Effect of aspirin response signature gene expression on preterm birth and preeclampsia among women with lupus: a pilot study.

BACKGROUND: Women with lupus have an increased risk of preeclampsia and preterm birth, and aspirin 81 mg/day is recommended as a preventative measure for preeclampsia. This pilot study quantified the association between a 60-gene aspirin response signature (ARS) gene expression with preterm birth and preeclampsia risk among women with lupus taking aspirin. METHODS: The analysis included 48 RNA samples from 23 pregnancies in the Duke Autoimmunity Pregnancy Registry. RNA was isolated from peripheral blood, and quantitative polymerase chain reaction was performed for ARS genes. The primary outcome was poor pregnancy outcome (preeclampsia or preterm birth). Gene expression was modeled as a response to presence or absence of a poor pregnancy outcome using linear regression models, stratified by trimester. RESULTS: Of the 23 pregnancies, nine delivered preterm and four had preeclampsia. Expression of PBX1 and MMD was higher in the second trimester among patients who experienced a poor pregnancy outcome compared to those who did not. However, in a global test of all ARS genes, we identified no association between expression of ARS genes and poor pregnancy outcomes. CONCLUSION: Our pilot study identified two candidate genes that are reflective of the platelet function response to aspirin. Further work is needed to determine the role of these genes in identifying women with lupus at high risk for preeclampsia and preterm delivery despite aspirin therapy.

Genetic associations with viral respiratory illnesses and asthma control in children.

BACKGROUND: Viral respiratory infections can cause acute wheezing illnesses in children and exacerbations of asthma. OBJECTIVE: We sought to identify variation in genes with known antiviral and pro-inflammatory functions to identify specific associations with more severe viral respiratory illnesses and the risk of virus-induced exacerbations during the peak fall season. METHODS: The associations between genetic variation at 326 SNPs in 63 candidate genes and 10 phenotypes related to viral respiratory infection and asthma control were examined in 226 children enrolled in the RhinoGen study. Replication of asthma control phenotypes was performed in 2128 children in the Copenhagen Prospective Study on Asthma in Childhood (COPSAC). Significant associations in RhinoGen were further validated using virus-induced wheezing illness and asthma phenotypes in an independent sample of 122 children enrolled in the Childhood Origins of Asthma (COAST) birth cohort study. RESULTS: A significant excess of P values smaller than 0.05 was observed in the analysis of the 10 RhinoGen phenotypes. Polymorphisms in 12 genes were significantly associated with variation in the four phenotypes showing a significant enrichment of small P values. Six of those genes (STAT4, JAK2, MX1, VDR, DDX58, and EIF2AK2) also showed significant associations with asthma exacerbations in the COPSAC study or with asthma or virus-induced wheezing phenotypes in the COAST study. CONCLUSIONS: We identified genetic factors contributing to individual differences in childhood viral respiratory illnesses and virus-induced exacerbations of asthma. Defining mechanisms of these associations may provide insight into the pathogenesis of viral respiratory infections and virus-induced exacerbations of asthma.

Targeting acute ischemic stroke with a calcium-sensitive opener of maxi-K potassium channels.

During ischemic stroke, neurons at risk are exposed to pathologically high levels of intracellular calcium (Ca++), initiating a fatal biochemical cascade. To protect these neurons, we have developed openers of large-conductance, Ca++-activated (maxi-K or BK) potassium channels, thereby augmenting an endogenous mechanism for regulating Ca++ entry and membrane potential. The novel fluoro-oxindoles BMS-204352 and racemic compound 1 are potent, effective and uniquely Ca++-sensitive openers of maxi-K channels. In rat models of permanent large-vessel stroke, BMS-204352 provided significant levels of cortical neuroprotection when administered two hours after the onset of occlusion, but had no effects on blood pressure or cerebral blood flow. This novel approach may restrict Ca++ entry in neurons at risk while having minimal side effects.

Population dynamics of exploited fish stocks at low population levels.

Models of population dynamics in which per capita reproductive success declines at low population levels (variously known as depensation, the Allee effect, and inverse density-dependence) predict that populations can have multiple equilibria and may suddenly shift from one equilibrium to another. If such depensatory dynamics exist, reduced mortality may be insufficient to allow recovery of a population after abundance has been severely reduced by harvesting. Estimates of spawner abundance and number of surviving progeny for 128 fish stocks indicated only 3 stocks with significant depensation. Estimates of the statistical power of the tests strengthen the conclusion that depensatory dynamics are not apparent for fish populations at the levels studied.

Identifying HIV-2-seropositive individuals by reevaluating HIV-1 indeterminate sera.

HIV-2 infections are rare in North America, with less than 30 cases identified since 1988. We conducted a surveillance for HIV-2 seroprevalence by re-evaluating 457 HIV-1 indeterminate serology specimens submitted to the Maryland Department of Health Laboratories from January 1, 1988 to July 15, 1991. All indeterminates were screened using a combination HIV-1/HIV-2 synthetic peptide EIA. The presence of HIV-2-specific antibodies in initially reactive sera was confirmed utilizing a selective HIV-2 synthetic peptide EIA and Western blotting. Eight sera from four adult males attending public health clinics in suburban Washington, D.C. were found to be specifically reactive for HIV-2 antibodies. One is a native West African; the others remain anonymous. All eight sera demonstrated a gag (core) and pol (polymerase) only pattern of reactivity on HIV-1 Western blots. Targeting selected groups of HIV-1 indeterminate sera from patients attending public health clinics may represent a more appropriate strategy to monitor the spread of HIV-2 in North America than testing similar samples from the blood donor population.

Orogenital sex as a cause of nonfatal air embolism in pregnancy.

A case of nonfatal air embolism from orogenital sex in the 30th week of pregnancy is described. Because of a delay in the diagnosis, the patient did not receive hyperbaric oxygen therapy until 39 hours after the incident. Severe neurologic dysfunction persisted despite hyperbaric therapy. The world literature on orogenital sex in pregnancy with resultant air embolism is reviewed. The pathophysiology of air embolism and the rationale for hyperbaric oxygen treatment are presented. It is strongly recommended that survivors of this form of air embolism be transferred to hyperbaric facilities as soon as possible to reduce the long-term neurologic sequelae.

The effects of hyperbaric oxygen on free flaps in rats.

The effects of hyperbaric oxygen on survival were investigated in free flaps and island flaps. Skin flaps transplanted following 18, 21, and 24 hours of preservation at 24 degrees C demonstrated survival rates of 20%, 10%, and 0%, respectively. Treatment with hyperbaric 100% oxygen improved the survival rates to 66%, 67%, and 40%. A preservation time of 21 to 24 hours at room temperature appears to be the threshold of irreversible ischemic damage. In acute island flaps, flap survival was improved significantly from 35% to 53% and 64% of the random flap area by preoperative or postoperative treatment, respectively. Prolonged preoperative and postoperative treatment improved survival to 66%.

Naloxone-reversible peripheral electroanalgesia in intact and spinal rats.

Peripheral electrical stimulation of the rat produced a "dose-dependent" analgesia both in intact and in spinal animals. Naloxone, a narcotic antagonist, almost completely reversed this analgesia. It is felt that peripheral electroanalgesia acts via the release of endogenous narcotic-like substances, the enkephalins, at spinal and supraspinal centres.

Pathophysiology of sea nettle (Chrysaora quinquecirrha), envenomation in a rat model and the effects of hyperbaric oxygen and verapamil treatment.

The effect of lethal sea nettle envenomation on the morphology and blood flow in various rat organs was characterized and the influence of two antidotes (hyperbaric oxygen and verapamil) was compared. Either antidote slightly prolonged survival, but the protective effects were not statistically significant. The venom caused no histologic alterations in brain, heart, or lungs but induced hepatic and renal necrosis. Hepatocytes in mid-zonal regions and renal tubular epithelium were the cell types predominantly affected. Hyperbaric oxygen and verapamil did not decrease the hepatic injury. The venom did not influence central hemodynamics until preterminally and it diminished blood flow to brain, but not to liver or kidney. Hyperbaric oxygenation protected against venom-induced decreases in blood flow to the brain. These results add toxic hepatic and renal necrosis and cerebral ischemia to the pathophysiology of envenomation in this model.

The microbiology of necrotizing soft tissue infections.

OBJECTIVE: A large number of necrotizing soft tissue infections (NSTI) treated at a single institution over an 8-year period were analyzed with respect to microbial pathogens recovered, treatment administered, and outcome. Based on this analysis, optimal empiric antibiotic coverage is proposed. METHODS: A retrospective chart review of all patients with documented NSTI was conducted. Microbiologic variables were tested for impact on outcome using Fisher's exact test and multivariate analysis by logistic regression. RESULTS: Review of the charts of 198 patients with documented NSTI revealed 182 patients with sufficient microbiologic information for analysis. These 182 patients grew an average of 4.4 microbes from original wound cultures, although a single pathogen was responsible in 28 patients. Eighty-five patients had combined aerobic and anaerobic growth, the most common organisms being, in order, Bacteroides species, aerobic streptococci, staphylococci, enterococci, Escherichia coli, and other gram-negative rods. Clostridial growth was common but did not affect mortality unless associated with pure clostridial myonecrosis. Mortality was affected by the presence of bacteremia, delayed or inadequate surgery, and degree of organ system dysfunction on admission. CONCLUSIONS: NSTI are frequently polymicrobial and initial antibiotic coverage with a broad-spectrum regimen is warranted. The initial regimen should include agents effective against aerobic gram-positive cocci, gram-negative rods, and a variety of anaerobes. The most common organisms not covered by initial therapy were enterococci. All wounds should be cultured at initial debridement, as changes in antibiotic coverage are frequent once isolates are recovered.

Circumcision: its nature and practice among some ethnic groups in southern Nigeria.

A questionnaire survey carried out in five rural communities in mid-southern Nigeria documents the degree and range of male and female circumcision practices among Bini, Esan, Etsako, Ijaw and Ukwuani ethnic groups. Two hundred and eighty adults (154 males and 126 females) reported on themselves and their 1417 children (757 sons and 660 daughters). Circumcision of both sexes remains widely practised, though the timing of the event and extent of surgery show wide variations among, and sometimes, within ethnic groups. The commonest reason for the practice is a strong desire to continue ethnic traditions. Altered sexual urge for women, increased sexual performance for men, protection of baby's health, as well as general reproductive and aesthetic consideration are also important reasons. Traditional surgeons usually perform the operation and few complications were reported to be associated with the procedure in either sex. Female circumcision in this area is not as destructive or mutilating as in some Arabic and East African cultures. Because of the relatively low rate of complications a major campaign against circumcision in these areas does not at present seem warranted.

Mating success of alternative maturation phenotypes in male Atlantic salmon, Salmo salar.

Mature male parr successfully fertilized eggs of anadromous female Atlantic salmon, Salmo salar, in competition with anadromous males under simulated natural conditions. Mating situations were created in which mature male parr and anadromous males competing for the opportunity to spawn with an anadromous female differed in allelic forms of the same enzyme. Females deposited eggs into a sequence of 3 or 4 eggs nests. The mean proportion of eggs in a redd fertilized by parr increased with increasing numbers of parr present at a redd, reaching 23% at male parr: anadromous male ratios of 20:1. Single male parr fertilized, on average, 5% of the eggs in a redd. The proportion of eggs in an egg nest fertilized by parr also depended upon the order of egg nest construction, such that parr mating success was highest at the initial nest constructed and lowest at the final nest. Parr have relatively high fertilization success for their size when compared with the smaller maturation phenotype of other salmonids.

Dissolution of carboxylic acids. III: The effect of polyionizable buffers.

The dissolution behavior of three carboxylic acids of variable aqueous solubility but with approximately equal pKa values into aqueous buffered solutions has been studied as a function of pH and of buffer properties. The dissolution from constant-surface-area compressed disks of benzoic acid, 2-naphthoic acid, and indomethacin into solutions of constant ionic strength (mu = 0.5 with potassium chloride) and constant pH (maintained by pH stat) at 25 degrees C using a rotating disk apparatus was evaluated. Models for dissolution of these weak acids into diprotic and triprotic buffering media are developed to predict the flux of the acid as a function of bulk solution pH and the physical and chemical properties of the buffer and acid. The models assume that mass transfer can be represented by a single second order diffusive term and that instantaneous equilibrium between all reactive species exists. Values of flux and pH at the solid-liquid interface are calculated and the fluxes compared to experimentally determined values. Reasonable correlation was found between values predicted by the models and experimental flux values. Major influences on model accuracy are the Ka and physical properties of the buffer.

Hyperbaric medicine: state of the art, 1979.

An attempt has been made to determine the clinical usage of hyperbaric oxygen therapy at 83 North American hyperbaric treatment centers from 1971 to 1978. Questions were asked about the conditions or diseases treated, yearly case load for each condition, location of functional hyperbaric chambers, types of chambers used, operating costs, and personnel requirements. Commercial diving chambers that treat decompression sickness and air embolism from diving accidents were included in the last two years of the survey. Fifty-seven responses were received; 30 treatment centers had multiple chambers, 24 had monoplace chambers, and three had both types of chambers. A total of 10,942 patients were treated during the eight-year survey period; 8,408 patients (76%) had category I or II conditions, as defined by the Undersea Medical Society. Of the 20 most commonly treated conditions, 17 were in category I or II. During the survey period, the use of hyperbaric oxygen increased, particularly in the treatment of decompression sickness, carbon monoxide poisoning, and osteomyelitis and osteoradionecrosis.

Blood ethanol and serum osmolality in the trauma patient.

The relationships between blood alcohol concentrations and both "osmolar difference" (measured serum osmolality minus expected serum osmolality calculated from serum sodium, serum potassium, blood urea, and blood glucose concentrations) and total serum osmolality have been investigated in severely traumatized patients. Osmolar difference was found to be more strongly correlated to blood alcohol concentration than serum osmolality; however, the error in the slopes of the regression lines was essentially identical (approximately 17%). Consequently, indirect estimations of blood alcohol concentrations by calculating osmolar difference do not improve the accuracy obtained by the estimation by measurement of serum osmolality alone. It appears that the production of unidentified osmoles in traumatized patients significantly influences all indirect calculation of blood alcohol by osmometry. A direct determination of blood alcohol should be made whenever possible.

An augmented Clark model for stability of populations.

A simple modification of a frequently employed age-structured model for population dynamics is presented. This augmented formulation allows the assessment of the impact of age-dependent harvest mortality on population stability. The characteristic frequencies of the predicted oscillations are discussed. The period of oscillation is almost independent of survival and the exact functional form of the recruitment function, and it is not equal to twice the mean age of mature animals, as suggested earlier. It is shown that increased survival before reproduction has a destabilizing influence for populations exhibiting an overcompensatory recruitment function.

The clinical application of hyperbaric oxygen therapy in spinal cord injury: a preliminary report.

While reports of the beneficial effects of hyperbaric oxygen therapy in experimental use appear in the literature, there have been no reports of clinical trials with hyperbaric oxygen therapy of acute spinal cord injury. A series of treatment protocols have thus been designed for treatment of acute spinal cord injury utilizing hyperbaric oxygen. The study has been in progress for the last two years and involved more than 50 patients; results from the therapy trial in 25 patients over the last 18 months will be presented in this preliminary report. Hyperbaric oxygen therapy was generally initiated approximately 7 1/2 hours following injury. Pretreatment and posttreatment motor scores were compared with those of patients given conventional therapy for acute spinal cord injury. Under these circumstances, patients receiving hyperbaric oxygen therapy appeared to recover more quickly, although their final motor scores were about the same as those of patients receiving conventional therapy. Thus, alter the time course of recovery, perhaps without altering the final neurological outcome.

Functional and structural evaluation of the vasculature of skin flaps after ischemia and reperfusion.

Free radicals and other toxic oxygen species play a role in the pathogenesis of ischemic organ damage. The abdominal skin flap has been used as a model to study the effects of superoxide dismutase on the survival of ischemic skin. We have evaluated the evolution of functional and structural injury to the vasculature after ischemic injury in superoxide dismutase-treated and control skin flaps. Ischemia was induced by creating abdominal skin flaps and occluding either the venous or both the venous and arterial blood supplies. Superoxide dismutase was administered immediately after the occlusion was released. At 1 hour of reflow, erythrocyte stasis, platelet deposition, neutrophil adherence, and injury to the endothelium of the large vessels and of the microvasculature were evident. The blood flow in the ischemic skin was only 3 percent of normal. Superoxide dismutase caused no change in the ultrastructure of the vasculature and a marginal decrease in vascular permeability in the ischemic skin at 1 hour of reflow. Increased fluorescent staining of the skin was evident after 24 hours of reflow in the superoxide dismutase-treated flaps. These findings indicate that injury to vascular endothelium by ischemia and reperfusion plays a role in the evolution of skin necrosis.

Morphologic characterization of acute injury to vascular endothelium of skin after frostbite.

Cyclo-oxygenase inhibitors and free-radical scavengers protect the skin against necrosis induced by frostbite. However, the tissue component(s) that determine the evolution of skin necrosis and the mechanism of this pharmacologic protection are not precisely defined. We have studied freezing injury to rabbit ears by serial biopsies examined by light and electron microscopy. The morphologic evidence of skin injury due to freezing was localized exclusively in the endothelial cells, particularly in the arterioles. Within 1 hour, the entire microvasculature demonstrated endothelial damage. Intravascular platelet aggregation occurred just after thawing and closely paralleled the endothelial cell injury. Very few neutrophils were seen initially (at 10 minutes). By 1 hour, leukocyte aggregates were present, and they further increased at 6 hours. Swelling of the interstitium started 10 minutes after thawing, while extravasation of erythrocytes began to appear by 6 hours. Parenchymal elements of skin were relatively free of damage. In the ear cartilage, the chondrocytes showed evidence of damage immediately after freezing. The administration of superoxide dismutase (SOD) during thawing (reperfusion) did not qualitatively alter any of the initial morphologic changes induced by freezing. We conclude that the endothelial cell is the initial target of injury induced by freezing, an initial injury that is mediated by a non-free-radical-mediated mechanism. It is likely that this acute injury ultimately compromises blood flow and leads to skin necrosis.

Effects of hyperbaric oxygen and hyperbaric air on the survival of island skin flaps.

The effects of hyperbaric air and oxygen on skin survival were studied in acute 8 X 8 cm neurovascular island flaps in rats. Skin flaps treated with hyperbaric 8% oxygen (equivalent to room air at standard pressure) exhibited no improvement in skin survival. Skin flaps treated with hyperbaric air (21% oxygen) and hyperbaric 100% oxygen exhibited significant increases in survival.