodalton basic protein produced by all nucleated cells. The low molecular mass and the basic nature of cystatin C, in combination with its stable production rate, suggest that the glomerular filtration rate (GFR) is the major determinant of cystatin C concentration in the peripheral circulation. Recently published studies have shown that cystatin C correlates more strongly than creatinine with GFR measured using the ⁵¹Cr-EDTA clearance. The aim of this study was to evaluate serum cystatin C as a marker for GFR in children. GFR was determined on medical indications using the ⁵¹Cr-EDTA technique in pediatric patients (2–16 years) in our renal unit. Simultaneously their cystatin C and creatinine concentrations were also measured. Of our 52 patients, 19 had a reduced renal function (<GFR 89 ml/min per 1.73 m²) based on the ⁵¹Cr-EDTA clearance. The correlation of cystatin C with the isotopic measurement of GFR tended to be stronger (r=0.89, P=0.073) than that of creatinine (r=0.80). Receiver operating characteristic analysis showed that the diagnostic accuracy of cystatin C was better (P=0.037) than that of creatinine in discriminating between subjects with normal renal function and those with reduced GFR. This study demonstrates that serum cystatin C has an increased diagnostic accuracy for reduced GFR when compared with serum creatinine. Hence, cystatin C seems to be an attractive alternative for the estimation of GFR in children. Received: 13 May 1998 / Revised: 22 September 1998 / Accepted: 22 October 1998     

Endothelial injury and trapping of blood cells in human myocardium following coronary bypass surgery.

To investigate the focal myocytic and microvascular injury that develops during the first hour of reperfusion after hypothermic cardioplegic cardiac arrest, and to compare the influence of gentle versus more abrupt reperfusion, serial atrial biopsies were obtained from 14 patients undergoing uneventful coronary bypass surgery. The biopsies were taken before cardioplegia, at the start of reperfusion, and after 20 and 60 min of reperfusion. Transmission electron micrographs of biopsies examined by stereological techniques revealed endothelial injury. Following 20 min reperfusion there was accumulation of both red blood cells (p = 0.03) and polymorphonuclear leucocytes (p = 0.0004) were found. There was also intravascular accumulation of platelets (p = 0.008) and extravasation of red blood cells (p = 0.02), which increased throughout the observation period. If reperfusion was started with a gradual rise in temperature and pressure, the numbers of platelets in the microvessels were lower than following ordinary, abrupt reperfusion (p = 0.06). It is concluded that reperfusion injury is associated with microcirculatory disturbances with trapping of blood cells, changes which may be favourably modified by a gentle reperfusion technique.