Aircraft carriers, electrical power grids, and wildland firefighting, though seemingly different, are exemplars of high reliability organizations (HROs) - organizations that have the potential for catastrophic failure yet engage in nearly error-free performance. HROs commit to safety at the highest level and adopt a special approach to its pursuit. High reliability organizing has been studied and discussed for some time in other industries and is receiving increasing attention in health care, particularly in high-risk settings like the intensive care unit (ICU). The essence of high reliability organizing is a set of principles that enable organizations to focus attention on emergent problems and to deploy the right set of resources to address those problems. HROs behave in ways that sometimes seem counterintuitive - they do not try to hide failures but rather celebrate them as windows into the health of the system, they seek out problems, they avoid focusing on just one aspect of work and are able to see how all the parts of work fit together, they expect unexpected events and develop the capability to manage them, and they defer decision making to local frontline experts who are empowered to solve problems. Given the complexity of patient care in the ICU, the potential for medical error, and the particular sensitivity of critically ill patients to harm, high reliability organizing principles hold promise for improving ICU patient care.
Fecal pathogen contamination of watersheds worldwide is increasingly recognized, and natural wetlands may have an important role in mitigating fecal pathogen pollution flowing downstream. Given that waterborne protozoa, such as Cryptosporidium and Giardia, are transported within surface waters, this study evaluated associations between fecal protozoa and various wetland-specific and environmental risk factors. This study focused on three distinct coastal California wetlands: (i) a tidally influenced slough bordered by urban and agricultural areas, (ii) a seasonal wetland adjacent to a dairy, and (iii) a constructed wetland that receives agricultural runoff. Wetland type, seasonality, rainfall, and various water quality parameters were evaluated using longitudinal Poisson regression to model effects on concentrations of protozoa and indicator bacteria (Escherichia coli and total coliform). Among wetland types, the dairy wetland exhibited the highest protozoal and bacterial concentrations, and despite significant reductions in microbe concentrations, the wetland could still be seen to influence water quality in the downstream tidal wetland. Additionally, recent rainfall events were associated with higher protozoal and bacterial counts in wetland water samples across all wetland types. Notably, detection of E. coli concentrations greater than a 400 most probable number (MPN) per 100 ml was associated with higher Cryptosporidium oocyst and Giardia cyst concentrations. These findings show that natural wetlands draining agricultural and livestock operation runoff into human-utilized waterways should be considered potential sources of pathogens and that wetlands can be instrumental in reducing pathogen loads to downstream waters.
A patient with systemic cytomegalovirus (CMV), including chorioretinitis, received localized and systemic ganciclovir, systemic cidofovir analog, and localized foscarnet. Mutations conferring ganciclovir and cidofovir resistance were detected in CMV from the aqueous fluid but not in CMV from plasma. Quantifying CMV from aqueous fluid was valuable for monitoring the clinical response and predicting resistance.
We investigated whether omega-3 fatty acid intake and erythrocyte membrane omega-3 fatty acid levels are associated with conversion to type 1 diabetes in children with islet autoimmunity (IA).
The Diabetes Autoimmunity Study in the Young is following children at increased genetic risk for type 1 diabetes for the development of persistent IA, as defined as being positive for glutamic acid decarboxylase 65, i, or insulin autoantibodies on two consecutive visits, and then for the development of type 1 diabetes, as diagnosed by a physician. One hundred and sixty-seven children with persistent IA were followed for a mean of 4.8 yr, and 45 of these developed type 1 diabetes at a mean age of 8.7 yr. Erythrocyte membrane fatty acids (as a percent of total lipid) and dietary fatty acid intake (estimated via food frequency questionnaire) were analyzed as time-varying covariates in proportional hazards survival analysis, with follow-up time starting at detection of the first autoantibody.
Neither dietary intake of omega-3 fatty acids nor omega-6 fatty acids were associated with conversion to type 1 diabetes, adjusting for human leukocyte antigen (HLA)-DR, family history of type 1 diabetes, age at first IA positivity, maternal age, maternal education, and maternal ethnicity. Adjusting for HLA-DR, family history of type 1 diabetes and age at first IA positivity, omega-3 and omega-6 fatty acid levels of erythrocyte membranes were not associated with conversion to type 1 diabetes.
In this observational study, omega-3 fatty acid intake and status are not associated with conversion to type 1 diabetes in children with IA.
dietary intake; IA; omega-3 fatty acids; type 1 diabetes mellitus
Because the ability to flexibly experience and appropriately express emotions across a range of developmentally relevant contexts is crucial to adaptive functioning, we examined how adolescent attachment security may be related to more functional emotional behavior during a relationship promoting interaction task. Data were collected from 74 early adolescent girls (Mean age 13.45 years; SD = 0.68; 89% Caucasian) and their primary caregiver. Results indicated that, regardless of the parent’s interaction behavior and the level of stress in the parent-adolescent relationship, greater adolescent security was associated with more positive and less negative behavioral displays, including greater positivity, greater coherence of verbal content and affect, less embarrassment, and less emotional dysregulation in response to a situational demand for establishing intimacy with the parent. Implications for encouraging and fostering adolescents’ capacity to respond to interpersonal contexts in ways that promote the relationship are discussed.
adolescence; attachment; security; intimacy; parent-adolescent interaction
The study evaluated how spiritual and religious functioning (SRF), alcohol-related problems, and psychiatric symptoms change over the course of treatment and follow-up. Problem drinkers (n = 55, including 39 males and 16 females) in outpatient treatment were administered questionnaires at pretreatment, post-treatment, and follow up, which assessed two aspects of SRF (religious well-being and existential well-being), two aspects of alcohol misuse (severity and consequences), and two aspects of psychiatric symptoms (depression and anxiety). Significant improvements in SRF, psychiatric symptoms and alcohol misuse were observed from pretreatment to follow-up. Although SRF scores were significantly correlated with psychiatric symptoms at all three time points, improvement in the former did not predict improvement in the latter. When measured at the same time points, SRF scores were not correlated with the measures of alcohol misuse. However, improvement in SRF (specifically in existential well-being) over the course of treatment was predictive of improvement in the alcohol misuse measures at follow-up. These results suggest that the association between SRF, emotional problems, and alcohol misuse is complex. They further suggest that patients who improve spiritual functioning over the course of treatment are more likely to experience improvement in drinking behavior and alcohol-related problems after treatment has ended.
Alcohol; Spirituality; Psychiatric; Psychotherapy
The nutrient amino acid transporter (NAT) subfamily is the largest subdivision of the sodium neurotransmitter symporter family (SNF; also known as SLC6; HUGO). There are seven members of the NAT population in the African malaria mosquito Anopheles gambiae, two of which, AgNAT6 and AgNAT8, preferably transport indole- and phenyl-branched substrates, respectively. The relative expression and distribution of these aromatic NATs were examined with transporter-specific antibodies in Xenopus oocytes and mosquito larval alimentary canal, representing heterologous and tissue expression systems, respectively. NAT-specific aromatic-substrate-induced currents strongly corresponded with specific accumulation of both transporters in the plasma membrane of oocytes. Immunolabeling revealed elevated expressions of both transporters in specific regions of the larval alimentary canal, including salivary glands, cardia, gastric caeca, posterior midgut and Malpighian tubules. Differences in relative expression densities and spatial distribution of the transporters were prominent in virtually all of these regions, suggesting unique profiles of the aromatic amino acid absorption. For the first time reversal of the location of a transporter between apical and basal membranes was identified in posterior and anterior epithelial domains corresponding with secretory and absorptive epithelial functions, respectively. Both aromatic NATs formed putative homodimers in the larval gut whereas functional monomers were overexpressed heterologously in Xenopus oocytes. The results unequivocally suggest functional synergy between substrate-specific AgNAT6 and AgNAT8 in intracellular absorption of aromatic amino acids. More broadly, they suggest that the specific selectivity, regional expression and polarized membrane docking of NATs represent key adaptive traits shaping functional patterns of essential amino acid absorption in the metazoan alimentary canal and other tissues.
insect; mosquito; essential amino acid; nutrient amino acid transporter; NAT; co-transporter; phenylalanine; tryptophan; monoamine neurotransmitter; malaria; Anopheles gambiae
The Cepheid Xpert MTB/RIF research-use-only (RUO) assay and a laboratory-developed test (LDT) targeting IS6110 were evaluated and compared to mycobacterial culture as the gold standard. The performance characteristics of both molecular assays were determined by using 112 specimens from 90 patients, including 89 pulmonary specimens and 23 extrapulmonary specimens. Of the specimens tested, 37 (33%) were culture positive for the Mycobacterium tuberculosis complex; 29 were pulmonary, and 8 were extrapulmonary. Of these culture-positive specimens, 83% of the pulmonary specimens and 50% of the extrapulmonary specimens were smear positive. There was complete concordance between the smear-positive culture-positive specimens, independent of the anatomical site (100% sensitivity). The sensitivity of the MTB/RIF RUO assay for smear-negative specimens was 60% for pulmonary and 75% for extrapulmonary specimens, while the IS6110 LDT sensitivities were 40% and 0%, respectively. There was also complete concordance among the culture-negative specimens tested. Both assays showed 95% specificity, with four culture-negative specimens testing as positive. A review of patient records indicated that there was a high likelihood of the presence of M. tuberculosis complex DNA in the false-positive specimens. Biosafety analysis was performed and showed an acceptable reduction in organism viability using the processing methods described above. Both molecular assays are suitable for the detection of M. tuberculosis isolates in smear-positive pulmonary and extrapulmonary specimens, while the sensitivity of the detection of M. tuberculosis isolates in smear-negative specimens was variable.
We performed a retrospective (n = 121) and prospective (n = 305) verification of the Cepheid Xpert Flu assay to determine its performance characteristics. The overall sensitivity and specificity were 93% and 100%, respectively. Nasopharyngeal specimen sensitivities were 100% for seasonal influenza A/H1 virus and influenza A/H3 virus, 90% for influenza A/2009/H1N1 virus, and 95% for influenza B virus.
Fragment-based lead design (FBLD) has been used to identify new metal-binding groups for metalloenzyme inhibitors. When screened at 1 mM, a chelator fragment library (CFL-1.1) of 96 compounds produced hit rates ranging from 29–43% for five matrix metalloproteases (MMPs), 24% for anthrax lethal factor (LF), 49% for 5-lipoxygenase (5-LO), and 60% for tyrosinase (TY). The ligand efficiencies (LE) of the fragment hits are excellent, in the range of 0.4–0.8 kcal/mol. The MMP enzymes all generally elicit the same chelators as hits from CFL-1.1; however, the chelator fragments that inhibit structurally unrelated metalloenzymes (LF, 5-LO, TY) vary considerably. To develop more advanced hits, one hit from CFL-1.1, 8-hydroxyquinoline, was elaborated at four different positions around the ring system to generate new fragments. 8-Hydroxyquinoline fragments substituted at either the 5- or 7-positions gave potent hits against MMP-2, with IC50 values in the low micromolar range. The 8-hydroxyquinoline represents a promising, new chelator scaffold for the development of MMP inhibitors that was discovered by use of a metalloprotein-focused chelator fragment library.
In this observational study, we compared erythrocyte membrane fatty acids in infants consuming formula supplemented with docosahexaenoic acid (DHA) and arachidonic acid (ARA) with those consuming other types of milks. In 110 infants who were participants in a cohort study of otherwise healthy children at risk for developing type 1 diabetes, erythrocytes were collected at approximately 9 months of age, and fatty acid content was measured as a percent of total lipids. Parents reported the type of milk the infants consumed in the month of and prior to erythrocyte collection – infant formula supplemented with ARA and DHA (supplemented formula), formula with no ARA and DHA supplements (non-supplemented formula), breast-milk, or non-supplemented formula plus breast-milk. Membrane DHA (4.42 versus 1.79, p < 0.001) and omega-3 fatty acid (5.81 versus 3.43, p < 0.001) levels were higher in infants consuming supplemented versus non-supplemented formula. Omega-6 fatty acids were lower in infants consuming supplemented versus non-supplemented formula (26.32 versus 29.68, p = 0.023); ARA did not differ between groups. Infants given supplemented formula had higher DHA (4.42 versus 2.81, p < 0.001) and omega-3 fatty acids (5.81 versus 4.45, p = 0.008) than infants drinking breast-milk. In infants whose mothers did not receive any dietary advice, use of supplemented formula is associated with higher omega-3 and lower omega-6 fatty acid status.
Arachidonic Acid; Docosahexaenoic Acid; Breastfeeding; Infant Feeding; Infant Formula; Infant Feeding Behavior
Children attending child care centers (CCCs) are at increased risk for infections, including those caused by methicillin-resistant Staphylococcus aureus (MRSA). Nasal colonization often precedes infection, and MRSA colonization has been associated with increased infection risk. Community-associated MRSA (CA-MRSA) has caused increased MRSA infections in the general population, including children. Little is known about the frequency of MRSA nasal colonization in young children, particularly in those attending CCCs where disease transmission is common. We sampled the nares of 1,163 children in 200 classrooms from 24 CCCs in North Carolina and Virginia to assess S. aureus colonization. MRSA strains were molecularly analyzed for staphylococcal cassette chromosome mec (SCCmec) type, Panton-Valentine leukocidin status, and multilocus sequence type. A case-control study was performed to identify risk factors for MRSA colonization. We found that 18.1% children were colonized with S. aureus and 1.3% with MRSA. Molecular analysis of the MRSA strains identified 47% as CA-MRSA and 53% as health care-associated MRSA (HA-MRSA). Although two centers had multiple children colonized with MRSA, genotyping indicated that no transmission had occurred within classrooms. The case-control study did not detect statistically significant risk factors for MRSA colonization. However, MRSA-colonized children were more likely to be nonwhite and to have increased exposure to antibiotics and skin infections in the home. Both CA-MRSA and HA-MRSA strains were found colonizing the nares of children attending CCCs. The low frequency of colonization observed highlights the need for a large multicenter study to determine risk factors for MRSA colonization and subsequent infection in this highly susceptible population.
Reduced executive cognitive ability is associated with alcohol dependence (AD) and other comorbid externalizing disorders. Working memory capacity, short-term memory, conditional associative learning, and intelligence were assessed in a sample (N = 477) with variation in lifetime histories of externalizing problems (conduct disorder, adult antisocial behavior, substance problems); this included a subsample (n = 285) with a DSM-IV diagnosis of AD. Individuals with both AD and a history of childhood conduct disorder (CCD) scored lower on cognitive measures compared to those with AD and no history of CCD. Structural equation models showed that reduced ability in all cognitive domains was predicted by a latent externalizing factor reflecting covariation among lifetime problems with alcohol, drugs, childhood conduct, and adult antisocial behavior, and was not uniquely related to any one problem. Further, for those with AD, the externalizing factor was associated with reductions in all the domains of cognitive ability. The results suggest that the reduced executive cognitive ability observed in AD individuals is partly accounted for by a general latent externalizing factor, rather than alcohol-related problems per se.
Alcohol dependence; externalizing disorders; comorbidity; cognition; conduct disorder
Obesity increases the risk for development of cardiomyopathy in the absence of hypertension, diabetes or myocardial ischemia. Not all obese individuals, however, progress to heart failure. Indeed, obesity may provide protection from cardiovascular mortality in some populations. The fatty acid milieu, modulated by diet, may modify obesity-induced myocardial structure and function, lending partial explanation for the array of cardiomyopathic phenotypy in obese individuals.
Adult male Sprague-Dawley rats were fed 1 of the following 4 diets for 32 weeks: control (CON); 50% saturated fat (SAT); 40% saturated fat + 10% linoleic acid (SAT+LA); 40% saturated fat + 10% α-linolenic acid (SAT+ALA). Serum leptin, insulin, glucose, free fatty acids and triglycerides were quantitated. In vivo cardiovascular outcomes included blood pressure, heart rate and echocardiographic measurements of structure and function. The rats were sacrificed and myocardium was processed for fatty acid analysis (TLC-GC), and evaluation of potential modifiers of myocardial structure including collagen (Masson's trichrome, hydroxyproline quantitation), lipid (Oil Red O, triglyceride quantitation) and myocyte cross sectional area.
Rats fed SAT+LA and SAT+ALA diets had greater cranial LV wall thickness compared to rats fed CON and SAT diets, in the absence of hypertension or apparent insulin resistance. Treatment was not associated with changes in myocardial function. Myocardial collagen and triglycerides were similar among treatment groups; however, rats fed the high-fat diets, regardless of composition, demonstrated increased myocyte cross sectional area.
Under conditions of high-fat feeding, replacement of 10% saturated fat with either LA or ALA is associated with thickening of the cranial LV wall, but without concomitant functional changes. Increased myocyte size appears to be a more likely contributor to early LV thickening in response to high-fat feeding. These findings suggest that myocyte hypertrophy may be an early change leading to gross LV hypertrophy in the hearts of "healthy" obese rats, in the absence of hypertension, diabetes and myocardial ischemia.
Obesity; Cardiomyopathy; Polyunsaturated fatty acids; Left ventricular hypertrophy
Visual probe tasks are often used to measure attentional bias (AB) toward alcohol-related images in drinkers, but little is known about the effect of the properties of the images used in this task, specifically, image complexity.
AB was examined in a group of adult drinkers (n = 25). Two measures of attentional bias were obtained from a modified visual probe task. First, a traditional dot probe detection task measured attentional bias in drinkers based on their reaction times to probes replacing neutral and alcohol-related images. Second, an eye-tracking measure was applied to this task to directly assess the drinkers' eye gazes to the alcohol-related and neutral images. The effect of image complexity was examined by comparing AB toward images classified as simple and complex.
Results showed that drinkers only displayed AB toward simple alcohol-related images as measured by both probe RT and fixation times.
These findings suggest that complex alcohol-related images might be less effective at capturing drinkers' attention and could result in less attentional bias when used in visual probe tasks.
A severe flare of colitis in patients with IBD treated with immunosuppressive therapy may be complicated by an underlying CMV infection. The aim of this pilot study was to investigate the diagnostic efficacy of quantitative polymerase chain reaction (PCR) to detect CMV DNA in stool samples of IBD patients.
Twenty-one patients with a severe flare of IBD, incompletely responding or refractory to either steroids or immunosuppressive agents, were included in the study. Nineteen patients completed the study according to the protocol undergoing an endoscopy with biopsies and collection of stool samples. Biopsy and stool samples were qualitatively and quantitatively analyzed for CMV DNA using real-time PCR.
Thirty-two percent (6/19) of the patients had detectable CMV DNA in colonic biopsies and in five (83%) of those patients CMV DNA was detected in the stool. Thirteen patients had negative findings for CMV DNA in biopsy and stool samples. The sensitivity, specificity, and accuracy of the PCR-based stool test for detection of CMV DNA compared to PCR-based detection of CMV in mucosal biopsies were 83, 93, and 90%, respectively.
The pilot study suggests a high accuracy of this non-invasive testing method to detect CMV DNA in stool samples as compared to mucosal biopsies. This approach may offer a non-endoscopic testing modality for underlying CMV infection in patients with a severe flare of IBD, which could also be applied more broadly to determine the prevalence of CMV infections in patients with IBD.
Inflammatory bowel disease; Ulcerative colitis; Crohn's disease; Infectious colitis; Cytomegalovirus; Immunosuppression
The value of Bacteroidales genetic markers and fecal indicator bacteria (FIB) to predict the occurrence of waterborne pathogens was evaluated in ambient waters along the central California coast. Bacteroidales host-specific quantitative PCR (qPCR) was used to quantify fecal bacteria in water and provide insights into contributing host fecal sources. Over 140 surface water samples from 10 major rivers and estuaries within the Monterey Bay region were tested over 14 months with four Bacteroidales-specific assays (universal, human, dog, and cow), three FIB (total coliforms, fecal coliforms, and enterococci), two protozoal pathogens (Cryptosporidium and Giardia spp.), and four bacterial pathogens (Campylobacter spp., Escherichia coli O157:H7, Salmonella spp., and Vibrio spp.). Indicator and pathogen distribution was widespread, and detection was not highly seasonal. Vibrio cholerae was detected most frequently, followed by Giardia, Cryptosporidium, Salmonella, and Campylobacter spp. Bayesian conditional probability analysis was used to characterize the Bacteroidales performance assays, and the ratios of concentrations determined using host-specific and universal assays were used to show that fecal contamination from human sources was more common than livestock or dog sources in coastal study sites. Correlations were seen between some, but not all, indicator-pathogen combinations. The ability to predict pathogen occurrence in relation to indicator threshold cutoff levels was evaluated using a weighted measure that showed the universal Bacteroidales genetic marker to have a comparable or higher mean predictive potential than standard FIB. This predictive ability, in addition to the Bacteroidales assays providing information on contributing host fecal sources, supports using Bacteroidales assays in water quality monitoring programs.
A chelator fragment library based on a variety of metal binding groups was screened against a metalloproteinase. Lead hits were identified and an expanded library of select compounds was synthesized, resulting in numerous high-affinity hits against several metalloprotein targets. The findings clearly demonstrate that chelators can be used to generate libraries suitable for fragment-based lead design (FBLD) directed at important metalloproteins.
chelators; fragment-based lead design; libraries; metalloproteins; zinc
Tissue-encysting coccidia, including Toxoplasma gondii and Sarcocystis neurona, are heterogamous parasites with sexual and asexual life stages in definitive and intermediate hosts, respectively. During its sexual life stage, T. gondii reproduces either by genetic out-crossing or via clonal amplification of a single strain through self-mating. Out-crossing has been experimentally verified as a potent mechanism capable of producing offspring possessing a range of adaptive and virulence potentials. In contrast, selfing and other life history traits, such as asexual expansion of tissue-cysts by oral transmission among intermediate hosts, have been proposed to explain the genetic basis for the clonal population structure of T. gondii. In this study, we investigated the contributing roles self-mating and sexual recombination play in nature to maintain clonal population structures and produce or expand parasite clones capable of causing disease epidemics for two tissue encysting parasites. We applied high-resolution genotyping against strains isolated from a T. gondii waterborne outbreak that caused symptomatic disease in 155 immune-competent people in Brazil and a S. neurona outbreak that resulted in a mass mortality event in Southern sea otters. In both cases, a single, genetically distinct clone was found infecting outbreak-exposed individuals. Furthermore, the T. gondii outbreak clone was one of several apparently recombinant progeny recovered from the local environment. Since oocysts or sporocysts were the infectious form implicated in each outbreak, the expansion of the epidemic clone can be explained by self-mating. The results also show that out-crossing preceded selfing to produce the virulent T. gondii clone. For the tissue encysting coccidia, self-mating exists as a key adaptation potentiating the epidemic expansion and transmission of newly emerged parasite clones that can profoundly shape parasite population genetic structures or cause devastating disease outbreaks.
The parasites Toxoplasma gondii and Sarcocystis neurona have lifecycles that include a sexual stage in a definitive host and an asexual stage in intermediate hosts. For T. gondii, laboratory studies have demonstrated that the sexual stage can serve the dual purpose of producing new, virulent genotypes through recombination and promoting expansion of single clones via self-mating. Self-mating and other life history traits of T. gondii, including transmission of asexual stages among intermediate hosts, are assumed to account for the clonal population genetic structure of this organism. However, the relative contributions of sexual recombination and self-mating verses other life history traits in causing disease outbreaks or in shaping Toxoplasma's population genetic structure have not been verified in nature, nor have these traits been extensively examined in related parasites. To address this knowledge gap, we conducted population genetic analyses on T. gondii and S. neurona strains isolated from naturally occurring outbreaks affecting humans and sea otters, respectively. Our results identify self-mating as a key trait potentiating disease outbreaks through the rapid amplification of a single clone into millions of infectious units. Selfing is likely a key adaptation for enhancing transmission of recently emerged, recombinant clones and reshaping population genetic structures among the tissue-cyst coccidia.
Aims: Considerable laboratory research indicates that moderate doses of alcohol impair a broad range of skilled activities related to driving performance in young adults. Although laboratory studies show that the intensity of impairment is generally dependent on the blood alcohol concentration, some reviews of this literature suggest that women might be more sensitive to the impairing effects of alcohol than men. The present study tested this hypothesis. Methods: Drawing on data from previous experiments in our laboratory, we compared men and women in terms of the degree to which a challenge dose of alcohol (0.65 g/kg) impaired their simulated driving performance and measures of three separate behavioral and cognitive functions important to driving performance: motor coordination, speed of information processing and information-processing capacity. Results: Alcohol significantly impaired all aspects of performance. Moreover, women displayed greater impairment than men on all behavioral tests and also reported higher levels of subjective intoxication compared with men. Conclusions: Both biological and social–cultural factors have been implicated in gender differences in the behavioral responses to alcohol. The current evidence of heightened sensitivity to alcohol in women highlights the need for better understanding the biological and environmental factors underlying this gender difference.
Summary: The introduction of in vitro nucleic acid amplification techniques, led by real-time PCR, into the clinical microbiology laboratory has transformed the laboratory detection of viruses and select bacterial pathogens. However, the progression of the molecular diagnostic revolution currently relies on the ability to efficiently and accurately offer multiplex detection and characterization for a variety of infectious disease pathogens. Microarray analysis has the capability to offer robust multiplex detection but has just started to enter the diagnostic microbiology laboratory. Multiple microarray platforms exist, including printed double-stranded DNA and oligonucleotide arrays, in situ-synthesized arrays, high-density bead arrays, electronic microarrays, and suspension bead arrays. One aim of this paper is to review microarray technology, highlighting technical differences between them and each platform's advantages and disadvantages. Although the use of microarrays to generate gene expression data has become routine, applications pertinent to clinical microbiology continue to rapidly expand. This review highlights uses of microarray technology that impact diagnostic microbiology, including the detection and identification of pathogens, determination of antimicrobial resistance, epidemiological strain typing, and analysis of microbial infections using host genomic expression and polymorphism profiles.
“Super-blooms” of cyanobacteria that produce potent and environmentally persistent biotoxins (microcystins) are an emerging global health issue in freshwater habitats. Monitoring of the marine environment for secondary impacts has been minimal, although microcystin-contaminated freshwater is known to be entering marine ecosystems. Here we confirm deaths of marine mammals from microcystin intoxication and provide evidence implicating land-sea flow with trophic transfer through marine invertebrates as the most likely route of exposure. This hypothesis was evaluated through environmental detection of potential freshwater and marine microcystin sources, sea otter necropsy with biochemical analysis of tissues and evaluation of bioaccumulation of freshwater microcystins by marine invertebrates. Ocean discharge of freshwater microcystins was confirmed for three nutrient-impaired rivers flowing into the Monterey Bay National Marine Sanctuary, and microcystin concentrations up to 2,900 ppm (2.9 million ppb) were detected in a freshwater lake and downstream tributaries to within 1 km of the ocean. Deaths of 21 southern sea otters, a federally listed threatened species, were linked to microcystin intoxication. Finally, farmed and free-living marine clams, mussels and oysters of species that are often consumed by sea otters and humans exhibited significant biomagnification (to 107 times ambient water levels) and slow depuration of freshwater cyanotoxins, suggesting a potentially serious environmental and public health threat that extends from the lowest trophic levels of nutrient-impaired freshwater habitat to apex marine predators. Microcystin-poisoned sea otters were commonly recovered near river mouths and harbors and contaminated marine bivalves were implicated as the most likely source of this potent hepatotoxin for wild otters. This is the first report of deaths of marine mammals due to cyanotoxins and confirms the existence of a novel class of marine “harmful algal bloom” in the Pacific coastal environment; that of hepatotoxic shellfish poisoning (HSP), suggesting that animals and humans are at risk from microcystin poisoning when consuming shellfish harvested at the land-sea interface.
The zinc(II)-dependent matrix metalloproteinases (MMPs) are associated with a variety of diseases. Development of inhibitors to modulate MMP activity has been an active area of investigation for therapeutic development. Hydroxypyrones and hydroxythiopyrones are alternative zinc-binding groups (ZBGs) that, when combined with peptidomimetic backbones, comprise a novel class of MMP inhibitors (MMPi). In this report, a series of hydroxypyrone- and hydroxythiopyrone-based MMPi with aryl backbones at the 2-, 5-, and 6-positions of the hydroxypyrone ring have been synthesized. Synthetic routes for developing inhibitors with substituents at two of these positions (so-called double-handed inhibitors) are also explored. The MMP inhibition profiles and structure–activity relationship of synthesized hydroxypyrones and hydroxythiopyrones have been analyzed. The results here show that the ZBG, the position of the backbone on the ZBG, and the nature of the linker between the ZBG and backbone are critical for MMPi activities.
Drug design; Inhibitors; Metalloproteinases; Pyrones; Zinc
To examine the prevalence and correlates of physical activity in adult survivors of aggressive non-Hodgkin's Lymphoma (NHL) and to explore the association between physical activity level and health-related quality of life (HRQOL).
Patients and Methods
Physical activity and HRQOL data from 319 survivors of NHL (mean age, 59.8 years, standard deviation, ±14.8) who were diagnosed in Los Angeles County approximately 2 to 5 years before the study was analyzed.
One quarter of survivors of NHL met public health guidelines of 150 minutes or more of moderate to vigorous exercise per week. More than half (53%) reported some activity but less than 150 minutes per week, whereas 20% reported no physical activity. Females, those with lower perceived health competence, and individuals with more comorbid limitations were at increased risk for inactivity. Individuals who met public health guidelines reported better HRQOL than those who were sedentary. Interestingly, our findings suggest a significant positive association between HRQOL and those who get at least some exercise.
The effort to promote physical activity among cancer survivors, who are at risk for poor quality of life as a result of treatment, is of great importance to the health of this growing population. As NHL, similar to other cancers, becomes a disease that people live with as opposed to one that people die as a result of, oncologists and primary care physicians will be increasingly challenged to provide evidence-based guidance for the long-term management of the patient's health. Consideration should be given to how clinicians frame exercise-promoting messages to cancer survivors, especially to those who are sedentary.
We prospectively determined the prevalence of community-associated Staphylococcus aureus in a large cystic fibrosis (CF) center between October 2005 and October 2007. We found that 2.7% (19/707) of the CF patients who had cultures during the study period were infected with this organism, representing 14% of the total methicillin-resistant Staphylococcus aureus strains (n = 140) recovered from the patient population during the study period.