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Study Objective
To identify young women’s pros and cons (decisional balance) to seeking chlamydia (CT) and gonorrhea (NGC) screening.
Prospective, cross sectional study
Community-based reproductive health clinic
192 young women (66% African American; mean age 18.9 years).
Main Outcome Measure(s)
Content analysis of responses obtained during a decisional balance exercise (pros and cons) promoting CT and NGC screening was conducted. Thematic categories were developed through a coding process, and each response was assigned to one thematic category. The frequency of pros and cons responses for each category and the frequency of participants endorsing each category were calculated.
Ten thematic categories in relation to pros and cons of seeking CT and NGC screening were: being healthy; awareness of knowing the body; systemic factors around the clinic visit and testing procedures; benefits and aversions around treatment; partner relationship issues; confidentiality; prevention of long term adverse effects, protection of the body; concern for others; fear of results/aversion to testing; and logistical barriers. The three most often cited pros were awareness, healthy and treatment issues; and the three most often cited cons were logistical barriers (time/transportation), fear/aversion to testing, and systemic issues.
A variety of pros and cons to seeking CT and NGC screening were identified at a community-based clinic. Providers in clinical settings can utilize this information when encouraging patients to seek regular STI screening by elucidating and emphasizing those pros and cons that have the most influence on a young woman’s decision-making to seek screening.
PMCID: PMC2582049  PMID: 18656072
Chlamydia; STI screening; Chlamydia screening; Gonorrhea screening; Decisional Balance; Decisional Balance and STI screening; Transtheoretical model and STI screening
2.  Tetanus toxoid vaccine: Elimination of neonatal tetanus in selected states of India 
Human Vaccines & Immunotherapeutics  2012;8(10):1439-1442.
Tetanus is caused by a neurotoxin produced by Clostridium tetani (C. tetani), a spore-forming bacterium. Infection begins when tetanus spores are introduced into damaged tissue. Tetanus is characterized by muscle rigidity and painful muscle spasms caused by tetanus toxin’s blockade of inhibitory neurons that normally oppose and modulate the action of excitatory motor neurons. Maternal and neonatal tetanus (MNT) are caused by unhygienic methods of delivery, abortion, or umbilical-cord care. Maternal and neonatal tetanus are both forms of generalized tetanus and have similar clinical courses. About 90% of neonates with tetanus develop symptoms in the first 3–14 d of life, mostly on days 6–8, distinguishing neonatal tetanus from other causes of neonatal mortality which typically occur during the first two days of life. Overall case fatality rates for patients admitted to the hospital with neonatal tetanus in developing countries are 8–50%, while the fatality rate can be as high as 100% without hospital care. Tetanus toxoid (TT) vaccination of pregnant women to prevent neonatal tetanus was included in WHO’s Expanded Program on Immunization (EPI) a few years after its inception in 1974. In 2000, WHO, UNICEF, and UNFPA formed a partnership to relaunch efforts toward this goal, adding the elimination of maternal tetanus as a program objective, and setting a new target date of 2005. By February 2007, 40 countries had implemented tetanus vaccination campaigns in high-risk areas, targeting more than 94 million women, and protecting more than 70 million subjects with at least two doses of TT. In 2011, 653 NT cases were reported in India compared with 9313 in 1990. As of February 2012, 25 countries and 15 States and Union Territories of India, all of Ethiopia except Somaliland, and almost 29 of 34 provinces in Indonesia have been validated to have eliminated MNT.
PMCID: PMC3660763  PMID: 22894950
elimination; maternal; neonatal; tetanus; vaccine
3.  Promoting Advance Care Planning as Health Behavior Change: Development of Scales to Assess Decisional Balance, Medical and Religious Beliefs, and Processes of Change 
To develop measures representing key constructs of the Transtheoretical Model (TTM) of behavior change as applied to advance care planning (ACP) and to examine whether associations between these measures replicate the relationships posited by the TTM.
Sequential scale development techniques were used to develop measures for Decisional Balance (Pros and Cons of behavior change), ACP Values/Beliefs (religious beliefs and medical misconceptions serving as barriers to participation), Processes of Change (behavioral and cognitive processes used to foster participation) based on responses of 304 persons age ≥ 65 years.
Items for each scale/subscale demonstrated high factor loading (> .5) and good to excellent internal consistency (Cronbach α .76–.93). Results of MANOVA examining scores on the Pros, Cons, ACP Values/Beliefs, and POC subscales by stage of change for each of the six behaviors were significant, Wilks' λ= .555–.809, η2=.068–.178, p ≤ .001 for all models.
Core constructs of the TTM as applied to ACP can be measured with high reliability and validity.
Practice Implications
Cross-sectional relationships between these constructs and stage of behavior change support the use of TTM-tailored interventions to change perceptions of the pros and cons of participation in ACP and promote the use of certain processes of change in order to promote older persons' engagement in ACP.
PMCID: PMC3192927  PMID: 21741194
4.  Trends in Antibiotic Resistance in Coagulase-Negative Staphylococci in the United States, 1999 to 2012 
Coagulase-negative staphylococci (CoNS) are important bloodstream pathogens that are typically resistant to multiple antibiotics. Despite the concern about increasing resistance, there have been no recent studies describing the national prevalence of CoNS pathogens. We used national resistance data over a period of 13 years (1999 to 2012) from The Surveillance Network (TSN) to determine the prevalence of and assess the trends in resistance for Staphylococcus epidermidis, the most common CoNS pathogen, and all other CoNS pathogens. Over the course of the study period, S. epidermidis resistance to ciprofloxacin and clindamycin increased steadily from 58.3% to 68.4% and from 43.4% to 48.5%, respectively. Resistance to levofloxacin increased rapidly from 57.1% in 1999 to a high of 78.6% in 2005, followed by a decrease to 68.1% in 2012. Multidrug resistance for CoNS followed a similar pattern, and this rise and small decline in resistance were found to be strongly correlated with levofloxacin prescribing patterns. The resistance patterns were similar for the aggregate of CoNS pathogens. The results from our study demonstrate that the antibiotic resistance in CoNS pathogens has increased significantly over the past 13 years. These results are important, as CoNS can serve as sentinels for monitoring resistance, and they play a role as reservoirs of resistance genes that can be transmitted to other pathogens. The link between the levofloxacin prescription rate and resistance levels suggests a critical role for reducing the inappropriate use of fluoroquinolones and other broad-spectrum antibiotics in health care settings and in the community to help curb the reservoir of resistance in these colonizing pathogens.
PMCID: PMC3957827  PMID: 24342646
5.  Strength training improves muscle quality and insulin sensitivity in Hispanic older adults with type 2 diabetes 
Hispanics are at increased risk of morbidity and mortality due to their high prevalence of diabetes and poor glycemic control. Strength training is the most effective lifestyle intervention to increase muscle mass but limited data is available in older adults with diabetes. We determined the influence of strength training on muscle quality (strength per unit of muscle mass), skeletal muscle fiber hypertrophy, and metabolic control including insulin resistance (Homeostasis Model Assessment –HOMA-IR), C-Reactive Protein (CRP), adiponectin and Free Fatty Acid (FFA) levels in Hispanic older adults. Sixty-two community-dwelling Hispanics (>55 y) with type 2 diabetes were randomized to 16 weeks of strength training plus standard care (ST group) or standard care alone (CON group). Skeletal muscle biopsies and biochemical measures were taken at baseline and 16 weeks. The ST group show improved muscle quality (mean±SE: 28±3) vs CON (-4±2, p<0.001) and increased type I (860±252µm2) and type II fiber cross-sectional area (720±285µm2) compared to CON (type I: -164±290µm2, p=0.04; and type II: -130±336µm2, p=0.04). This was accompanied by reduced insulin resistance [ST: median (interquartile range) -0.7(3.6) vs CON: 0.8(3.8), p=0.05]; FFA (ST: -84±30µmol/L vs CON: 149±48µmol/L, p=0.02); and CRP [ST: -1.3(2.9)mg/L vs CON: 0.4(2.3)mg/L, p=0.05]. Serum adiponectin increased with ST [1.0(1.8)µg/mL] compared to CON [-1.2(2.2)µg/mL, p<0.001]. Strength training improved muscle quality and whole-body insulin sensitivity. Decreased inflammation and increased adiponectin levels were related with improved metabolic control. Further studies are needed to understand the mechanisms associated with these findings. However, these data show that strength training is an exercise modality to consider as an adjunct of standard of care in high risk populations with type 2 diabetes.
PMCID: PMC1752232  PMID: 17211497
diabetes; strength training; Hispanic; skeletal muscle; insulin sensitivity
6.  International comparisons of intensive care: informing outcomes and improving standards 
Current opinion in critical care  2012;18(6):700-706.
Purpose of review
Interest in international comparisons of critical illness is growing, but the utility of these studies is questionable. This review examines the challenges of international comparisons and highlights areas where international data provide information relevant to clinical practice and resource allocation.
Recent findings
International comparisons of ICU resources demonstrate that definitions of critical illness and Intensive Care Unit (ICU) beds vary due to differences in ability to provide organ support and variable staffing. Despite these limitations, recent international data provide key information to understand the pros and cons of different availability of ICU beds on patient flow and outcomes, and also highlight the need to ensure long-term follow-up due to heterogeneity in discharge practices for critically ill patients. With increasing emphasis on curbing costs of healthcare, systems that deliver lower cost care provide data on alternative options, such as regionalization, flexible allocation of beds, and bed rationing.
Differences in provision of critical care can be leveraged to inform decisions on allocation of ICU beds, improve interpretation of clinical outcomes, and assess ways to decrease costs of care. International definitions of key components of critical care are needed to facilitate research and ensure rigorous comparisons.
PMCID: PMC3551445  PMID: 22954664
Critical Care; Epidemiology; Healthcare Delivery; International Perspectives
7.  Coagulase-negative staphylococcal infections in a neonatal intensive care unit: In vivo response to cloxacillin 
Paediatrics & Child Health  2006;11(10):659-663.
Following the introduction of cloxacillin and gentamicin as the first line of treatment for possible late-onset sepsis (LOS) in the authors’ neonatal intensive care unit (NICU), it was subsequently noted that very low birth weight (VLBW) infants improved clinically, despite subsequently positive blood cultures for oxacillin-resistant, coagulase-negative Staphylococcus (CONS). The results of the management of VLBW infants with CONS sepsis during one calendar year, based on clinical rather than laboratory findings, are presented.
VLBW infants with LOS were identified through the neonatal database, and the charts of those with CONS were reviewed for antibiotic usage, antibiotic resistance pattern, clearance of CONS from the blood and NICU discharge status. Oxacillin sensitivity was determined by the presence of the mecA gene.
From January 1 to December 31, 2002, 27 VLBW infants, treated in the authors’ NICU for LOS due to CONS, were identified. The mean age of LOS infants with CONS was 15 days (median 12 days; range three to 54 days), the mean birth weight (± SD) was 904±247 g, and the mean gestational age at birth (± SD) was 27±2 weeks. All infants were started on cloxacillin and gentamicin, and improved clinically over the first 48 h. Six isolates were sensitive to cloxacillin. Twenty-three infants grew oxacillin-resistant CONS, eight of whom had persistence of CONS on repeat culture secondary to central lines. Two infants grew two strains of CONS. Eighteen of 22 infants (82%) with in vitro oxacillin-resistant CONS had clearance of bacteremia with cloxacillin and gentamicin. Ten infants (37%) received vancomycin, based on the authors’ guidelines. There were no cases of prolonged bacteremia requiring rifampicin. Three infants died, but none of the deaths could be attributed to CONS.
The authors describe clinical improvement with clearance of CONS using cloxacillin and gentamicin, despite laboratory results suggesting oxacillin resistance. The authors’ unit policy was based on clinical response and permitted the continuation of cloxacillin, provided that a repeat blood culture was negative. Vancomycin use was suggested for clinical deterioration or persistence of CONS. These results question the in vitro tests of resistance. Clearance of oxacillin-resistant CONS from the blood points to in vivo sensitivity, while the laboratory testing suggests in vitro resistance. The absence of subsequent positive blood cultures for CONS confirms clearance of this organism.
It was demonstrated that cloxacillin (150 mg/kg/day dose), along with gentamicin, can clear CONS from the blood within 48 h. The relationship between in vivo and in vitro sensitivities also needs to be further studied both in the laboratory and in a prospective trial.
PMCID: PMC2528592  PMID: 19030249
Antibiotic sensitivities; Coagulase-negative staphylococcal bacteremia; Very low birth weight
8.  Socio-demographic, psychosocial and home-environmental attributes associated with adults' domestic screen time 
BMC Public Health  2011;11:668.
Sedentary behaviors (involving prolonged sitting time) are associated with deleterious health consequences, independent of (lack of) physical activity. To inform interventions, correlates of prevalent sedentary behaviors need to be identified. We examined associations of socio-demographic, home-environmental and psychosocial factors with adults' TV viewing time and leisure-time Internet use; and whether psychosocial and environmental correlates differed according to gender, age and educational attainment.
This cross-sectional study was conducted in Ghent, Belgium, between March and May 2010. Respondents to a mail-out survey (n = 419; 20-65 years; mean age 48.5 [12.1] years; 47.3% men) completed a questionnaire on sedentary behaviors and their potential socio-demographic, psychosocial and home environmental correlates. Statistical analyses were performed using multiple linear regression models.
The independent variables explained 31% of the variance in TV viewing time and 38% of the variance in leisure-time Internet use. Higher education, greater perceived pros of and confidence about reducing TV time were negatively associated with TV viewing time; older age, higher body mass index, larger TV set size and greater perceived cons of reducing TV time showed positive associations. Perceived pros of and confidence about reducing Internet use were negatively associated with leisure-time Internet use; higher education, number of computers in the home, positive family social norms about Internet use and perceived cons of reducing Internet use showed positive associations. None of the socio-demographic factors moderated these associations.
Educational level, age, self-efficacy and pros/cons were the most important correlates identified in this study. If further cross-sectional and longitudinal research can confirm these findings, tailored interventions focusing on both psychosocial and environmental factors in specific population subgroups might be most effective to reduce domestic screen time.
PMCID: PMC3175191  PMID: 21864412
TV viewing time; leisure-time Internet use; Belgium; sedentary behavior; ecological model
9.  Ethnic, Racial and Cultural Identity and Perceived Benefits and Barriers Related to Genetic Testing for Breast Cancer among At-Risk Women of African Descent in New York City 
Public Health Genomics  2011;14(6):356-370.
Due to disparities in the use of genetic services, there has been growing interest in examining beliefs and attitudes related to genetic testing for breast and/or ovarian cancer risk among women of African descent. However, to date, few studies have addressed critical cultural variations among this minority group and their influence on such beliefs and attitudes.
We assessed ethnic, racial and cultural identity and examined their relationships with perceived benefits and barriers related to genetic testing for cancer risk in a sample of 160 women of African descent (49% self-identified African American, 39% Black-West Indian/Caribbean, 12% Black-Other) who met genetic risk criteria and were participating in a larger longitudinal study including the opportunity for free genetic counseling and testing in New York City. All participants completed the following previously validated measures: (a) the multi-group ethnic identity measure (including ethnic search and affirmation subscales) and other-group orientation for ethnic identity, (b) centrality to assess racial identity, and (c) Africentrism to measure cultural identity. Perceived benefits and barriers related to genetic testing included: (1) pros/advantages (including family-related pros), (2) cons/disadvantages (including family-related cons, stigma and confidentiality concerns), and (3) concerns about abuses of genetic testing.
In multivariate analyses, several ethnic identity elements showed significant, largely positive relationships to perceived benefits about genetic testing for breast and/or ovarian cancer risk, the exception being ethnic search, which was positively associated with cons/disadvantages, in general, and family-related cons/disadvantages. Racial identity (centrality) showed a significant association with confidentiality concerns. Cultural identity (Africentrism) was not related to perceived benefits and/or barriers.
Ethnic and racial identity may influence perceived benefits and barriers related to genetic testing for breast and/or ovarian cancer risk among at-risk women of African descent. Genetic counseling services may want to take into account these factors in the creation of culturally-appropriate services which best meet the needs of this heterogenous population.
PMCID: PMC3221259  PMID: 21540561
Breast cancer; Cultural identity; Ethnic identity; Genetic testing; Racial identity
10.  Comparative performance information plays no role in the referral behaviour of GPs 
BMC Family Practice  2014;15:146.
Comparative performance information (CPI) about the quality of hospital care is information used to identify high-quality hospitals and providers. As the gatekeeper to secondary care, the general practitioner (GP) can use CPI to reflect on the pros and cons of the available options with the patient and choose a provider best fitted to the patient’s needs. We investigated how GPs view their role in using CPI to choose providers and support patients.
We used a mixed-method, sequential, exploratory design to conduct explorative interviews with 15 GPs about their referral routines, methods of referral consideration, patient involvement, and the role of CPI. Then we quantified the qualitative results by sending a survey questionnaire to 81 GPs affiliated with a representative national research network.
Seventy GPs (86% response rate) filled out the questionnaire. Most GPs did not know where to find CPI (87%) and had never searched for it (94%). The GPs reported that they were not motivated to use CPI due to doubts about its role as support information, uncertainty about the effect of using CPI, lack of faith in better outcomes, and uncertainty about CPI content and validity. Nonetheless, most GPs believed that patients would like to be informed about quality-of-care differences (62%), and about half the GPs discussed quality-of-care differences with their patients (46%), though these discussions were not based on CPI.
Decisions about referrals to hospital care are not based on CPI exchanges during GP consultations. As a gatekeeper, the GP is in a good position to guide patients through the enormous amount of quality information that is available. Nevertheless, it is unclear how and whether the GP’s role in using information about quality of care in the referral process can grow, as patients hardly ever initiate a discussion based on CPI, though they seem to be increasingly more critical about differences in quality of care. Future research should address the conditions needed to support GPs’ ability and willingness to use CPI to guide their patients in the referral process.
PMCID: PMC4161854  PMID: 25160715
Primary care; Doctor-patient relationship; Access to care; Performance information; Quality of care; Qualitative research; Quantitative research; Mixed methods
11.  Exploring Primary Care Providers’ Interest in Using Patient Navigators to Assist in the Delivery of Tobacco Cessation Treatment to Low Income, Ethnic/Racial Minority Patients 
Journal of community health  2010;35(6):618-624.
We examined attitudes and practices regarding tobacco cessation interventions of primary care physicians serving low income, minority patients living in urban areas with a high smoking prevalence. We also explored barriers and facilitators to physicians providing smoking cessation counseling to determine the need for and interest in deploying a tobacco-focused patient navigator at community-based primary care practice sites. A self-administered survey was mailed to providers serving Medicaid populations in New York City’s Upper Manhattan and areas of the Bronx. Provider counseling practices were measured by assessing routine delivery (≥80% of the time) of a brief tobacco cessation intervention (i.e., “5 A’s”). Provider attitudes were assessed by a decisional balance scale comprising 10 positive (Pros) and 10 negative (Cons) perceptions of tobacco cessation counseling. Of 254 eligible providers, 105 responded (41%). Providers estimated 22% of their patients currently use tobacco and nearly half speak Spanish. A majority of providers routinely asked about tobacco use (92%) and advised users to quit (82%), whereas fewer assisted in developing a quit plan (32%) or arranged follow-up (21%). Compared to providers reporting <80% adherence to the “5 A’s”, providers reporting ≥80% adherence tended to have similar mean Pros and Cons scores for Ask, Advise, and Assess but higher Pros and lower Cons for Assist and Arrange. Sixty four percent of providers were interested in providing tobacco-related patient navigation services at their practices. Although most providers believe they can help patients quit smoking, they also recognize the potential benefit of having a patient navigator connect their patients with evidence-based cessation services in their community.
PMCID: PMC4097305  PMID: 20336355
Tobacco cessation; Primary care; Healthcare providers; Minority health; Patient navigation
12.  Evaluation of a social marketing intervention promoting oral rehydration salts in Burundi 
BMC Public Health  2011;11:155.
Diarrhea is the second leading cause of death for children under five in Burundi; however, use of oral rehydration salts (ORS), the recommended first-line treatment, remains low. In 2004, PSI/Burundi launched a social marketing intervention to promote ORASEL among caregivers of children under five; the product was relaunched in 2006 with a new flavor. This study evaluates the intervention after the ORASEL relaunch, which included mass media and interpersonal communication activities. The study looks at trends in ORASEL use in Burundi and in behavioral determinants that may be related to its use.
In 2006 and 2007, PSI conducted household surveys among Burundian females of reproductive age (15-49). Both surveys used a two-stage sampling process to select 30 households in each of 115 rural and urban collines throughout the nation. Survey respondents were asked about diarrhea treatment-related behavior; key behavioral determinants; and exposure to the ORASEL intervention. Data were analyzed to identify trends over time, characteristics of ORASEL users, and associations between exposure to the intervention and changes in ORASEL use and related behavioral determinants.
ORASEL use among caregivers at their children's last diarrheal episode increased significantly from 20% in 2006 to 30% in 2007, and there were also desirable changes in several behavioral determinants associated with ORASEL use. Evaluation analysis showed that a higher level of exposure to the social marketing campaign was associated with greater use of ORASEL and with significant improvements in perceived availability, knowledge of the signs of diarrhea and dehydration, social support, and self-efficacy.
ORS use can be improved through social marketing and educational campaigns that make the public aware of the availability of the product, encourage dialogue about its use, and increase skills and confidence relating to correct product preparation and administration. Further interventions in Burundi and elsewhere should promote ORS through a variety of mass media and interpersonal communication channels, and should be rigorously evaluated in the context of the total market for diarrhea treatment products.
PMCID: PMC3062608  PMID: 21385460
13.  Studies of Two Subpopulations of Human Lymphocytes Differing in Responsiveness to Concanavalin A 
Journal of Clinical Investigation  1972;51(12):3225-3234.
We have identified two populations of human lymphocytes differing in responsiveness to the plant mitogen concanavalin A (Con-A). When peripheral blood lymphocytes are passed through a nylon column a population of lymphocytes highly responsive to Con-A adheres to the fibers while a second population of cells relatively unresponsive to Con-A emerges from the column. The untreated peripheral blood lymphocytes are termed “unfiltered” cells while the lymphocytes which pass through the column are termed “filtered” cells.
Under standard assay conditions the Con-A-stimulated DNA synthesis is 6.5-fold greater, and the percentage blast formation is four-to fivefold greater in the unfiltered than in the filtered population. Mixing unfiltered with filtered cells fails to induce responsiveness in the latter indicating that a “helper” cell is not involved. The failure of filtered cells to respond to Con-A is specific for that mitogen since both populations respond nearly equally to erythroagglutinating phytohemagglutinin (E-PHA) and the poke weed mitogen (PWM). Binding studies with Con-A-131I demonstrate that the unfiltered population possesses approximately three times as many Con-A receptor sites per cell as the filtered cells, although both cell populations bind the mitogen with the same affinity (apparent association constant [K] of 1.67 × 106m−1).
The relationship between Con-A binding and lymphocyte activation was determined by measuring the effect on DNA synthesis of incubating the two lymphocyte populations with increasing amounts of Con-A. The concentration of Con-A required for half-maximal stimulation of DNA synthesis was 5-14 times greater for the filtered cells. However in the presence of very high Con-A concentrations the filtered cells achieved a maximal rate of DNA synthesis approaching that of the unfiltered population. These data implicate the decreased number of Con-A receptor sites on the filtered cells in their failure to respond to low concentrations of Con-A. A crucial event in the activation of lymphocytes by plant mitogens may be the binding of a critical number of the mitogen molecules to the cell surface.
PMCID: PMC333004  PMID: 4640956
14.  Pretreatment With TCDD Exacerbates Liver Injury From Concanavalin A: Critical Role for NK Cells 
Toxicological Sciences  2013;136(1):72-85.
For many liver diseases, including viral and autoimmune hepatitis, immune cells play an important role in the development and progression of liver injury. Concanavalin A (Con A) administration to rodents has been used as a model of immune-mediated liver injury resembling human autoimmune hepatitis. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been demonstrated to alter the development of immune-mediated diseases. Mice pretreated with TCDD developed exacerbated liver injury in response to administration of a mild dose (6mg/kg) of Con A. In the present study, we tested the hypothesis that TCDD pretreatment exacerbates Con A-induced liver injury by enhancing the activation and recruitment of accessory cell types including neutrophils, macrophages, and natural killer (NK) cells. Mice were treated with 0, 0.3, 3, or 30 μg/kg TCDD and 4 days later with Con A or saline. TCDD pretreatment with doses of 3 and 30 μg/kg significantly increased liver injury from Con A administration. The plasma concentrations of neutrophil chemokines were significantly increased in TCDD-pretreated mice after Con A administration. NKT cell-deficient (CD1d KO) mice were used to examine whether NKT cells were required for TCDD/Con A-induced liver injury. CD1d KO mice were completely protected from liver injury induced by treatment with Con A alone, whereas the injury from TCDD/Con A treatment was reduced but not eliminated. However, T-cell deficient (RAG1 KO) mice were protected from liver injury induced by Con A irrespective of pretreatment with TCDD. TCDD/Con A treatment increased the percentage of NK cells expressing the activation marker CD69. Depletion of NK cells prior to treatment resulted in significant reductions in plasma interferon-γ and liver injury from TCDD/Con A treatment. In summary, exposure to TCDD exacerbated the immune-mediated liver injury induced by Con A, and our findings suggest that NK cells play a critical role in this response.
PMCID: PMC3829569  PMID: 23970800
dioxin; autoimmune; inflammation; chemokines; liver.
15.  Ligand-binding domain subregions contributing to bimodal agonism in cyclic nucleotide–gated channels 
The Journal of General Physiology  2011;137(6):591-603.
Cyclic nucleotide–gated (CNG) channels bind cGMP or cAMP in a cytoplasmic ligand–binding domain (BD), and this binding typically increases channel open probability (Po) without inducing desensitization. However, the catfish CNGA2 (fCNGA2) subtype exhibits bimodal agonism, whereby steady-state Po increases with initial cGMP-binding events (“pro” action) up to a maximum of 0.4, but decreases with subsequent cGMP-binding events (“con” action) occurring at concentrations >3 mM. We sought to clarify if low pro-action efficacy was either necessary or sufficient for con action to operate. To find BD residues responsible for con action or low pro-action efficacy or both, we constructed chimeric CNG channels: subregions of the fCNGA2 BD were substituted with corresponding sequence from the rat CNGA4 BD, which does not support con action. Constructs were expressed in frog oocytes and tested by patch clamp of cell-free membranes. For nearly all BD elements, we found at least one construct where replacing that element preserved robust con action, with a ratio of steady-state conductances, g(10 mM cGMP)/g(3 mM cGMP) < 0.75. When all of the BD sequence C terminal of strand β6 was replaced, g(10 mM cGMP)/g(3 mM cGMP) was increased to 0.95 ± 0.05 (n = 7). However, this apparent attenuation of con action could be explained by an increase in the efficacy of pro action for all agonists, controlled by a conserved “phosphate-binding cassette” motif that contacts ligand; this produces high Po values that are less sensitive to shifts in gating equilibrium. In contrast, substituting a single valine in the N-terminal helix αA abolished con action (g(30 mM cGMP)/g(3 mM cGMP) increased to 1.26 ± 0.24; n = 7) without large increases in pro-action efficacy. Our work dissociates the two functional features of low pro-action efficacy and con action, and moreover identifies a separate structural determinant for each.
PMCID: PMC3105518  PMID: 21624949
16.  Effects of the neurological wake-up test on clinical examination, intracranial pressure, brain metabolism and brain tissue oxygenation in severely brain-injured patients 
Critical Care  2012;16(6):R226.
Daily interruption of sedation (IS) has been implemented in 30 to 40% of intensive care units worldwide and may improve outcome in medical intensive care patients. Little is known about the benefit of IS in acutely brain-injured patients.
This prospective observational study was performed in a neuroscience intensive care unit in a tertiary-care academic center. Twenty consecutive severely brain-injured patients with multimodal neuromonitoring were analyzed for levels of brain lactate, pyruvate and glucose, intracranial pressure (ICP), cerebral perfusion pressure (CPP) and brain tissue oxygen tension (PbtO2) during IS trials.
Of the 82 trial days, 54 IS-trials were performed as interruption of sedation and analgesics were not considered safe on 28 days (34%). An increase in the FOUR Score (Full Outline of UnResponsiveness score) was observed in 50% of IS-trials by a median of three (two to four) points. Detection of a new neurologic deficit occurred in one trial (2%), and in one-third of IS-trials the trial had to be stopped due to an ICP-crisis (> 20 mmHg), agitation or systemic desaturation. In IS-trials that had to be aborted, a significant increase in ICP and decrease in PbtO2 (P < 0.05), including 67% with critical values of PbtO2 < 20 mmHg, a tendency to brain metabolic distress (P < 0.07) was observed.
Interruption of sedation revealed new relevant clinical information in only one trial and a large number of trials could not be performed or had to be stopped due to safety issues. Weighing pros and cons of IS-trials in patients with acute brain injury seems important as related side effects may overcome the clinical benefit.
PMCID: PMC3672610  PMID: 23186037
17.  Conantokins Derived from the Asprella Clade Impart ConRl-B, an NMDA Receptor Antagonist with a Unique Selectivity Profile for NR2B Subunits 
Biochemistry  2012;51(23):4685-4692.
Using molecular phylogeny has accelerated the discovery of peptidic ligands targeted to ion channels and receptors. One clade of venomous cone snails, Asprella, appears to be significantly enriched in conantokins, antagonists of N-Methyl D-Asparate receptors (NMDARs). Here, we describe the characterization of two novel conantokins from Conus rolani, including conantokin conRl-B that has shown an unprecedented selectivity for blocking NMDARs that contain NR2B subunits. ConRl-B shares only some sequence similarity to the most studied NR2B-selective conantokin, conG. The divergence between conRl-B and conG in the second inter-Gla loop was used to design analogs for structure-activity studies; the presence of Pro10 was found to be key to the high potency of conRl-B for NR2B, whereas the ε-amino group of Lys8 contributed to discrimination in blocking NR2B- and NR2A-containing NMDARs. In contrast to previous findings from Tyr5 substitutions in other conantokins, conRl-B [L5Y] showed potencies on the four NR2 NMDA receptor subtypes that were similar to those of the native conRl-B. When delivered into the brain, conRl-B was active in suppressing seizures in the model of epilepsy in mice, consistent with NR2B-containing NMDA receptors being potential targets for antiepileptic drugs. Circular dichroism experiments confirmed that the helical conformation of conRl-B is stabilized by divalent metal ions. Given the clinical applications of NMDA antagonists, conRl-B provides a potentially important pharmacological tool for understanding the differential roles of NMDA receptor subtypes in the nervous system. This work shows the effectiveness of coupling molecular phylogeny, chemical synthesis and pharmacology for discovering new bioactive natural products.
PMCID: PMC4153739  PMID: 22594498
Conus peptides; conantokin; NMDA antagonist; NR2B subunits; epilepsy; anticonvulsant
18.  Pro/con clinical debate: The use of prone positioning in the management of patients with acute respiratory distress syndrome 
Critical Care  2002;6(1):15-17.
Critical care medicine is a relatively new specialty and as such there is not a great deal of accumulated data to allow clinicians to practice 'evidence-based medicine' in all situations they encounter. When evidence does exist, intensivists may choose not to follow it based on 'gut feelings' or their own interpretation of how the data apply to their patient. It is perhaps not surprising that these latter events occur given that intensivists are often literally fighting for their patient's lives. Prone positioning evokes a large emotional response from many intensivists. Despite accumulating data there appears to be two camps of clinicians: those who strongly believe in the therapy, and those who want more data. The emotion and rationale for the mindset of the two camps is evident in this issue of Critical Care Forum. With compelling arguments on both sides of the fence, it is apparent that this debate is far from over. The authors of this pro/con debate, which is based on a clinical scenario, first describe their position and then respond to their opponent's position.
PMCID: PMC137391  PMID: 11940260
prone position; ventilation; ventilation–perfusion ratio
19.  Effect of Dietary Supplementation of Procyanidin on Growth Performance and Immune Response in Pigs 
This study was performed to determine the effect of dietary supplementation of procyanidin on growth performance, blood characteristics, and immune function in growing pigs. In experiment 1 (Exp. 1), thirty-two crossbred pigs with an initial BW of 19.2±0.3 kg were allocated into 4 treatments for an 8-wk experiment: i) CON (basal diet), ii) MOS 0.1 (basal diet+0.1% mannanoligosaccharide), iii) Pro-1 (basal diet+0.01% procyanidin), and iv) Pro-2 (basal diet+0.02% procyanidin). Pigs fed Pro-1 and Pro-2 diets had greater (p<0.05) gain:feed ratio compared with those fed CON or MOS 0.1 diets. Serum creatinine concentration was less (p<0.05) in Pro-2 treatment than those in CON, MOS 0.1 and Pro-1 treatments. In Exp. 2, twelve pigs (BW 13.4±1.3 kg) received basal diet with i) 0 (CON), ii) 0.02% (Pro-0.02%), and iii) 0.04% procyanidin (Pro-0.04%) for 4 wk. Concentration of platelets was lower (p<0.05) in the Pro-0.04% group compared to CON at 24 h after lipopolysaccharide (LPS) challenge. In addition, secretion of cytokines from cultured peripheral blood mononuclear cells (PBMC) in the presence or absence of procyanidin was examined. The levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α were lower (p<0.05) in Pro (LPS-stimulated PBMCs+procyanidin) than those in CON (LPS-stimulated PBMCs+PBS) at 4 h after LPS challenge. These data suggest that dietary addition of procyanidin improves feed efficiency and anti-inflammatory cytokines of pigs.
PMCID: PMC4093277  PMID: 25049935
Growth Performance; Immune Response; Lipopolysaccharide; Pigs; Procyanidin
20.  Turning off the spigot: reducing drug-resistant tuberculosis transmission in resource-limited settings 
Ongoing transmission and re-infection, primarily in congregate settings, is a key factor fueling the global multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB) epidemic, especially in association with the human immunodeficiency virus. Even as efforts to broadly implement conventional TB transmission control measures begin, current strategies may be incompletely effective under the overcrowded conditions extant in high-burden, resource-limited settings. Longstanding evidence suggesting that TB patients on effective therapy rapidly become non-infectious and that unsuspected, untreated TB cases account for the most transmission makes a strong case for the implementation of rapid point-of-care diagnostics coupled with fully supervised effective treatment. Among the most important decisions affecting transmission, the choice of an MDR-TB treatment model that includes community-based treatment may offer important advantages over hospital or clinic-based care, not only in cost and effectiveness, but also in transmission control. In the community, too, rapid identification of infectious cases, especially drug-resistant cases, followed by effective, fully supervised treatment, is critical to stopping transmission. Among the conventional interventions available, we present a simple triage and separation strategy, point out that separation is intimately linked to the design and engineering of clinical space and call attention to the pros and cons of natural ventilation, simple mechanical ventilation systems, germicidal ultraviolet air disinfection, fit-tested respirators on health care workers and short-term use of masks on patients before treatment is initiated.
PMCID: PMC3709569  PMID: 20843413
nosocomial; resistance; drug; tuberculosis
21.  Coagulase-negative Staphylococcal Infections in the Neonatal Intensive Care Unit 
Coagulase-negative staphylococci (CoNS) are the most commonly isolated pathogens in the neonatal intensive care unit (NICU). CoNS infections are associated with increased morbidity including neurodevelopmental impairment.
Describe the epidemiology of CoNS infections in the NICU. Determine mortality among infants with definite, probable, or possible CoNS infections.
We performed a retrospective cohort study of all blood, urine, and cerebrospinal fluid cultures from infants <121 postnatal days.
248 NICUs managed by the Pediatrix Medical Group from 1997 to 2009.
We identified 16,629 infants with 17,624 episodes of CoNS infection: 1734 (10%) definite, 3093 (17%) probable, and 12,797 (73%) possible infections. Infants with lower gestational age and birth weight had a higher incidence of CoNS infection. Controlling for gestational age, birth weight, and 5-minute Apgar score, infants with definite, probable, or possible CoNS infection had lower mortality—OR=0.74 (95% confidence interval; 0.61, 0.89), OR= 0.68 (0.59, 0.79), and OR=0.69 (0.63, 0.76)—compared to infants with negative cultures (P<0.001). No significant difference in overall mortality was found in infants with definite CoNS infection compared to those with probable or possible CoNS infection—OR=0.93 (0.75, 1.16) and OR=0.85 (0.70, 1.03), respectively.
CoNS infection was strongly related to lower gestational age and birth weight. Infants with clinical sepsis and culture-positive CoNS infection had lower mortality rates than infants with clinical sepsis and negative blood culture results. No difference in mortality between infants diagnosed with definite, probable, or possible CoNS infection was observed.
PMCID: PMC3238054  PMID: 21666399
nosocomial infection; infant; prematurity; Staphylococcus
22.  Borna Disease Virus Infection, a Human Mental-Health Risk 
Clinical Microbiology Reviews  2003;16(3):534-545.
This article focuses on human Borna disease virus (BDV) infections, most notably on the development of valid diagnostic systems, which have arisen as a major research issue in the past decade. The significance of a novel modular triple enzyme-linked immunosorbent assay that is capable of specifically measuring anti-BDV antibodies as well as major structural proteins N (p40) and P (p24) in the blood, either as free antigens in the plasma or as antibody-bound circulating immune complexes (CICs), is explained. The impact of CICs and plasma antigen, which indicate periods of antigenemia in the course of BDV infection, along with other infection markers that are still in use is discussed. The review further provides new insight into possible links of BDV to human diseases, summarizing cross-sectional and longitudinal data which correlate acute depression with the presence and amount of antigen and CICs. Moreover, BDV prevalence in healthy people is reevaluated, suggesting that this was previously underestimated. Antiviral efficacy of amantadine, in vivo and in vitro, is outlined as well, with emphasis on wild-type (human and equine) versus laboratory strains. Finally, the pros and cons of the association of BDV with human disease, as detailed in the literature, are critically discussed and related to our data and concepts. This article supports existing correlative evidence for a pathogenic role of BDV infection in particular human mental disorders, in analogy to what has been proven for a variety of animal species.
PMCID: PMC164222  PMID: 12857781
23.  High-resolution cryo-electron microscopy on macromolecular complexes and cell organelles 
Protoplasma  2014;251(2):417-427.
Cryo-electron microscopy techniques and computational 3-D reconstruction of macromolecular assemblies are tightly linked tools in modern structural biology. This symbiosis has produced vast amounts of detailed information on the structure and function of biological macromolecules. Typically, one of two fundamentally different strategies is used depending on the specimens and their environment. A: 3-D reconstruction based on repetitive and structurally identical unit cells that allow for averaging, and B: tomographic 3-D reconstructions where tilt-series between approximately ±60 and ±70° at small angular increments are collected from highly complex and flexible structures that are beyond averaging procedures, at least during the first round of 3-D reconstruction. Strategies of group A are averaging-based procedures and collect large number of 2-D projections at different angles that are computationally aligned, averaged together, and back-projected in 3-D space to reach a most complete 3-D dataset with high resolution, today often down to atomic detail. Evidently, success relies on structurally repetitive particles and an aligning procedure that unambiguously determines the angular relationship of all 2-D projections with respect to each other. The alignment procedure of small particles may rely on their packing into a regular array such as a 2-D crystal, an icosahedral (viral) particle, or a helical assembly. Critically important for cryo-methods, each particle will only be exposed once to the electron beam, making these procedures optimal for highest-resolution studies where beam-induced damage is a significant concern. In contrast, tomographic 3-D reconstruction procedures (group B) do not rely on averaging, but collect an entire dataset from the very same structure of interest. Data acquisition requires collecting a large series of tilted projections at angular increments of 1–2° or less and a tilt range of ±60° or more. Accordingly, tomographic data collection exposes its specimens to a large electron dose, which is particularly problematic for frozen-hydrated samples. Currently, cryo-electron tomography is a rapidly emerging technology, on one end driven by the newest developments of hardware such as super-stabile microscopy stages as well as the latest generation of direct electron detectors and cameras. On the other end, success also strongly depends on new software developments on all kinds of fronts such as tilt-series alignment and back-projection procedures that are all adapted to the very low-dose and therefore very noisy primary data. Here, we will review the status quo of cryo-electron microscopy and discuss the future of cellular cryo-electron tomography from data collection to data analysis, CTF-correction of tilt-series, post-tomographic sub-volume averaging, and 3-D particle classification. We will also discuss the pros and cons of plunge freezing of cellular specimens to vitrified sectioning procedures and their suitability for post-tomographic volume averaging despite multiple artifacts that may distort specimens to some degree.
PMCID: PMC3927062  PMID: 24390311
Cryo-electron microscopy; Cryo-electron tomography; 3-D reconstruction of macromolecular complexes; CTF-correction; Volume-averaging; 3-D particle classification
24.  Predictors of Decision Making in Families at Risk for Inherited Breast/Ovarian Cancer 
The purpose of this study was to identify factors associated with decision making about inherited cancer risk information within families and determine the interdependence between survivors’ and relatives’ decision making.
A descriptive, cross-sectional design using a population-based sample of 146 dyads (N=292) was used. Analyses included multilevel modeling using the Actor-Partner-Interdependence Model
Main Outcome Measure
Decision making was the main outcome, along with the pros and cons in making a decision regarding inherited cancer risk information.
Overall, results indicate several individual and family factors that survivors and female relatives contribute toward their own and each other’s decision making about inherited cancer risk information. Individual factors included the individual’s perceptions of their family communication and their family’s cancer history. Among family dyadic factors, survivors and family members’ age, communication and coping style influenced the decision making of the other member of the dyad. Cancer worries and a monitoring coping style affected both seeking and avoiding decision making for survivors and their relatives.
In view of the importance of genetic information upon family health outcomes, it is critical to address both individual and family factors that may influence decision making about cancer risk information and surveillance options for all members within the family.
PMCID: PMC3947576  PMID: 19210016
Breast/Ovarian Cancer; Decision Making; Family; Inherited Cancer Risk
25.  From meta-omics to causality: experimental models for human microbiome research 
Microbiome  2013;1:14.
Large-scale ‘meta-omic’ projects are greatly advancing our knowledge of the human microbiome and its specific role in governing health and disease states. A myriad of ongoing studies aim at identifying links between microbial community disequilibria (dysbiosis) and human diseases. However, due to the inherent complexity and heterogeneity of the human microbiome, cross-sectional, case–control and longitudinal studies may not have enough statistical power to allow causation to be deduced from patterns of association between variables in high-resolution omic datasets. Therefore, to move beyond reliance on the empirical method, experiments are critical. For these, robust experimental models are required that allow the systematic manipulation of variables to test the multitude of hypotheses, which arise from high-throughput molecular studies. Particularly promising in this respect are microfluidics-based in vitro co-culture systems, which allow high-throughput first-pass experiments aimed at proving cause-and-effect relationships prior to testing of hypotheses in animal models. This review focuses on widely used in vivo, in vitro, ex vivo and in silico approaches to study host-microbial community interactions. Such systems, either used in isolation or in a combinatory experimental approach, will allow systematic investigations of the impact of microbes on the health and disease of the human host. All the currently available models present pros and cons, which are described and discussed. Moreover, suggestions are made on how to develop future experimental models that not only allow the study of host-microbiota interactions but are also amenable to high-throughput experimentation.
PMCID: PMC3971605  PMID: 24450613
Causality; Diet; Human microbiome; Hypothesis testing; In vivo model; In vitro model; Ex vivo model; In silico model; Dysbiosis; Disease; Microfluidics; Host-microbe interactions

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