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.

Dasatinib sensitizes KRAS mutant colorectal tumors to cetuximab.

KRAS mutation is a predictive biomarker for resistance to cetuximab (Erbitux) in metastatic colorectal cancer (mCRC). This study sought to determine if KRAS mutant CRC lines could be sensitized to cetuximab using dasatinib (BMS-354825, Sprycel), a potent, orally bioavailable inhibitor of several tyrosine kinases, including the Src family kinases (SFKs). We analyzed 16 CRC lines for: (1) KRAS mutation status, (2) dependence on mutant KRAS signaling and (3) expression level of epidermal growth factor receptor (EGFR) and SFKs. From these analyses, we selected three KRAS mutant (LS180, LoVo and HCT116) cell lines and two KRAS wild-type cell lines (SW48 and CaCo2). In vitro, using poly-D-lysine/laminin plates, KRAS mutant cell lines were resistant to cetuximab, whereas KRAS wild-type lines showed sensitivity to cetuximab. Treatment with cetuximab and dasatinib showed a greater antiproliferative effect on KRAS mutant lines when compared with either agent alone in vitro and in vivo. To investigate potential mechanisms for this antiproliferative response in the combinatorial therapy, we performed Human Phospho-Kinase Antibody Array analysis, measuring the relative phosphorylation levels of 39 intracellular proteins in untreated, cetuximab, dasatinib or the combinatorial treatment in the KRAS mutant lines LS180, LoVo and HCT116 cells. The results of this experiment showed a decrease in a broad spectrum of kinases centered on the ß-catenin pathway, the mitogen-activated protein kinase (MAPK) pathway, AKT/mammalian target of rapamycin (mTOR) pathway and the family of signal transducers and activators of transcription (STATs) when compared with the untreated control or monotherapy treatments. Next, we analyzed tumor growth with cetuximab, dasatinib or their combination in vivo. KRAS mutant xenografts showed resistance to cetuximab therapy, whereas KRAS wild type demonstrated an antitumor response when treated with cetuximab. KRAS mutant tumors exhibited minimal response to dasatinib monotherapy. However, as in vitro, KRAS mutant lines exhibited a response to the combination of cetuximab and dasatinib. Combinatorial treatment of KRAS mutant xenografts resulted in decreased cell proliferation, as measured by Ki67, and higher rates of apoptosis, as measured by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling). The data presented in this study indicate that dasatinib can sensitize KRAS mutant CRC tumors to cetuximab and may do so by altering the activity of several key signaling pathways. Furthermore, these results suggest that signaling via EGFR and SFKs may be necessary for cell proliferation and survival of KRAS mutant CRC tumors. These data strengthen the rationale for clinical trials combining cetuximab and dasatinib in the KRAS mutant CRC genetic setting.

The first laboratory-confirmed rabid pig in Maryland, 2003.

This article is the first to describe the clinical picture and potential human health impact of laboratory-confirmed rabies infection in a pet Vietnamese pot-bellied pig in Maryland. Although cases of confirmed rabies infection have been infrequently reported in pet or agricultural during the past 10 years in the United States, exposure to rabies-positive animals remains a public health concern particularly for veterinarians, pet owners and other animal caretakers. It is important that individuals who are in a high-risk rabies exposure group remain vigilant to this potential public health threat in all mammal species.

Premorbid proneness to distress and episodic memory impairment in Alzheimer's disease.

BACKGROUND: Chronic stress has been associated with impaired episodic memory, but the association of premorbidly experienced distress with memory function in Alzheimer's disease is unknown. OBJECTIVE: To investigate the link between proneness to distress and Alzheimer's disease. METHODS: Participants were 363 persons with clinically diagnosed Alzheimer's disease. At baseline, a knowledgeable informant rated each person's premorbid personality (that is, before dementia onset) along five dimensions, one of which was the tendency to experience psychological distress. Participants underwent structured clinical evaluations at baseline and then annually for up to four years. Each evaluation included 17 cognitive tests from which previously established measures of episodic memory, visuoconstruction, repetition, and naming were derived. RESULTS: In a series of random effects models adjusted for age, sex, and education, premorbid distress proneness was associated with baseline impairment in episodic memory but not with impairment in other cognitive domains, or with change in any cognitive domain. No other trait was related to baseline function or rate of decline in any cognitive domain. CONCLUSIONS: The results suggest that premorbid proneness to experience psychological distress is related to level of impairment in episodic memory in persons with Alzheimer's disease, but neither distress proneness nor other personality traits are related to disease progression.

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.

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.

Hyperbaric oxygen therapy for trauma: crush injury, compartment syndrome, and other acute traumatic peripheral ischemias.

In the future, the indications for HBO therapy in acute peripheral ischemic injuries will likely be based on objective criteria rather than, as at present, on clinical diagnoses alone. This chapter offers objective criteria for using HBO in crush injuries and compartment syndromes. The pathophysiology of ATPI are well defined. Hyperbaric oxygen mediates the effects of ATPI through four mechanisms: hyperoxygenation, vasoconstriction, reperfusion, and host factors. The cost benefits of using HBO will be substantial, since complications from ATPI are very expensive. As objective criteria replace the presently used subjective criteria, hyperbaric oxygen therapy will become an integral part of trauma management of these injuries.

Cervical necrotizing fasciitis of odontogenic origin: a case report and review of 12 cases.

PURPOSE: This article reviews the demographics, presentation, cause, clinical findings, and treatment of 12 cases of cervical necrotizing fasciitis of odontogenic origin. PATIENTS AND METHODS: A retrospective chart review of 12 cases treated between 1987 and 1997 was done. RESULTS: Most cases resulted from an abscessed mandibular molar. The most common significant medical conditions in the patient's history were diabetes, hypertension, obesity, and substance abuse. All patients were treated surgically within 24 hours of admission. Hyperbaric oxygen (HBO) was used as adjunctive treatment in all cases. The average length of hospital stay was 31 days. All patients recovered. CONCLUSION: Early surgical intervention and the use of HBO decreases morbidity and improves the clinical outcome.

Chronic carbon monoxide exposure: a clinical syndrome detected by neuropsychological tests.

Chronic exposure to carbon monoxide produces a clinical syndrome that is often overlooked because of obscure symptomatology, a range of presentations, and lack of awareness of the problem. To help physicians recognize and treat the chronic carbon monoxide exposure syndrome, the authors present its objective symptomatology, an approach to diagnosis emphasizing neuropsychological tests, a treatment protocol, and theoretical considerations for the mechanism of hyperbaric oxygen's therapeutic action. For elucidation, eight patients treated in the hyperbaric chamber at a tertiary care facility are described. Diagnosis can be facilitated by recognizing the syndrome based on the patient's history, as well as physical and neuropsychological examinations, with emphasis on identifying potential sources of carbon monoxide exposure. The evaluation and treatment protocols presented, though still experimental, show promise for improving functional, cognitive, and psychiatric capacities.

Outpatient management of HIV-infected adults. The varied challenges for primary care.

Care of persons infected with HIV presents many challenges to primary care physicians. In addition to keeping current on the rapidly advancing medical aspects of the disease, physicians also must be prepared to recognize the complex psychosocial issues that confront their patients. In this article, Dr Myers reviews essential aspects of primary care for HIV-infected adults.

The accuracy of diagnostic laparoscopy in trauma patients: a prospective, controlled study.

BACKGROUND: Numerous studies advocate the use of diagnostic laparoscopy (DL) for abdominal trauma, but none have documented its ability to diagnose specific injuries. This study tests the hypothesis that DL can accurately identify all significant intra-abdominal injuries in trauma patients. METHODS: Of trauma patients requiring laparotomy for presumed injuries, 47 underwent DL followed by laparotomy. Injuries noted at laparoscopy were compared with those found at laparotomy. RESULTS: Of these, 14 patients had no significant injuries necessitating operative intervention noted at laparoscopy and celiotomy. The remaining 33 patients harbored 93 significant injuries at laparotomy, of which only 57.0% were found by DL. DL possessed poor sensitivity (<50%) for injuries to hollow viscera. Despite DL's poor performance in finding specific injuries, it possessed excellent sensitivity (96.2%), and specificity (100%) for determining the need for therapeutic celiotomy. CONCLUSIONS: DL offers no clear advantage over diagnostic peritoneal lavage and computed tomography in blunt trauma. Its utility lies in assessment of the need for laparotomy in patients with penetrating wounds. Currently, DL cannot consistently identify all abdominal injuries, disqualifying it as a therapeutic tool in abdominal trauma.

Confirmation of the pulse oximetry gap in carbon monoxide poisoning.

STUDY OBJECTIVES: To demonstrate the degree to which pulse oximetry overestimates actual oxyhemoglobin (O2Hb) saturation in patients with carbon monoxide (CO) poisoning. This phenomenon has been reported in fewer than 20 humans in the English medical literature. METHODS: A retrospective chart review of 191 patients evaluated for CO poisoning at a regional hyperbaric center identified 124 patients 10 years of age and older who had had both arterial blood gas and pulse oximetry measurements and who had received either high-flow oxygen through a nonrebreather mask or 100% inspired oxygen through an endotracheal tube. Blood gas measurements, including direct spectrophotometric determination of O2Hb and carboxyhemoglobin (COHb) saturation values, were compared with finger-probe pulse oximetry readings. RESULTS: Measured O2Hb saturation (mean +/- SD, 88.7 +/- 10.2%; range, 51.4% to 99.0%) decreased linearly and predictably with rising COHb levels (10.7 +/- 10.4%; range, .2% to 46.4%). Pulse oximetry saturation (99.2% +/- 1.3%; range, 92% to 100%) remained elevated across the range of COHb levels and failed to detect decreased O2Hb saturation. The pulse oximetry gap, defined as the difference between pulse oximetry saturation and actual O2Hb saturation (10.5% +/- 9.7%; range, 0% to 40.6%), approximated the COHb level. CONCLUSION: There is a linear decline in O2Hb saturation as COHb saturation increases. This decline is not detected by pulse oximetry, which therefore overestimates O2Hb saturation in patients with increased COHb levels. The pulse oximetry gap increases with higher levels of COHb and approximates the COHb level. In patients with possible CO poisoning, pulse oximetry must be considered unreliable and interpreted with caution until the COHb level has been measured.

Necrotizing soft tissue infections. Risk factors for mortality and strategies for management.

OBJECTIVE: The authors evaluate in a retrospective fashion the factors influencing outcome in a large group of patients presenting with necrotizing soft tissue infections, and, based on this analysis, propose a plan for optimal care of such patients. SUMMARY BACKGROUND DATA: In many smaller series of patients with necrotizing soft tissue infections, similar analyses of risk factors for mortality have been performed, producing conflicting conclusions regarding optimal care. In particular, debate exists regarding the impact of concurrent physiologic derangements, type and extent of infection, and the role of hyperbaric oxygen in treatment. METHODS: A retrospective chart review of 198 consecutive patients with documented necrotizing soft tissue infections, treated at a single institution during an 8-year period, was conducted. Using a model for logistic regression analysis, characteristics of each patient and his/her clinical course were tested for impact on outcome. RESULTS: The mortality rate among the 198 patients was 25.3%. The most common sites of origin of infection were the perineum (Fournier's disease; 36% of cases) and the foot (in diabetics; 15.2%). By logistic regression analysis, risk factors for death included age, female gender, extent of infection, delay in first debridement, elevated serum creatinine level, elevated blood lactate level, and degree of organ system dysfunction at admission. Diabetes mellitus did not predispose patients to death, except in conjunction with renal dysfunction or peripheral vascular disease. Myonecrosis, noted in 41.4% of the patients who underwent surgery, did not influence mortality. CONCLUSIONS: Necrotizing soft tissue infections represent a group of highly lethal infections best treated by early and repeated extensive debridement and broad-spectrum antibiotics. Hyperbaric oxygen appears to offer the advantage of early wound closure. Certain markers predict those individuals at increased risk for multiple-organ failure and death and therefore assist in deciding allocation of intensive care resources.

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.

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.

A preliminary report on hyperbaric oxygen in the relief of migraine headache.

Oxygen inhalation was early advocated as a treatment for migraine headache. It has been theorized that the efficacy of raising blood oxygen levels in vascular headache is mediated by vasoconstriction and metabolic effects. Hyperbaric oxygen can provide a much greater level of blood oxygenation than can provide a much greater level of blood oxygenation than normobaric oxygen, and in recent studies it has been used in the treatment of cluster headache. The purpose of this study was to compare the effects of hyperbaric oxygen and normobaric oxygen in migraine. Twenty migraineurs were divided randomly into two groups and studied in a hyperbaric chamber during a typical headache attack. Global headache severity was measured by a verbal descriptor scale before and after exposure to oxygen. One group received 100% oxygen at 1 atmosphere of pressure (normobaric) while the other received 100% oxygen at 2 atmospheres of pressure (hyperbaric). One of the 10 patients in the normobaric group achieved significant relief of headache symptoms, while 9 of 10 in the hyperbaric group found relief. Based on a chi-square test, this difference is significant at the P < .005 level. Those patients who did not find significant relief from normobaric oxygen were given hyperbaric oxygen as above. All nine found significant relief. The results suggest that hyperbaric (but not normobaric) oxygen may be useful in the abortive management of migraine headache. Possibilities for the mechanism of this effect, in addition to vasoconstriction, include an increase in the rate of energy-producing and neurotransmitter-related metabolic reactions in the brain which require molecular oxygen.

Regional hemodynamics in 1-day-delayed rodent island flaps.

We have studied the recovery of microvascular function in ischemic epigastric skin flaps by characterizing the regional hemodynamics in the axial and random portions of double- and single-pedicle island skin flaps in the rat. Blood flows were measured with radiolabeled microspheres 1 day after bipedicle flaps were elevated and at 4 hr, 72 hr, and 1 week after ligation of one of the pedicles. These hemodynamic measurements were correlated with assessments of angiogenesis and skin necrosis performed by lectin histochemistry and histopathology. Twenty-four hours after the skin flap elevation, the mean blood flow was 0.26 ml.min-1.g-1. After the ligation of one pedicle, the blood flow in the axial portion of the skin flap was unchanged at 4 hr (0.22 ml.min-1.g-1), declined insignificantly at 72 hr (0.15 ml.min-1.g-1), and remained normal at 1 week. In the random portion of the skin flap very little collateral blood flow was present at 4 hr (0.06 ml.min-1.g-1) and 72 hr (0.09 ml.min-1.g-1). Blood flow in the random skin flap returned to normal by 1 week (0.27 ml.min-1.g-1). Reelevation of the skin flap at 1 week caused an insignificant decline (10%) in total blood flow to the skin flap. Skin necrosis was detected histologically at 72 hr only in the lateral portion of the random skin flap, where blood flow was less than 0.03 ml.min-1.g-1. Increased areas of lectin binding to vascular endothelium were seen in the subdermal layers of the skin flap by 1 week, presumably due to angiogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)