Characterization of an early dendritic cell precursor derived from murine lineage-negative hematopoietic progenitor cells

OBJECTIVE: We define characteristics of a dendritic cell (DC) precursor generated from murine lineage-negative (Lin(-)) Sca1(+) hematopoietic progenitor cells (HPC). MATERIALS AND METHODS: Lin(-)Sca1(+) HPC cultured 9 days in 100 ng/mL stem cell factor (SCF), 20 ng/mL interleukin-3 (IL-3), 50 ng/mL monocyte colony-stimulating factor (M-CSF), 5 ng/mL granulocyte-monocyte colony-stimulating factor (GM-CSF), and 25 ng/mL FLT3-ligand (FLT3-L) proliferate 387-fold and differentiate into DC precursors. Switch to > or =100 ng/mL GM-CSF + 1500 U/mL IL-4 or 500 U/mL tumor necrosis factor-alpha (TNF-alpha) for 3 days induces development into immature DC that are responsive to bacterial lipopolysaccharide (LPS)-induced maturation. RESULTS: Lin(-)Sca1(+) HPC in the first 9 days of culture differentiate into DC precursors expressing surface CD11b(bright), CD11c(mod), CD86(low-mod), major histocompatibility class II antigen (MHC) II(low), DEC 205(low), but are surface CD40(-) and contain high levels of intracellular MHC II. Unlike immature DC described by others, these DC precursors are refractory to maturation with LPS and minimally stimulate allogeneic T lymphocytes in mixed leukocyte reactions (MLR). Switch to high-dose GM-CSF alone with IL-4 or TNF-alpha differentiates these DC precursors into immature DC. LPS treatment of the immature DC results in mature DC that express surface CD40(high) and CD86(high), secrete IL-1beta and IL-12, and strongly stimulate MLR. CONCLUSIONS: These studies define a distinct DC precursor derived from murine HPC that precedes development of immature and mature DC.     

Simultaneous Primary Carcinomas��A Report of Three Cases

Two separate primary carcinomas occurring simultaneously in the esophagus and stomach are uncommon. The authors report three cases of this entity, squamous cell carcinoma of the osophagus and adenocarcinoma of the stomach, one of which is classified as a collision carcinoma of the stomach. Because of the rarity of collision tumors of this histologic variety, the world literature was reviewed. Diagnostic features and the relative prognosis of dual primary carcinomas are discussed.     

Which mental disorders are associated with the greatest impairment in functioning?

Objective

The objective of this study is to estimate the comparative associations of mental disorders with three measures of functional impairment: the Global Assessment of Functioning (GAF); the number of days in the past 12 months of total inability to work or carry out normal activities because of emotions, nerves, or mental health (i.e., days out of role); and a modified version of the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0).

Methods

Secondary data analysis of the linked Mental Health Surveillance Study and the National Survey on Drug Use and Health (n?=?5653), nationally representative population surveys conducted in the United States. Generalized linear models assessed the independent effects of mental disorders on each measure of functional impairment, controlling for mental disorder comorbidity, physical health disorders, and sociodemographic factors.

Results

The results varied across measures of functional impairment. However, mood disorders generally tended to be associated with the greatest functional impairment, anxiety disorders with intermediate impairment, and substance use disorders with the least impairment. All 15 disorders were significantly associated with the GAF score in multiple regression models, eight disorders were significantly associated with the WHODAS score, and three disorders were significantly associated with days out of role.

Conclusions

Our results highlight the value of complementary measures of functional impairment.

     

Can vascular surgery be performed soon after myocardial infarction?

We undertook the present study to test the hypothesis that in a contemporary setting of high rates of use of effective medical therapy and coronary revascularization, vascular surgery soon after myocardial infarction (MI) may not be prohibitively risky within 1 year. Elective vascular surgery is generally contraindicated within the first six months of MI. However, this principle is based on high complication rates from old case series. Forty six consecutive patients underwent 63 vascular procedures after MI. Thirty major arterial reconstructions, 9 thromboembolectomies, and 22 amputations or revisions were performed. We compared patients who had vascular surgery within six months after MI (Group I, n=30) to patients who had surgery six to 12 months after MI, Group II (n=16). Both groups had similar demographic characteristics, coronary risk factors and Goodman and Cooperman scores of operative risk. The high overall prevalence of coronary revascularizations (37%) and treatment with aspirin (87%), beta-blockers (65%) and ACE-inhibitors (76%), did not differ significantly between both groups. There was no significant difference in the incidence of reinfarction, cardiac mortality, or total mortality in the two groups. Patients undergoing vascular surgical procedures soon after acute MI may not have prohibitively high rates of death and cardiovascular complications. These favorable outcomes may be associated with the use of effective medical therapy and coronary revascularization. Vascular surgery should not be postponed in patients with recent MI.     

Photosensitized electron transport across lipid vesicle walls: Enhancement of quantum yield by ionophores and transmembrane potentials

The photosensitized reduction of heptylviologen in the bulk aqueous phase of phosphatidylcholine vesicles containing EDTA inside and a membrane-bound tris(2,2′-bipyridine)ruthenium(2+) derivative is enhanced by a factor of 6.5 by the addition of valinomycin in the presence of K⁺. A 3-fold stimulation by gramicidin and carbonyl cyanide m-chlorophenylhydrazone is observed. The results suggest that, under these conditions, the rate of photoinduced electron transfer across vesicle walls in the absence of ion carriers is limited by cotransport of cations. The rate of electron transfer across vesicle walls could be influenced further by generating transmembrane potentials with K⁺ gradients in the presence of valinomycin. When vesicles are made with transmembrane potentials, interior more negative, the quantum yield of heptylviologen reduction is doubled, and, conversely, when vesicles are made with transmembrane potentials, interior more positive, the quantum yield is decreased and approaches the value found in the absence of valinomycin.     

A comparison of acute coronary syndrome care at academic and nonacademic hospitals

Purpose

Although adherence to guidelines recommendations is assumed to be more difficult for nonacademic community hospitals, patterns of adherence have not been evaluated by hospital type. We sought to identify hospital characteristics associated with high levels of adherence in order to gain insight into successful processes of care.

Methods

From January 2001 through March 2004, we analyzed data from 86,042 patients in the CRUSADE Initiative with high-risk non-ST-segment elevation acute coronary syndromes (NSTE ACS) defined by positive cardiac markers or ischemic ST-segment changes. Academic sites were defined by Council of Teaching Hospital affiliation in the American Hospital Association database. Adherence was determined for each hospital based on guidelines recommendations for the use of 4 acute (<24 hrs) and 5 discharge therapies in patients without contraindications. Multivariable modeling was used to standardize hospital estimates for patient characteristics and control for clustering within centers.

Results

A total of 60,285 patients were admitted to nonacademic hospitals (n = 355), and 25,757 were admitted to academic hospitals (n = 125). Academic hospitals were larger (median 500 vs 268 beds, P <.001) and more often had bypass services (88% vs 60%, P <.001). Composite adherence to recommended therapies was slightly higher at academic vs. nonacademic hospitals (median 77.8% vs 73.7%, P <0.01), and variance in individual hospital performance was greater among nonacademic sites. Nonacademic hospitals accounted for 15 of the 20 highest performing sites and 19 of the 20 lowest performing sites. In-hospital clinical outcomes, including cardiogenic shock, stroke, and death were similar for patients admitted to both types of hospital.

Conclusion

Adherence to American College of Cardiology and American Heart Association (ACC/AHA) guidelines for NSTE ACS care at academic hospitals is slightly higher than at nonacademic hospitals; however there is significant room for improvement within both systems. The larger performance variation in care among nonacademic hospitals highlights the need for continued emphasis on consistent care processes.     

Inhaled nitric oxide therapy during the transport of neonates with persistent pulmonary hypertension or severe hypoxic respiratory failure

Our aim was to determine whether starting inhaled nitric oxide (iNO) on critically ill neonates with severe hypoxemic respiratory failure and/or persistent pulmonary hypertension (PPH), at a referring hospital at the start of transport, decreases the need for extracorporeal membrane oxygenation (ECMO), lessens the number of hospital days and improves survival in comparison with those patients who were started on iNO only at the receiving facility. The study was a retrospective review of 94 charts of neonates that had iNO initiated by the transport team at a referring hospital or only at the tertiary neonatal intensive care unit (NICU) of the receiving hospital. Data collected included demographics, mode of transport, total number of hospital days, days on inhaled nitric oxide and ECMO use. Of the 94 patients, 88 were included. Of these, 60 were started on iNO at the referring facility (Field-iNO) and 28 were started at the receiving NICU (CHLA-iNO). All patients survived transport to the receiving NICU. Death rates and ECMO use were similar in both groups. Overall, patients who died were younger and had lower birth weights and Apgar scores. For all surviving patients who did not require ECMO, the length of total hospital stay (median days 22 versus 38, P = 0.018), and the length of the hospital stay at the receiving hospital (median days 18 versus 29, P = 0.006), were significantly shorter for the Field-iNO patients than for the CHLA-iNO patients, respectively. Earlier initiation of iNO may decrease length of hospital stay in surviving neonates with PPH not requiring ECMO.     

Postnatal maternal cortisol levels predict temperament in healthy breastfed infants

BACKGROUND: The implications of the biologically active elements in breast milk for the breastfed infant are largely unknown. Animal models suggest that ingestion of glucocorticoids during the neonatal period influences fear behavior and modifies brain development. AIMS: To determine the association between postnatal maternal cortisol levels and temperament in breastfed infants. STUDY DESIGN: The relation between maternal cortisol and infant temperament was examined in breastfed and formula-fed infants. Plasma cortisol was used as a surrogate measure for breast milk cortisol levels (plasma and milk levels are correlated in the 0.6 to 0.7 range; [Patacchioli FR, Cigliana G, Cilumbriello A, Perrone G, Capri O, Alemà GS, et al. Maternal plasma and milk free cortisol during the first 3 days of breast-feeding following spontaneous delivery or elective cesarean section. Gynecologic and Obstetric Investigations 1992;34:159-163.]. If exposure to elevated cortisol levels during infancy influences temperament, then a relation between the two should be found among the breastfed infants, but not among the formula-fed infants. SUBJECTS: Two hundred fifty-three two-month-old infants and their mothers. OUTCOME MEASURES: Fearful temperament assessed with the Infant Behavior Questionnaire [Garstein MR, Rothbart MK. Studying infant temperament via the revised infant behavior questionnaire. Infant Behavior and Development 2003;26:64-86]. RESULTS: Among the breastfed infants, higher maternal cortisol levels were associated with reports of increased infant fear behavior (partial r=0.2; p<0.01). This relation did not exist among the formula-fed infants. Negative maternal affect at the time of assessment did not account for the positive association in the breastfed group. CONCLUSIONS: The findings are consistent with our proposal that exposure to cortisol in breast milk influences infant temperament. Biologically active components in breast milk may represent one avenue through which the mother shapes the development of the human infant during the postnatal period.     

Transduction of umbilical cord blood CD34+ NOD/SCID-repopulating cells by simian foamy virus type 1 (SFV-1) vector

Foamy viruses are nonpathogenic retroviruses that offer unique opportunities for gene transfer into various cell types including hematopoietic stem cells. We used a simian foamy virus type 1 vector (SFV-1) containing a LacZ reporter gene with a titer of 1-5 x 10(6) viral particles/ml that was free of replication-competent retrovirus to transduce human umbilical cord blood CD34+ cells. Transduced CD34+ cord blood cells were transplanted into NOD/SCID mice and plated in serum-free methylcellulose culture to determine the transduction efficiency of human hematopoietic progenitor cells. A transduction efficiency of about 20% was obtained. At 6-10 weeks posttransplantation, human hematopoietic cell engraftment and marking were determined. Marrow from transplanted mice demonstrated human cell engraftment by the presence of human (CD45+) cells containing both CD19+ lymphoid and CD33+ myeloid cells. Serial sampling of NOD/SCID bone marrow revealed the presence of 6.7-14.0% CD45+ cells at 6 weeks posttransplant as compared to 3.6-27.2% CD45+ cells at 9-10 weeks posttransplant. Human progenitors examined from NOD/SCID bone marrow cells 9 weeks posttransplant revealed from 7.4 to 25.9% of the colonies exhibiting X-gal staining. Our study demonstrates the ability of a simian foamy virus vector to transduce the SCID-repopulating cell and offers a promising new gene delivery system for use in hematopoietic stem cell gene therapy.