bluuebunny/crossref_metadata_2025 huggingface dataset:
Negative Pressure Therapy
Authors: Franklin Morris E. , Alvarez Allen , Russek Karla
Published: January 2012

Background. Management of the open abdomen (OA) is challenging for surgeons and requires experienced medical teamwork. The need for improvements in temporary abdominal closure methods has led to the development of a negative-pressure therapy (NPT; ABThera OA NPT, KCI USA, Inc, San Antonio, TX). Method. The authors present a 19-patient case series documenting their use of NPT for OA management in nontraumatic surgery. All received NPT until the fascia was considered ready for closure. Results. Of 19 patients, 17 (89.5%) achieved fascial closure with a Kaplan-Meier (KM) median time to closure of 6 days. Mean hospital and intensive care unit stays were 32.1 and 26.6 days, respectively. During their hospitalization, 5 patients (26.3%) died, with a KM median time to mortality of 53 days. Conclusion. These findings demonstrate effective use of NPT for managing the OA in critically ill patients, and this has led the authors to use it in their general surgery practice.
Perspectives on African American Men’s Health
Authors: Bonhomme Jean J. , Essuon Aba D.
Published: January 2012

The overall life expectancy of African American men significantly lags behind that of other major demographic groups in the United States. African American men as a group suffer extremely high rates of cancer, heart disease and many other conditions that cause substantial morbidity as well as premature and unnecessary loss of life. However, it is now widely accepted that lifestyle and environmental factors play a major role in shaping mortality and morbidity outcomes in the United States. As a result, substantial opportunities exist for improved health outcomes among African American men through intervention involving disease prevention education and lifestyle modifications aimed at promoting as well as maintaining health promoting behavioral change. This commentary examines key contributory factors to preventable morbidity and mortality among African American men as well as promising interventions for reducing existing health disparities. Such adverse factors include limited heath care access, relative underutilization of the healthcare system compared with other demographic groups, suboptimal overall levels of physical activity, poor dietary habits leading to excessive caloric intake, tobacco and alcohol use, substance use disorders (often with co-morbid infectious diseases), sexual risk behaviors, unrecognized mental health disorders driving high homicide and suicide rates, and greatly disproportionate rates of incarceration. Several intervention methodologies with potential for widespread replication are discussed. In addition, African American men’s health is presented as an integral but commonly overlooked aspect of African American community health, with wide ranging impact on African American women and children in terms of economics, relationships and overall health status.
The Case of the Disappearing Allergy Medications
Authors: Evans Antonina G.
Published: January 2012

Many commonly prescribed combination cough, cold, and allergy products have disappeared from pharmacy shelves. In 2011, the US Food and Drug Administration (FDA) took action to remove these products from the US marketplace. This article discusses why the medications are unavailable and how to determine if a product you intend to prescribe is a part of this FDA action. The available alternative antihistamine products are discussed.
Older Adult Opinions About Driving Cessation
Authors: Betz Marian E. , Schwartz Robert , Valley Morgan , Lowenstein Steven R.
Published: January 2012

Objectives: To describe older adults’ opinions about driving cessation and driver retesting. Methods: Older adult (≥ 65 years) patients visiting the emergency department or geriatric clinic at a university hospital completed a confidential survey regarding attitudes toward driving tests and restrictions. Results: The response rate was 50% (N = 169). The median age was 75 years (range, 65-98); 53% were women. Most reported driving at least occasionally (78%; 95% confidence interval [95% CI], 72-84). Twelve percent (95% CI, 7-18) reported a crash in the prior year; most (84%; 95% CI, 78-90) reported at least 1 medical diagnosis possibly linked to increased crash risk. Most participants (74%; 95% CI, 67-81) supported mandatory, age-based driver retesting but thought family (73%; 95% CI, 68-81) or physicians (60%; 95% CI, 54-69) should determine license revocation for an unsafe driver rather than the Department of Motor Vehicles (34%; 95% CI, 28-42) or the police (30%; 95% CI, 23-37). Almost all reported they would consider driving cessation if recommended by a physician (88%; 95% CI, 82-94) or family member (71%; 95% CI, 63-79), without significant age or sex differences. Conclusions: Older drivers support mandatory age-based testing but appear more likely to follow recommendations from physicians or family members, thereby supporting a role for physician counseling, driver evaluations, and advanced driving directives.
Colorectal Cancer Educational Intervention Targeting Latino Patients Attending a Community Health Center
Authors: Castañeda Sheila F. , Xiong Yer , Gallo Linda C. , Yepes-Rios Monica , Ji Ming , Talavera Ana C. , Mendoza Paulina M. , Talavera Gregory A.
Published: January 2012

Objective: Colorectal cancer (CRC) is the third leading cause of cancer death for Latino men and women; and Latinos are more likely to be diagnosed at a later stage, which is most likely due to underutilization of CRC preventive screening. The purpose of this study was to determine whether a brief, clinic-based intervention by a community health advisor (CHA) would increase CRC knowledge compared with traditional educational methodologies (eg, use of print materials). Methods: Latino adults 50 years and older attending a San Diego community health center were recruited while waiting for their primary care provider routine visit and were randomly assigned to receive 1 of 3 CRC educational interventions: community health advisor (CHA) plus CRC educational brochure (CHA intervention group), CRC educational brochure (minimal intervention group), or 5-a-day nutrition brochure (usual care). CRC knowledge was assessed before and after the primary care provider visit for 130 participants. Results: Results demonstrate that the CRC educational brochure (minimal intervention group) was effective at increasing CRC screening knowledge as compared to usual care. Conclusions: Future research is needed to explore innovative health education strategies that improve knowledge and subsequent CRC screening behaviors among low-income, low-literacy, unacculturated Latinos.
Improved survival in chronic myeloid leukemia since the introduction of imatinib therapy: a single-institution historical experience
Authors: Kantarjian Hagop , O'Brien Susan , Jabbour Elias , Garcia-Manero Guillermo , Quintas-Cardama Alfonso , Shan Jenny , Rios Mary Beth , Ravandi Farhad , Faderl Stefan , Kadia Tapan , Borthakur Gautam , Huang Xuelin , Champlin Richard , Talpaz Moshe , Cortes Jorge
Published: January 2012

A total of 1569 patients with chronic myeloid leukemia (CML) referred to our institution within 1 month of diagnosis since 1965 were reviewed: 1148 chronic phase (CP), 175 accelerated phase (AP), and 246 blastic phase (BP). The median survival was 8.9 years in CP, 4.8 years in AP, and 6 months in BP. In CP, the 8-year survival was ≤ 15% before 1983, 42%-65% from 1983-2000, and 87% since 2001. Survival was worse in older patients (P = .004), but this was less significant since 2001 (P = .07). Survival by Sokal risk was significantly different before 2001 (P < .001), but not since 2001 (P = .4). In AP, survival improved over time (P < .001); the 8-year survival in patients treated since 2001 was 75%. Survival by age was not different in years < 2001 (P = .09), but was better since 2001 in patients ≤ 70 years of age (P = .004). In BP, the median survival improved over time (P < .001), although it has been only 7 months since 2001. In summary, survival in CML has significantly improved since 2001, particularly so in CP-AML and AP-CML. Imatinib therapy minimized the impact of known prognostic factors and Sokal risk in CP-CML and accentuated the impact of age in AP- and BP-CML.
Bone marrow homing and engraftment of human hematopoietic stem and progenitor cells is mediated by a polarized membrane domain
Authors: Larochelle Andre , Gillette Jennifer M. , Desmond Ronan , Ichwan Brian , Cantilena Amy , Cerf Alexandra , Barrett A. John , Wayne Alan S. , Lippincott-Schwartz Jennifer , Dunbar Cynthia E.
Published: January 2012

Manipulation of hematopoietic stem/progenitor cells (HSPCs) ex vivo is of clinical importance for stem cell expansion and gene therapy applications. However, most cultured HSPCs are actively cycling, and show a homing and engraftment defect compared with the predominantly quiescent noncultured HSPCs. We previously showed that HSPCs make contact with osteoblasts in vitro via a polarized membrane domain enriched in adhesion molecules such as tetraspanins. Here we show that increased cell cycling during ex vivo culture of HSPCs resulted in disruption of this membrane domain, as evidenced by disruption of polarity of the tetraspanin CD82. Chemical disruption or antibody-mediated blocking of CD82 on noncultured HSPCs resulted in decreased stromal cell adhesion, homing, and engraftment in nonobese diabetic/severe combined immunodeficiency IL-2γnull (NSG) mice compared with HSPCs with an intact domain. Most leukemic blasts were actively cycling and correspondingly displayed a loss of domain polarity and decreased homing in NSG mice compared with normal HSPCs. We conclude that quiescent cells, unlike actively cycling cells, display a polarized membrane domain enriched in tetraspanins that mediates homing and engraftment, providing a mechanistic explanation for the homing/engraftment defect of cycling cells and a potential new therapeutic target to enhance engraftment.
Emerging roles for multipotent, bone marrow–derived stromal cells in host defense
Authors: Auletta Jeffery J. , Deans Robert J. , Bartholomew Amelia M.
Published: January 2012

Multipotent, bone marrow–derived stromal cells (BMSCs, also known as mesenchymal stem cells [MSCs]), are culture-expanded, nonhematopoietic cells with immunomodulatory effects currently being investigated as novel cellular therapy to prevent and to treat clinical disease associated with aberrant immune response. Emerging preclinical studies suggest that BMSCs may protect against infectious challenge either by direct effects on the pathogen or through indirect effects on the host. BMSCs may reduce pathogen burden by inhibiting growth through soluble factors or by enhancing immune cell antimicrobial function. In the host, BMSCs may attenuate pro-inflammatory cytokine and chemokine induction, reduce pro-inflammatory cell migration into sites of injury and infection, and induce immunoregulatory soluble and cellular factors to preserve organ function. These preclinical studies provide provocative hints into the direction MSC therapeutics may take in the future. Notably, BMSCs appear to function as a critical fulcrum, providing balance by promoting pathogen clearance during the initial inflammatory response while suppressing inflammation to preserve host integrity and facilitate tissue repair. Such exquisite balance in BMSC function appears intrinsically linked to Toll-like receptor signaling and immune crosstalk.
Generic and oral quality of life is affected by oral mucosal diseases
Authors: Liu Li-Jun , Xiao Wen , He Qing-Bo , Jiang Wei-Wen
Published: January 2012

Background

The generic and oral health-related quality of life (QoL) has provided opportunity for investigation of the interrelations among generic health, oral health, and related outcomes. The purpose of this study was to identify the generic and oral QoL in the patients with oral mucosal disease (OMD).

Methods

Five hundred and thirty-eight OMDs were recruited in this study. The instruments applied were Chinese version of the 36-item short form health survey (SF-36) and the short-form of Oral Health Impact Profile (OHIP-14).

Results

The mean score of sum OHIP-14 was significantly higher in the patients with OMD (10.81 ± 9.01) compared with those in the healthy subjects (HS) (6.55 ± 6.73) (p < 0.001, Mann-Whitney U test). 56.51% of the OMD patients and 12.94% of the HS reported at least one oral negative impact (p < 0.001, Chi-square test). The overall mean score of SF-36 was significantly lower in the patients with OMD (74.54 ± 12.77) compared with those in the HS (77.97 ± 12.39) (p = 0.021, t-test).

Conclusions

Administration of specific and generic questionnaires of QoL can provide us a detailed picture of the impact of OMDs on patients, and both generic and oral QoL were impaired in the patients with OMD.
Immunological characterization and transcription profiling of peripheral blood (PB) monocytes in children with autism spectrum disorders (ASD) and specific polysaccharide antibody deficiency (SPAD): case study
Authors: Jyonouchi Harumi , Geng Lee , Streck Deanna L , Toruner Gokce A
Published: January 2012

Introduction

There exists a small subset of children with autism spectrum disorders (ASD) characterized by fluctuating behavioral symptoms and cognitive skills following immune insults. Some of these children also exhibit specific polysaccharide antibody deficiency (SPAD), resulting in frequent infection caused by encapsulated organisms, and they often require supplemental intravenous immunoglobulin (IVIG) (ASD/SPAD). This study assessed whether these ASD/SPAD children have distinct immunological findings in comparison with ASD/non-SPAD or non-ASD/SPAD children.

Case description

We describe 8 ASD/SPAD children with worsening behavioral symptoms/cognitive skills that are triggered by immune insults. These ASD/SPAD children exhibited delayed type food allergy (5/8), treatment-resistant seizure disorders (4/8), and chronic gastrointestinal (GI) symptoms (5/8) at high frequencies. Control subjects included ASD children without SPAD (N = 39), normal controls (N = 37), and non-ASD children with SPAD (N = 12).

Discussion and Evaluation

We assessed their innate and adaptive immune responses, by measuring the production of pro-inflammatory and counter-regulatory cytokines by peripheral blood mononuclear cells (PBMCs) in responses to agonists of toll like receptors (TLR), stimuli of innate immunity, and T cell stimulants. Transcription profiling of PB monocytes was also assessed. ASD/SPAD PBMCs produced less proinflammatory cytokines with agonists of TLR7/8 (IL-6, IL-23), TLR2/6 (IL-6), TLR4 (IL-12p40), and without stimuli (IL-1ß, IL-6, and TNF-α) than normal controls. In addition, cytokine production of ASD/SPAD PBMCs in response to T cell mitogens (IFN-γ, IL-17, and IL-12p40) and candida antigen (Ag) (IL-10, IL-12p40) were less than normal controls. ASD/non-SPAD PBMDs revealed similar results as normal controls, while non-ASD/SPAD PBMCs revealed lower production of IL-6, IL-10 and IL-23 with a TLR4 agonist. Only common features observed between ASD/SPAD and non-ASD/SPAD children is lower IL-10 production in the absence of stimuli. Transcription profiling of PB monocytes revealed over a 2-fold up (830 and 1250) and down (653 and 1235) regulation of genes in ASD/SPAD children, as compared to normal (N = 26) and ASD/non-SPAD (N = 29) controls, respectively. Enriched gene expression of TGFBR (p < 0.005), Notch (p < 0.01), and EGFR1 (p < 0.02) pathways was found in the ASD/SPAD monocytes as compared to ASD/non-SPAD controls.

Conclusions

The Immunological findings in the ASD/SPAD children who exhibit fluctuating behavioral symptoms and cognitive skills cannot be solely attributed to SPAD. Instead, these findings may be more specific for ASD/SPAD children with the above-described clinical characteristics, indicating a possible role of these immune abnormalities in their neuropsychiatric symptoms.
Association between being African-American, serum urate levels and the risk of developing hyperuricemia: findings from the Coronary Artery Risk Development in Young Adults cohort
Authors: Gaffo Angelo L , Jacobs David R , Lewis Cora E , Mikuls Ted R , Saag Kenneth G
Published: January 2012

Introduction

Findings that African-American race/ethnicity is associated with higher concentrations of serum urate have not been adjusted for possible confounding factors or have not explored this question as a primary outcome. We tested this hypothesis in a bi-racial cohort of younger African-American and white men and women.

Methods

Data from 5,049 participants at the Coronary Artery Risk Development in Young Adults (CARDIA) cohort baseline (1985 to1986) and follow-up for up to 20 years of individuals without hyperuricemia (defined as a serum urate of 6.8 mg/dL or more) at baseline were utilized. We determined associations between race, serum urate and the development of hyperuricemia in sex-specific cross-sectional and longitudinal analyses. Confounding factors examined included: age at enrollment, body mass index, development of hypertension, glomerular filtration rate, medication use, diet and alcohol intake and menopausal symptoms in women.

Results

Referent to whites, African-American men and women had significantly lower concentrations of serum urate at baseline. African-American men had an essentially equal risk of developing incident hyperuricemia during follow-up compared with white men (multivariable adjusted HR = 1.12 (0.88 to1.40)). African-American women developed a significantly increased risk of hyperuricemia when compared to white women (HR = 2.31 (1.34 to 3.99)).

Conclusions

Young African-American men and women had lower concentrations of serum urate than whites. During longitudinal follow-up, African-American women had a significantly increased risk of developing hyperuricemia when compared with white women, a difference that was not observed in men. Differences in production of serum urate or a more rapid decline in fractional excretion of serum urate are potential, albeit still unproven, explanations for these findings in African-American women.
Involvement of Nav 1.8 sodium ion channels in the transduction of mechanical pain in a rodent model of osteoarthritis
Authors: Schuelert Niklas , McDougall Jason J
Published: January 2012

Introduction

A subgroup of voltage gated sodium channels including Nav1.8 are exclusively expressed on small diameter primary afferent neurons and are therefore believed to be integral to the neurotransmission of nociceptive pain. The present study examined whether local application of A-803467, a selective blocker of the Nav 1.8 sodium channel, can reduce nociceptive transmission from the joint in a rodent model of osteoarthritis (OA).

Methods

OA-like changes were induced in male Wistar rats by an intra-articular injection of 3 mg sodium monoiodoacetate (MIA). Joint nociception was measured at day 14 by recording electrophysiologically from knee joint primary afferents in response to non-noxious and noxious rotation of the joint both before and following close intra-arterial injection of A-803467. The effect of Nav1.8 blockade on joint pain perception and secondary allodynia were determined in MIA treated animals by hindlimb incapacitance and von Frey hair algesiometry respectively.

Results

A-803467 significantly reduced the firing rate of joint afferents during noxious rotation of the joint but had no effect during non-noxious rotation. In the pain studies, peripheral injection of A-803467 into OA knees attenuated hindlimb incapacitance and secondary allodynia.

Conclusions

These studies show for the first time that the Nav1.8 sodium channel is part of the molecular machinery involved in mechanotransduction of joint pain. Targeting the Nav1.8 sodium channel on joint nociceptors could therefore be useful for the treatment of OA pain, avoiding the unwanted side effects of non-selective nerve blocks.
Hypoxia-inducible factor 1α promotes primary tumor growth and tumor-initiating cell activity in breast cancer
Authors: Schwab Luciana P , Peacock Danielle L , Majumdar Debeshi , Ingels Jesse F , Jensen Laura C , Smith Keisha D , Cushing Richard C , Seagroves Tiffany N
Published: January 2012

Introduction

Overexpression of the oxygen-responsive transcription factor hypoxia-inducible factor 1α (HIF-1α) correlates with poor prognosis in breast cancer patients. The mouse mammary tumor virus polyoma virus middle T (MMTV-PyMT) mouse is a widely utilized preclinical mouse model that resembles human luminal breast cancer and is highly metastatic. Prior studies in which the PyMT model was used demonstrated that HIF-1α is essential to promoting carcinoma onset and lung metastasis, although no differences in primary tumor end point size were observed. Using a refined model system, we investigated whether HIF-1α is directly implicated in the regulation of tumor-initiating cells (TICs) in breast cancer.

Methods

Mammary tumor epithelial cells were created from MMTV-PyMT mice harboring conditional alleles of Hif1a, followed by transduction ex vivo with either adenovirus β-galactosidase or adenovirus Cre to generate wild-type (WT) and HIF-1α-null (KO) cells, respectively. The impact of HIF-1α deletion on tumor-initiating potential was investigated using tumorsphere assays, limiting dilution transplantation and gene expression analysis.

Results

Efficient deletion of HIF-1α reduced primary tumor growth and suppressed lung metastases, prolonging survival. Loss of HIF-1α led to reduced expression of markers of the basal lineage (K5/K14) in cells and tumors and of multiple genes involved in the epithelial-to-mesenchymal transition. HIF-1α also enhanced tumorsphere formation at normoxia and hypoxia. Decreased expression of several genes in the Notch pathway as well as Vegf and Prominin-1 (CD133)was observed in response to Hif1a deletion. Immunohistochemistry confirmed that CD133 expression was reduced in KO cells and in tumorspheres. Tumorsphere formation was enhanced in CD133hi versus CD133neg cells sorted from PyMT tumors. Limiting dilution transplantation of WT and KO tumor cells into immunocompetent recipients revealed > 30-fold enrichment of TICs in WT cells.

Conclusion

These results demonstrate that HIF-1α plays a key role in promoting primary mammary tumor growth and metastasis, in part through regulation of TICs. HIF-1α regulates expression of several members of the Notch pathway, CD133 and markers of the basal lineage in mammary tumors. Our results suggest that CD133, which has not been profiled extensively in breast cancer, may be a useful marker of TICs in the PyMT mouse model. These data reveal for the first time that HIF-1α directly regulates breast TIC activity in vivo.
No evidence for association of inherited variation in genes involved in mitosis and percent mammographic density
Authors: Vachon Celine M , Li Jingmei , Scott Christopher G , Hall Per , Czene Kamila , Wang Xianshu , Liu Jianjun , Fredericksen Zachary S , Rider David N , Wu Fang-Fang , Olson Janet E , Cunningham Julie M , Stevens Kristen N , Sellers Thomas A , Pankratz Shane V , Couch Fergus J
Published: January 2012

Introduction

Increased mammographic breast density is one of the strongest risk factors for breast cancer. While two-thirds of the variation in mammographic density appears to be genetically influenced, few variants have been identified. We examined the association of inherited variation in genes from pathways that mediate cell division with percent mammographic density (PMD) adjusted for age, body mass index (BMI) and postmenopausal hormones, in two studies of healthy postmenopausal women.

Methods

We investigated 2,058 single nucleotide polymorphisms (SNPs) in 378 genes involved in regulation of mitosis for associations with adjusted PMD among 484 unaffected postmenopausal controls (without breast cancer) from the Mayo Clinic Breast Cancer Study (MCBCS) and replicated the findings in postmenopausal controls (n = 726) from the Singapore and Sweden Breast Cancer Study (SASBAC) study. PMD was assessed in both studies by a computer-thresholding method (Cumulus) and linear regression approaches were used to assess the association of SNPs and PMD, adjusted for age, BMI and postmenopausal hormones. A P-value threshold of 4.2 × 10-5 based on a Bonferroni correction of effective number of independent tests was used for statistical significance. Further, a pathway-level analysis was conducted of all 378 genes using the self-contained gene-set analysis method GLOSSI.

Results

A variant in PRPF4, rs10733604, was significantly associated with adjusted PMD in the MCBCS (P = 2.7 × 10-7), otherwise, no single SNP was associated with PMD. Additionally, the pathway analysis provided no evidence of enrichment in the number of associations observed between SNPs in the mitotic genes and PMD (P = 0.60). We evaluated rs10733604 (PRPF4), and 73 other SNPs at P < 0.05 from 51 genes in the SASBAC study. There was no evidence of an association of rs10733604 (PRPF4) with adjusted PMD in SASBAC (P = 0.23). There were, however, consistent associations (P < 0.05) of variants at the putative locus, LOC375190, Aurora B kinase (AURKB), and Mini-chromosome maintenance complex component 3 (MCM3) with adjusted PMD, although these were not statistically significant.

Conclusions

Our findings do not support a role of inherited variation in genes involved in regulation of cell division and adjusted percent mammographic density in postmenopausal women.
Plasma neutrophil gelatinase-associated lipocalin for the prediction of acute kidney injury in acute heart failure
Authors: Breidthardt Tobias , Socrates Thenral , Drexler Beatrice , Noveanu Markus , Heinisch Corinna , Arenja Nisha , Klima Theresia , Züsli Christina , Reichlin Tobias , Potocki Mihael , Twerenbold Raphael , Steiger Jürg , Mueller Christian
Published: January 2012

Introduction

The accurate prediction of acute kidney injury (AKI) in patients with acute heart failure (AHF) is an unmet clinical need. Neutrophil gelatinase-associated lipocalin (NGAL) is a novel sensitive and specific marker of AKI.

Methods

A total of 207 consecutive patients presenting to the emergency department with AHF were enrolled. Plasma NGAL was measured in a blinded fashion at presentation and serially thereafter. The potential of plasma NGAL levels to predict AKI was assessed as the primary endpoint. We defined AKI according to the AKI Network classification.

Results

Overall 60 patients (29%) experienced AKI. These patients were more likely to suffer from pre-existing chronic cardiac or kidney disease. At presentation, creatinine (median 140 (interquartile range (IQR), 91 to 203) umol/L versus 97 (76 to 132) umol/L, P < 0.01) and NGAL (114.5 (IQR, 67.1 to 201.5) ng/ml versus 74.5 (60 to 113.9) ng/ml, P < 0.01) levels were significantly higher in AKI compared to non-AKI patients. The prognostic accuracy for measurements obtained at presentation, as quantified by the area under the receiver operating characteristic curve was mediocre and comparable for the two markers (creatinine 0.69; 95%CI 0.59 to 0.79 versus NGAL 0.67; 95%CI 0.57 to 0.77). Serial measurements of NGAL did not further increase the prognostic accuracy for AKI. Creatinine, but not NGAL, remained an independent predictor of AKI (hazard ratio (HR) 1.12; 95%CI 1.00 to 1.25; P = 0.04) in multivariable regression analysis.

Conclusions

Plasma NGAL levels do not adequately predict AKI in patients with AHF.
Tissue stroma as a regulator of leukocyte recruitment in inflammation
Authors: McGettrick Helen M , Butler Lynn M , Buckley Chris D , Ed Rainger G , Nash Gerard B
Published: January 2012

The stromal milieu (cellular and matrix components) helps establish tissue “address-codes” that direct leukocyte behavior in inflamed tissue. Coordinated interactions among the stroma, leukocytes, and ECs dictate which leukocytes are recruited, whether they are retained within the inflamed site, and how long they survive. Herein, we discuss how the stromal milieu influences the leukocyte recruitment cascade. Moreover, we explore how corruption of the stromal phenotype in chronic inflammatory diseases contributes to undesired, continuous recruitment of leukocytes. Emerging complex, multicellular, multilayered (co-)culture models are now addressing the molecular circuitry involved in regulating stromal organization during inflammation. Understanding context-specific changes in pro- or anti-inflammatory agents derived from the stroma, such as IL-6 (and its cofactors), is important for the generation of therapeutic strategies that restore the balance between recruitment and clearance of the inflammatory infiltrate in chronic disease.
Unusual timing of CD127 expression by mouse uterine natural killer cells
Authors: Zhang Jianhong , Chen Zhilin , Fritz Jörg H , Rochman Yrina , Leonard Warren J , Gommerman Jennifer L , Plumb Adam W , Abraham Ninan , Croy B Anne
Published: January 2012

Decidualization, a progesterone-dependent process that alters endometrial stromal cells at implantation sites in humans and rodents, is accompanied by a highly regulated, NK cell-dominated leukocyte influx into decidual basalis (DB). Whether uNK cells differentiate from uterine progenitor cells is unknown, as are the mechanisms restricting leukocytes to DB. We asked if cells expressing the early NK lineage marker CD127 (IL-7Rα) occurred in mouse decidua. CD127 was absent from gd6.5 decidual lymphoid cells but became expressed by a mature uNK cell subset in gd10.5 DB. DB and transient myometrial structures (MLAp) that ring maternal blood vessels supplying placentae expressed IL-7 and TSLP, the CD127 ligands, but with differing temporal and spatial patterns. UNK cells expressed TSLPR, and study of gd10.5 implantation sites from mice deleted for IL-7, CD127, or TSLPR suggested that IL-7 and its receptor have physiological roles in limiting expansion of immature uNK cells within MLAp, while the TSLP signaling pathway is used in DB to sustain IFN-γ production from a subset of mature uNK cells. Regionalized, dynamic expression of the additional lymphoid organ stromal markers gp38/podoplanin and ER-TR7, but not CD157, were seen by immunohistochemistry in implantation sites, and DB and MLAp contained transcripts for Aire, a tolerance-promoting factor. These observations suggest that CD127+ NK lineage progenitors are not present in the early postimplantation period of mouse uterus and that decidualized endometrial stroma has key immunoregulatory properties.
Sall1 regulates cortical neurogenesis and laminar fate specification, implications for neural abnormalities in Townes Brocks Syndrome
Authors: Harrison Susan J. , Nishinakamura Ryuichi , Jones Kevin R. , Monaghan A. Paula
Published: January 2012

Progenitor cells in the cerebral cortex undergo dynamic cellular and molecular changes during development. Sall1 is a putative transcription factor that is highly expressed in progenitor cells during development. In humans, the autosomal dominant developmental disorder, Townes Brocks syndrome is associated with mutations of the SALL1 gene. Townes Brocks syndrome is characterized by renal, anal, limb, and auditory abnormalities. Although neural deficits have not been recognized as a diagnostic characteristic of the disease, ~10% of patients exhibit neural or behavioral abnormalities. We demonstrate that Sall1 is robustly expressed in progenitor cells of the central nervous system, in addition to peripheral organs. Both classical and condition knockout studies indicate that the cerebral cortex is particularly sensitive to loss of Sall1. In the absence of Sall1 both the surface area and depth of the cerebral cortex were decreased at E18.5. These deficiencies are associated with changes in progenitor cell properties during development. In early cortical progenitor cells Sall1 promotes proliferative over neurogenic division whereas at later developmental stages, Sall1 regulates the production and differentiation of intermediate progenitor cells. Furthermore, Sall1 influences the temporal specification of cortical laminae. These findings present novel insights into the function of Sall1 in the developing cortex and provide avenues for future research into potential neural deficits in Townes Brocks patients.
A model 450 million years in the making: zebrafish and vertebrate immunity
Authors: Renshaw Stephen A. , Trede Nikolaus S.
Published: January 2012

Since its first splash 30 years ago, the use of the zebrafish model has been extended from a tool for genetic dissection of early vertebrate development to the functional interrogation of organogenesis and disease processes such as infection and cancer. In particular, there is recent and growing attention in the scientific community directed at the immune systems of zebrafish. This development is based on the ability to image cell movements and organogenesis in an entire vertebrate organism, complemented by increasing recognition that zebrafish and vertebrate immunity have many aspects in common. Here, we review zebrafish immunity with a particular focus on recent studies that exploit the unique genetic and in vivo imaging advantages available for this organism. These unique advantages are driving forward our study of vertebrate immunity in general, with important consequences for the understanding of mammalian immune function and its role in disease pathogenesis.
Absence of the Cdk5 activator p35 causes adult-onset neurodegeneration in the central brain of Drosophila
Authors: Trunova Svetlana , Giniger Edward
Published: January 2012

Altered function of Cdk5 kinase is associated with many forms of neurodegenerative disease in humans. We show here that inactivating the Drosophila Cdk5 ortholog, by mutation of its activating subunit, p35, causes adult-onset neurodegeneration in the fly. In the mutants, a vacuolar neuropathology is observed in a specific structure of the central brain, the ‘mushroom body’, which is the seat of olfactory learning and memory. Analysis of cellular phenotypes in the mutant brains reveals some phenotypes that resemble natural aging in control flies, including an increase in apoptotic and necrotic cell death, axonal fragmentation, and accumulation of autophagosomes packed with crystalline-like depositions. Other phenotypes are unique to the mutants, notably age-dependent swellings of the proximal axon of mushroom body neurons. Many of these phenotypes are also characteristic of mammalian neurodegenerative disease, suggesting a close relationship between the mechanisms of Cdk5-associated neurodegeneration in fly and human. Together, these results identify the cellular processes that are unleashed in the absence of Cdk5 to initiate the neurodegenerative program, and they provide a model that can be used to determine what part each process plays in the progression to ultimate degeneration.
A FRT-flankedp53mouse to generate primary tumors with Flp recombinase
Authors: Lee Chang-Lung , Moding Everett J. , Huang Xiaofang , Li Yifan , Woodlief Loretta Z. , Rodrigues Rafaela C. , Ma Yan , Kirsch David G.
Published: January 2012

The site-specific recombinases Cre and Flp can mutate genes in a spatially and temporally restricted manner in mice. Conditional recombination of the tumor suppressor p53 using the Cre-loxP system has led to the development of multiple genetically engineered mouse models of human cancer. However, initiation of tumors with Cre recombinase limits the utilization of Cre to genetically modify other genes in stromal cells. To overcome this limitation, we inserted FRT sites flanking exons 2 through 6 of the endogenous p53 gene in mice to generate a p53FRT allele that can be deleted by Flp recombinase. We show that FlpO-mediated deletion of p53 in mouse embryonic fibroblasts impairs the p53-dependent response to genotoxic stress in vitro. In addition, using FSF-KrasG12D/+; p53FRT/FRT mice, we demonstrate an adenovirus expressing FlpO recombinase can initiate primary lung cancers and sarcomas in mice. p53FRT mice will enable dual recombinase technology to study cancer biology because Cre is available to modify genes specifically in stromal cells to investigate their role in tumor development, progression, and response to therapy.
Alteration in myocardial prostaglandin D synthase expression in pressure overload-induced left ventricular remodeling in rats
Authors: Nagalla Krishna T , Gole Monica , Claudino Mario A , Gardner Jason D , Murray David B
Published: January 2012

We hypothesized that acute pharmacological blockade of cyclooxygenase-2 (COX-2) using nimesulide (Nime) would prevent maladaptive changes in left ventricular (LV) structure and function secondary to abdominal aortic coarctation-induced pressure overload (PO). In vivo LV chamber dimension and function were assessed by pressure/volume admittance catheter at 14 days' postsurgery in three groups ( n ≥ 6/group): sham-operated (Sham); untreated PO; and selective COX-2 inhibitor nimesulide-treated PO (PO + Nime; 25 mg/kg/d). Treatment was initiated 24 h prior to surgical induction of PO. Relative to Sham, there was a marked increase in LV mass index in the PO groups (2.2 ± 0.01 mg/g versus 2.9 ± 0.10 mg/g Sham versus PO, PO+Nime: 2.5 ± 0.03 mg/g). End diastolic volume, an indicator of chamber size, was significantly decreased in the PO animals compared with Sham (202 ± 17 μL versus 143 ± 16 μL Sham versus PO, PO + Nime: 226 ± 9 μL). Collagen levels in PO rats assessed by hydroxyproline analysis were significantly elevated relative to Sham values. Nimesulide treatment attenuated: (1) the increase in LV mass index; (2) the reduction in end diastolic volume; and (3) the PO-induced increase in myocardial collagen. In summary, acute COX-2 inhibition with nimesulide attenuated the maladaptive changes in the LV after PO. Acknowledging the clinical failure of chronic COX-2 inhibitor use, we propose that acute treatment with COX-2 inhibition during the initial stages of cardiac remodeling can be beneficial in maintaining the normal cardiac structure and function during PO.
A custom rat and baboon hypertension gene array to compare experimental models
Authors: Northcott Carrie A , Glenn Jeremy P , Shade Robert E , Kammerer Candace M , Hinojosa-Laborde Carmen , Fink Gregory D , Haywood Joseph R , Cox Laura A
Published: January 2012

One challenge in understanding the polygenic disease of hypertension is elucidating the genes involved and defining responses to environmental factors. Many studies focus on animal models of hypertension; however, this does not necessarily extrapolate to humans. Current technology and cost limitations are prohibitive in fully evaluating hypertension within humans. Thus, we have designed a single-array platform that allows direct comparison of genes relevant to hypertension in animal models and non-human primates/human hypertension. The custom array is targeted to 328 genes known to be potentially related to blood pressure control. Studies compared gene expression in the kidney from normotensive rats and baboons. We found 74 genes expressed in both the rat and baboon kidney, 41 genes expressed in the rat kidney that were not detected in the baboon kidney and 34 genes expressed in the baboon kidney that were not detected in the rat kidney. To begin the evaluation of the array in a pathological condition, kidney gene expression was compared between the salt-sensitive deoxycorticosterone acetate (DOCA) rat model of hypertension and sham animals. Gene expression in the renal cortex and medulla from hypertensive DOCA compared with sham rats revealed three genes differentially expressed in the renal cortex: annexin A1 (up-regulated; relative intensity: 1.316 ± 0.321 versus 2.312 ± 0.283), glutamate-cysteine ligase (down-regulated; relative intensity: 3.738 ± 0.174 versus 2.645 ± 0.364) and glutathione- S transferase (down-regulated; relative intensity: 5.572 ± 0.246 versus 4.215 ± 0.411) and 21 genes differentially expressed in the renal medulla. Interestingly, few genes were differentially expressed in the kidney in the DOCA-salt model of hypertension; this may suggest that the complexity of hypertension may be the result of only a few gene-by-environment responsive events.
Hormônio de crescimento em crianças e adolescentes com fibrose cística
Authors: Amorim Pollyana Garcia , Mendes Thaís de Barros , Oliveira Lílian Santiago Pinho de , Guerra-Júnior Gil , Ribeiro José Dirceu
Published: January 2012

O hormônio de crescimento recombinante humano (rhGH) pode melhorar o ganho ponderal, o crescimento físico e as condições clínicas e pulmonares na fibrose cística (FC). Entretanto, o uso rotineiro, embora promissor, não está estabelecido na literatura. O objetivo deste trabalho foi verificar os benefícios do rhGH em crianças e adolescentes com FC. Realizou-se uma revisão sistemática nas bases de dados PubMed, Lilacs, SciELO, Cochrane, no período de 20002010, utilizando-se as palavras-chave: "fibrose cística", "hormônio de crescimento", "crianças" e "adolescentes". Foram encontrados 77 artigos, sendo incluídos 11 estudos randomizados controlados, com 290 crianças e adolescentes com FC. O uso em curto prazo (1-24 meses) do rhGH melhorou estatura, peso, velocidade de crescimento, massa óssea e componentes da função pulmonar. Efeitos adversos como diabetes não foram observados nos estudos. O uso em curto prazo do rhGH melhorou o crescimento e a composição corporal em pacientes com FC.
Treatment of mild to moderate Graves' ophthalmopathy with sodium diclofenac: a pilot study
Authors: Bloise Walter , Mimura Lidia Yuri , Moura Janete , Nicolau Wilian
Published: January 2012

OBJECTIVE: To report the use of sodium diclofenac, an antagonist of PPAR-gamma and cyclooxigenase-2 (COX-2) inhibitor in the treatment of mild to moderate Graves' ophthalmopathy. SUBJECTS AND METHODS: Thirteen patients with clinical activity score (CAS) 2 to 7 were treated during a period ranging from 3 to 12 months (mean 7.8 ± 3.4) with oral sodium diclofenac, 50 mg every 12 hours. RESULTS: Extra-ocular muscle restriction and CAS improved significantly, p = 0.003 and = 0.004, respectively. Ocular pain and diplopia disappeared, except for one patient who reported improvement of these symptoms. No recurrence was found after interruption of treatment. CONCLUSIONS: Treatment of moderate Graves' ophthalmopathy with oral sodium diclofenac is a good, safe and less expensive therapeutic option. Like others new treatment trials, findings must be confirmed in a greater number of patients in a controlled study.
Diabetes mellitus and spinal epidural abscess: clinical or surgical treatment?
Authors: Felício João S. , Martins Carlliane Lins P. , Liberman Bernardo
Published: January 2012

Spinal epidural abscess (SEA) is an uncommon condition and its most important predisposing factor is diabetes mellitus. Although the treatment of choice is prompt surgical abscess evacuation, followed by antibiotic therapy, successful conservative treatment of SEA has been reported in some cases. We describe a SEA case in a 23-year old white woman with diabetes for 14 years, who was successfully treated only with antibiotics, and achieved full recovery at the fourth month of follow-up.
Epidemiological aspects of dengue in Aracaju, State of Sergipe, Brazil
Authors: Alves José Antonio Barreto , Santos Jokasta Rodrigues , Mendonça Emanuelle Nabuco de , Abud Ana Cristina Freire , Nunes Mariangela da Silva , Fakhouri Ricardo , Inagaki Ana Dorcas de Melo , Marchioro Murilo , Antoniolli Angelo Roberto
Published: January 2012

INTRODUCTION: The dengue fever remains to be a disease of serious public health concern, and its incidence has increased in the past decades. This study aimed to characterize the epidemiological incidence of dengue in the period 2001-2010. METHODS: This is an epidemiological study of dengue in the municipality of Aracaju, state of Sergipe, in the period between 2001 and 2010, whose data were obtained from the Information System of Diseases Notifications. A descriptive analysis of the number of confirmed cases of dengue, according to year, semester, sanitary district, age, and sex, was performed. RESULTS: There were 16,462 confirmed cases, especially in 2008, which obtained the highest incidence of the disease, with 10,485 confirmed cases. The first semester obtained the highest registration of cases during the years of research; this was predominated by females between 15 and 49 years old. With regard to the territorial distribution, the second district of the municipality obtained the highest number of cases. CONCLUSIONS: In 2008, in the City of Aracaju, SE, a significant increase in the proportion of dengue cases compared with other years was verified. However, a fast decline in the other years was observed, possibly because of the intensification of preventive actions to combat the mosquito that transmits the dengue virus.
Prevalence of Trypanosoma cruzi antibodies and inflammatory markers in uncompensated heart failure
Authors: Tobar Iván Bravo , Parra Freddy , Pérez Carlota Nello , Rodríguez-Bonfante Claudina , Useche Franco , Bonfante-Cabarcas Rafael
Published: January 2012

INTRODUCTION: Heart failure (HF) represents the final stage of chronic chagasic cardiomyopathy (CChC). The diagnosis of CChC is based on the demonstration of anti-Trypanosoma cruzi antibodies (aTcAg) and clinical and epidemiological data. In Venezuela, there are no data about the prevalence of chagasic HF. The aim of this study was to determine the epidemiological, clinical, and inflammatory risk factors associated with seronegative or seropositive HF patients. METHODS: We performed a cross-sectional study in the Venezuelan central-west states among a healthy rural population and in patients admitted to the emergency room with uncompensated HF. RESULTS: The seroprevalence rates of Trypanosoma cruzi antibodies were 11.2% and 40.1% in the healthy population and in HF patients, respectively. Seropositivity in healthy individuals was associated with age, knowledge on triatomine vectors, and having seen wild reservoirs in the house; in HF patients, with contact with the vector and previous clinical diagnosis of Chagas' disease; and in both groups taken together, with age, knowledge on triatomines, and HF. Seropositive patients had prolonged QRS, decreased ejection fraction, and high serum magnesium, all significant as compared with HF seronegative cases. Left atrium enlargement and ventricular hypertrophy were most frequently observed in HF seronegative patients. CRP, IL6, ILβ1, IL2, and FNTα were elevated in 94.5%, 48%, 17.8%, 13.7%, and 6.9% of HF patients, respectively, but only IL2 levels were associated with chagasic HF. CONCLUSIONS: There is a high prevalence of aTcAg in HF patients from the central-west region of Venezuela, and their epidemiological, clinical, and inflammatory features are discreetly different as compared with those of seronegative cases.