OBJECTIVE

To quantify the risk and severity of negative effects of treatment for localised prostate cancer on long term quality of life.

METHODS

Population based, prospective cohort study with follow-up over three years.

METHODS

New South Wales, Australia.

METHODS

Men with localised prostate cancer were eligible if aged less than 70 years, diagnosed between October 2000 and October 2002, and notified to the New South Wales central cancer registry. Controls were randomly selected from the New South Wales electoral roll and matched to cases by age and postcode.

METHODS

General health specific and disease specific function up to three years after diagnosis, according to the 12 item short form health survey and the University of California, Los Angeles prostate cancer index.

RESULTS

1642 (64%) cases and 495 (63%) eligible and contacted controls took part in the study. After adjustment for confounders, all active treatment groups had low odds of having better sexual function than controls, in particular men on androgen deprivation therapy (adjusted odds ratio (OR) 0.02, 95% CI 0.01 to 0.07). Men treated surgically reported the worst urinary function (adjusted OR 0.17, 95% CI 0.13 to 0.22). Bowel function was poorest in cases who had external beam radiotherapy (adjusted OR 0.44, 95% CI 0.30 to 0.64). General physical and mental health scores were similar across treatment groups, but poorest in men who had androgen deprivation therapy.

CONCLUSIONS

The various treatments for localised prostate cancer each have persistent effects on quality of life. Sexual dysfunction three years after diagnosis was common in all treatment groups, whereas poor urinary function was less common. Bowel function was most compromised in those who had external beam radiotherapy. Men with prostate cancer and the clinicians who treat them should be aware of the effects of treatment on quality of life, and weigh them up against the patient's age and the risk of progression of prostate cancer if untreated to make informed decisions about treatment.

CD8(+) T cells are essential for long-term, vaccine-induced resistance against intracellular pathogens. Here we show that natural antibodies, acting in concert with complement, are endogenous adjuvants for the generation of protective CD8(+) T cells after vaccination against visceral leishmaniasis. IL-4 was crucial for the priming of vaccine-specific CD8(+) T cells, and we defined the primary source of IL-4 as a CD11b(+)CD11c(lo) phagocyte. IL-4 secretion was not observed in antibody-deficient mice and could be reconstituted with serum from normal, but not Btk immune-deficient, mice. Similarly, no IL-4 response or CD8(+) T-cell priming was seen in C1qa(-/-) mice. These results identify a new pathway by which immune complex-mediated complement activation can regulate T-cell-mediated immunity. We propose that this function of natural antibodies could be exploited when developing new vaccines for infectious diseases.

Young men who have sex with men (YMSM) are at alarming risk for HIV acquisition, demonstrating the highest rates of incident infection of any age-risk group. GRINDR is a global positioning service-based social networking application popular with YMSM for sexual partnering. To assess the characteristics of YMSM who use GRINDR, we conducted a computer-assisted self-interview-based survey of 375 YMSM using GRINDR in metropolitan Los Angeles, recruited using the GRINDR platform. The median age was 25 (interquartile range, 22-27) years old, 42.4 % caucasian, 6.4 % African American, 33.6 % Latino, and 14.1 % Asian/Pacific Islander. Participants reported high rates of sexual partnering and unprotected anal intercourse (UAI). The majority (70 %) of those reporting unprotected anal intercourse reported low perception of HIV-acquisition risk. Of the participants, 83.1 % reported HIV testing within the past 12 months; 4.3 % had never been HIV tested. Of the participants, 4.5 % reported HIV-positive serostatus; 51.7 % indicated that they would be interested in participating in a future HIV prevention trial. Latinos were more likely than either caucasians or African Americans to endorse trial participation interest (odds ratio, 1.9; 95 % confidence interval [1.1-3.3]). HIV-positive test results were associated with increased number of anal sex partners in the past 3 months (adjusted odds ratio (AOR), 1.53 [0.97-2.40]), inconsistent inquiry about partners' serostatus (AOR, 3.63 [1.37-9.64]), reporting the purpose for GRINDR use including "friendship" (AOR, 0.17 [0.03-1.06), and meeting a sexual partner in a bookstore in the past 3 months (AOR, 33.84 [0.99-1152]). Men recruited via GRINDR were high risk for HIV acquisition or transmission and interested in clinical trial participation, suggesting potential for this method to be used for recruitment of YMSM to HIV prevention trials.

Inflammation associated with bacterial infections is a risk factor for cancers in humans, yet its role in breast cancer remains poorly understood. We have previously shown that innate immune inflammatory response against intestinal bacteria is sufficient to induce colon cancer. Here we report that infecting Rag2-deficient C57BL/6 Apc(Min/+) mice with an intestinal bacterial pathogen, Helicobacter hepaticus, significantly promotes mammary carcinoma in females and enhances intestinal adenoma multiplicity by a tumor necrosis factor alpha (TNFalpha)-dependent mechanism. The mammary and intestinal tumor development as well as the increase in proinflammatory mediators is suppressed by adoptive transfer of interleukin 10-competent CD4+CD45RB(lo)CD25+ regulatory (T(R)) cells. Furthermore, prior exposure of donor mice to H. hepaticus significantly enhances antitumor potency of their T(R) cells. Interestingly, these microbially experienced T(R) cells suppress tumorigenesis more effectively in recipient mice irrespective of their tumor etiology. These data suggest that infections with enteric pathogens enhance T(R)-cell potency and protect against epithelial cancers later in life, potentially explaining paradoxical increases in cancer risk in developed countries having more stringent hygiene practices. The possibility that dysregulated gut microbial infections in humans may lead to cancer in anatomically distant organs, such as breast, highlights the need for novel immune-based strategies in cancer prevention and treatment.

OBJECTIVE

Length of stay (LOS) is an important outcome as a marker of resource consumption. Determining which factors increase LOS may provide information on reducing costs and improving the delivery of care. The purpose of this study was to determine the independent association of intraoperative process of care and postoperative events with prolonged LOS after adjusting for preoperative severity of illness in patients undergoing major elective surgery.

METHODS

Cases representing 11 elective operations from the National VA Surgical Quality Improvement Program were analyzed using multivariate logistic regression analysis. The outcome, prolonged LOS, was defined as an LOS greater than or equal to the 75th percentile (in days) for each operation. Hierarchical modeling was used to assess the independent association of groups of variables (preoperative patient characteristics, intraoperative process of care, and postoperative adverse events) with prolonged LOS.

RESULTS

For the 11 operations explored, there were 23,919 cases. Common preoperative variables associated with prolonged LOS were functional status, American Society of Anesthesiology class, and age. The most predictive intraoperative and postoperative variables included intraoperative blood transfusion, operative time, return to the operating room, and the number of complications after surgery.

CONCLUSIONS

Prolonged LOS is associated with preoperative, intraoperative, and postoperative factors. Although preoperative factors were independently associated with a prolonged LOS, the factors generating the highest risks for a prolonged LOS were the intraoperative process of care and postoperative adverse events. To reduce costs, efforts should be made to improve the intraoperative process of care and to minimize postoperative complications.

OBJECTIVE

To determine the ideal cutpoint for defining prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP). Although various cutpoints have been used, a recent study suggested that 0.4 ng/mL may be the most appropriate.

METHODS

A retrospective survey of 358 men undergoing RP at the West Los Angeles Veterans Affairs Medical Center between 1991 and 2001 was undertaken. The 3-year and 5-year risk of PSA recurrence was estimated by Kaplan-Meier analyses using various cutpoints of postoperative PSA to define recurrence: greater than 0.1, greater than 0.2, greater than 0.3, greater than 0.4, and greater than 0.5 ng/mL. The 1 and 3-year risk of PSA progression after a detectable PSA level (PSA rising to a higher cutpoint) was evaluated for each definition of PSA recurrence using Kaplan-Meier analyses. Multivariate analysis using a Cox proportional hazards model was used to determine the clinical variables that were significant independent predictors of PSA recurrence at each cutpoint.

RESULTS

For patients with a detectable postoperative PSA value from 0.11 to 0.2 ng/mL, the 1 and 3-year risk of PSA progression was 64% (95% confidence interval [CI] 46% to 82%) and 93% (95% CI 74% to 99%), respectively. For patients with a PSA value from 0.21 to 0.3 ng/mL, the 1 and 3-year risk of PSA progression was 86% (95% CI 69% to 97%) and 100% (95% CI 87% to 100%), respectively. The use of higher PSA cutpoints to define recurrence resulted in a lower 5-year risk of PSA recurrence. The 5-year risk of PSA recurrence using a greater than 0.1 ng/mL cutpoint resulted in a 43% (95% CI 36% to 50%) risk of recurrence compared with only 23% (95% CI 18% to 30%) for a greater than 0.5 ng/mL cutpoint. In multivariate analysis, PSA and biopsy Gleason score were significant independent predictors of biochemical recurrence, regardless of the definition of PSA recurrence used (P <or=0.002).

CONCLUSIONS

PSA and biopsy Gleason score were significant predictors of biochemical failure, regardless of the definition of failure used. However, the definition of PSA recurrence dramatically affected the perceived success of therapy. Patients with a postoperative PSA value greater than 0.2 ng/mL are at very high risk of developing an additional rise in PSA. On the basis of this finding, a PSA value greater than 0.2 ng/mL is an appropriate cutpoint to define PSA recurrence after RP.

Lipooligosaccharides (LOSs) are the major glycolipids expressed on mucosal Gram-negative bacteria, including members of the genera Neisseria, Haemophilus, Bordetella, and Branhamella. They can also be expressed on some enteric bacteria such as Campylobacter jejuni and Campylobacter coli strains. LOS is analogous to the lipopolysaccharide (LPS) found in other Gram-negative families. LOSs share similar lipid A structures with an identical array of functional activities as LPSs. LOSs lack O-antigen units with the LOS oligosaccharide structures limited to 10 saccharide units. The LOS species of pathogenic Neisseria can play a major role in pathogenesis through enhancing the resistance of the organism to killing by normal human serum. Other distinguishing characteristics of LOS are the structural and antigenic similarity of some LOS species to human glycolipids and the potential for certain LOSs to be modified in vivo by host substances or secretions. These modifications of LOS in different environments of the host result in synthesis of new LOS structures that probably benefit the survival of the pathogen. The LOS of N. gonorrhoeae can act as a ligand of human receptors, promoting invasion of host cells. It is becoming clearer that LOSs are crucial factors in the pathogenesis of bacteria that express them.

Determination of the attributable hospital cost and length of stay (LOS) are of critical importance for patients, providers, and payers who must make rational and informed decisions about patient care and the allocation of resources. The objective of the present study was to determine the additional total hospital cost and LOS attributable to health care-associated infections (HAIs) caused by antibiotic-resistant, gram-negative (GN) pathogens. A single-center, retrospective, observational comparative cohort study was performed. The study involved 662 patients admitted from 2000 to 2008 who developed HAIs caused by one of following pathogens: Acinetobacter spp., Enterobacter spp., Escherichia coli, Klebsiella spp., or Pseudomonas spp. The attributable total hospital cost and LOS for HAIs caused by antibiotic-resistant GN pathogens were determined by comparison with the hospital costs and LOS for a control group with HAIs due to antibiotic-susceptible GN pathogens. Statistical analyses were conducted by using univariate and multivariate analyses. Twenty-nine percent of the HAIs were caused by resistant GN pathogens, and almost 16% involved a multidrug-resistant GN pathogen. The additional total hospital cost and LOS attributable to antibiotic-resistant HAIs caused by GN pathogens were 29.3% (P < 0.0001; 95% confidence interval, 16.23 to 42.35) and 23.8% (P = 0.0003; 95% confidence interval, 11.01 to 36.56) higher than those attributable to HAIs caused by antibiotic-susceptible GN pathogens, respectively. Significant covariates in the multivariate analysis were age>>or=12 years, pneumonia, intensive care unit stay, and neutropenia. HAIs caused by antibiotic-resistant GN pathogens were associated with significantly higher total hospital costs and increased LOSs compared to those caused by their susceptible counterparts. This information should be used to assess the potential cost-efficacy of interventions aimed at the prevention of such infections.

Visual perception fluctuates across repeated presentations of the same near-threshold stimulus. These perceptual fluctuations have often been attributed to baseline shifts--i.e., ongoing modulations of neuronal activity in visual areas--driven by top-down attention. Using magnetoencephalography, we directly tested whether ongoing attentional modulations could fully account for the perceptual impact of prestimulus activity on a subsequent seen-unseen decision. We found that prestimulus gamma-band fluctuations in lateral occipital areas (LO) predicted visual awareness, but did not reflect the focus of spatial attention. Moreover, these prestimulus signals influenced the decision outcome independently from the strength of the following visual response, suggesting that baseline shifts alone could not explain their perceptual impact. Using a straightforward decision-making model based on the accumulation of sensory evidence over time, we show that prestimulus gamma-band fluctuations in LO behave as a decision bias at stimulus onset, irrespectively of subsequent stimulus processing. In contrast, spatial attention suppressed prestimulus alpha-band signals in the same region, and produced a sustained baseline shift that also predicted the outcome of the seen-unseen decision. Together, our results indicate that prestimulus fluctuations in visual areas can influence the conscious detection of an upcoming stimulus via two distinct mechanisms: an attention-driven baseline shift in the alpha range, and a decision bias in the gamma range.

OBJECTIVE

To describe the study design, operational strategies, procedures, and baseline characteristics of the Los Angeles Latino Eye Study (LALES), a population-based assessment of the prevalence of visual impairment, ocular disease, and visual functioning in Latinos.

METHODS

Population-based, cross-sectional study.

METHODS

Six thousand three hundred fifty-seven Latinos 40 years and older from 6 census tracts in Los Angeles, California.

METHODS

A detailed interview and eye examination were performed on each eligible participant. The interview included an assessment of demographic, behavioral, and ocular risk factors and health-related and vision-related quality of life. The eye examination included a measurement of visual acuity, intraocular pressure, and visual fields; fundus and optic disc photography; a detailed anterior and posterior segment examination; and measurement of blood pressure, glycosylated hemoglobin levels, and blood glucose levels.

METHODS

Prevalence of visual impairment, blindness, cataract, glaucoma, diabetic retinopathy, and age-related macular degeneration constitute the study's primary outcome variables. Secondary outcomes include odds ratios for risk factors associated with eye disease, health-related quality of life, and vision-related quality of life. Response rates and baseline characteristics are presented.

RESULTS

Of the 7789 individuals eligible for LALES, 6357 (82%) had a clinical examination; an additional 524 completed only an in-home interview. The majority of participants were female (58%), the average (+/- standard deviation) age was 54.9 (+/-10.8) years, and 80.0% were of Mexican origin and 0.4% self-identified as American Indian or Alaskan Native. The age distribution of LALES participants was similar to that of Latinos of Mexican origin in the rest of the United States.

CONCLUSIONS

The LALES has recruited Latinos 40 and older for an ophthalmic epidemiologic study. The LALES cohort will provide information about the prevalence and risk factors of ocular disease in the largest and fastest growing minority in the United States.

The murine gamma-herpesvirus 68 has many similarities to EBV, and induces a syndrome comparable to infectious mononucleosis (IM). The frequency of activated CD8+ T cells (CD62L(lo)) in the peripheral blood increased greater than fourfold by 21 d after infection of C57BL/6J (H-2(b)) mice, and remained high for at least a further month. The spectrum of T cell receptor usage was greatly skewed, with as many as 75% of the CD8+ T cells in the blood expressing a Vbeta4+ phenotype. Interestingly, the Vbeta4 dominance was also seen, to varying extents, in H-2(k), H-2(d), H-2(u), and H-2(q) strains of mice. In addition, although CD4 depletion from day 11 had no effect on the Vbeta4 bias of the T cells, the Vbeta4+CD8+ expansion was absent in H-2IA(b)-deficient congenic mice. However, the numbers of cycling cells in the CD4 antibody-depleted mice and mice that are CD4 deficient as a consequence of the deletion of MHC class II, were generally lower. The findings suggest that the IM-like disease is driven both by cytokines provided by CD4+ T cells and by a viral superantigen presented by MHC class II glycoproteins to Vbeta4+CD8+ T cells.

Determining rates of HIV transmission risk behavior among HIV-positive individuals is a public health priority, especially as infected persons live longer because of improved medical treatments. Few studies have assessed the potential for transmission to the partners of HIV-positive persons who engage in high-risk activities. A total of 3723 HIV-infected persons (1918 men who have sex with men [MSM], 978 women, and 827 heterosexual men) were interviewed in clinics and community-based agencies in Los Angeles, Milwaukee, New York City, and San Francisco from June 2000 to January 2002 regarding sexual and drug use behaviors that confer risk for transmitting HIV. Less than one quarter of women and heterosexual men had 2 or more sexual partners, whereas 59% of MSM reported having multiple partners. Most unprotected vaginal and anal sexual activity took place in the context of relationships with other HIV-positive individuals. Approximately 19% of women, 15.6% of MSM, and 13.1% of heterosexual men engaged in unprotected vaginal or anal intercourse with partners who were HIV-negative or whose serostatus was unknown. The majority of sexually active participants disclosed their serostatus to all partners with whom they engaged in unprotected intercourse. An estimated 30.4 new infections (79.7% as a result of sexual interactions with MSM) would be expected among the sex partners of study participants during the 3-month reporting period. Eighteen percent of 304 participants who injected drugs in the past 3 months reported lending their used injection equipment to others. In addition to the more traditional approaches of HIV test counseling and of focusing on persons not infected, intensive prevention programs for persons with HIV infection are needed to stem the future spread of the virus.

This study assessed HIV-positive men's sexual behaviours with partners at risk for infection, and examined the extent to which safer sex was associated with interpersonal communication variables, namely, (1). disclosure of one's seropositive status and (2). specific communication with partners about safer-sex practices. A total of 105 HIV-positive men (43% homosexual, 38% bisexual, 19% heterosexual), randomly sampled at an HIV outpatient clinic in Los Angeles, completed a behavioural questionnaire assessing events in their most recent sexual encounter with an HIV-negative or unknown serostatus partner. Results indicated that men who disclosed their seropositive status and explicitly discussed the topic of safer sex with their at-risk partners had a significantly higher prevalence of protected anal or vaginal intercourse than did men who disclosed only. The findings suggest that post-test counselling regarding the importance of disclosing one's seropositive status to sex partners should be augmented by behavioural interventions that enhance seropositive persons' skills in communicating explicitly with partners about safer sex to help reduce transmission of HIV.

To ascertain whether the development of dendritic cells (DC) in mouse lymphoid organs is dependent on granulocyte/macrophage colony-stimulating factor (GM-CSF), we determined the number of DC in the thymus, spleen and lymph nodes of normal mice, of mice with the genes coding for GM-CSF or its receptor inactivated, and of transgenic mice with excessive levels of GM-CSE DC were extracted from the tissues and enriched prior to flow cytometric analysis. The total DC level and the incidence of DC expressing lymphoid-related markers (CD8(hi) CD11b(lo)) and myeloid-related markers (CD8(lo) CD11b(hi)) were monitored. Both in GM-CSF null mice, and GM-CSF receptor null mice, DC of all surface phenotypes were present in all lymphoid organs; only small decreases in DC levels were recorded, except for the lymph nodes of GM-CSF receptor null mice which showed a more pronounced (threefold) decrease in DC numbers. Since the GM-CSF receptor null mice lacked the beta chain common to the GM-CSF, interleukin (IL)-3 and IL-5 receptors, the development of DC in the absence of GM-CSF was not due to common beta chain mediated developmental signals elicited by IL-3 or IL-5. In GM-CSF transgenic mice, there was only a 50 % increase in DC numbers in thymus and spleen, paralleling an increase in overall cellularity, but a more pronounced (threefold) increase in DC numbers in lymph nodes. There was no evidence that GM-CSF had a selective effect on any particular DC subpopulation defined by CD8 or CD11b expression. We conclude that the development of most lymphoid tissue DC can proceed in the absence of GM-CSF, although this cytokine can produce some elevation of DC levels. It is not clear whether the enhancing effect of GM-CSF is direct or an indirect effect mediated by other cytokines.

BACKGROUND

Myocardial damage in myocarditis is mediated, in part, by immunological mechanisms. High-dose intravenous gamma-globulin (IVIG) is an immunomodulatory agent that is beneficial in myocarditis secondary to Kawasaki disease, as well as in murine myocarditis. Since 1990, the routine management of presumed acute myocarditis at Children's Hospital, Boston, and Children's Hospital, Los Angeles, has included administration of high-dose IVIG.

RESULTS

We treated 21 consecutive children presenting with presumed acute myocarditis with IVIG, 2 g/kg, over 24 hours, in addition to anticongestive therapies. A comparison group comprised 25 recent historical control patients meeting identical eligibility criteria but not receiving IVIG therapy. Left ventricular function was assessed during five time intervals: 0 to 7 days, 1 to 3 weeks, 3 weeks to 3 months, 3 to 6 months, and 6 to 12 months. At presentation, the IVIG and non-IVIG groups had comparable left ventricular enlargement and poor fractional shortening. Compared with the non-IVIG group, those treated with IVIG had a smaller mean adjusted left ventricular end-diastolic dimension and higher fractional shortening in the periods from 3 to 6 months (P = .008 and P = .033, respectively) and 6 to 12 months (P = .072 and P = .029, respectively). When adjusting for age, biopsy status, intravenous inotropic agents, and angiotensin-converting enzyme inhibitors, patients treated with IVIG were more likely to achieve normal left ventricular function during the first year after presentation (P = .03). By 1 year after presentation, the probability of survival tended to be higher among IVIG-treated patients (.84 versus .60, P = .069). We observed no adverse effects of IVIG administration.

CONCLUSIONS

These data suggest that use of high-dose IVIG for treatment of acute myocarditis is associated with improved recovery of left ventricular function and with a tendency to better survival during the first year after presentation.

Eosinophil lineage-committed progenitors (EoPs) are phenotypically isolatable in the steady-state murine bone marrow. Purified granulocyte/monocyte progenitors (GMPs) gave rise to eosinophils as well as neutrophils and monocytes at the single cell level. Within the short-term culture of GMPs, the eosinophil potential was found exclusively in cells activating the transgenic reporter for GATA-1, a transcription factor capable of instructing eosinophil lineage commitment. These GATA-1-activating cells possessed an IL-5Ralpha(+)CD34(+)c-Kit(lo) phenotype. Normal bone marrow cells also contained IL-5Ralpha(+)CD34(+)c-Kit(lo) EoPs that gave rise exclusively to eosinophils. EoPs significantly increased in number in response to helminth infection, suggesting that the EoP stage is physiologically involved in eosinophil production in vivo. EoPs expressed eosinophil-related genes, such as the eosinophil peroxidase and the major basic protein, but did not express basophil/mast cell-related mast cell proteases. The enforced retroviral expression of IL-5Ralpha in GMPs did not enhance the frequency of eosinophil lineage read-outs, whereas IL-5Ralpha(+) GMPs displayed normal neutrophil/monocyte differentiation in the presence of IL-5 alone. Thus, IL-5Ralpha might be expressed specifically at the EoP stage as a result of commitment into the eosinophil lineage. The newly identified EoPs could be the cellular target in the treatment of a variety of disorders mediated by eosinophils.

BACKGROUND

Delirium is a frequent source of morbidity in intensive care units (ICUs). Most data on its epidemiology is from single-center studies. Our aim was to conduct a multicenter study to evaluate the epidemiology of delirium in the ICU.

METHODS

A 1-day point-prevalence study was undertaken in 104 ICUs from 11 countries in South and North America and Spain.

RESULTS

In total, 975 patients were screened, and 497 fulfilled inclusion criteria and were enrolled (median age, 62 years; 52.5% men; 16.7% and 19.9% for ICU and hospital mortality); 64% were admitted to the ICU because of medical causes, and sepsis was the main diagnosis (n = 76; 15.3%). In total, 265 patients were sedated with the Richmond agitation and sedation scale (RASS) deeper than -3, and only 232 (46.6%) patients could be evaluated with the confusion-assessment method for the ICU. The prevalence of delirium was 32.3%. Compared with patients without delirium, those with the diagnosis of delirium had a greater severity of illness at admission, demonstrated by higher sequential organ-failure assessment (SOFA (P = 0.004)) and simplified acute physiology score 3 (SAPS3) scores (P < 0.0001). Delirium was associated with increased ICU (20% versus 5.7%; P = 0.002) and hospital mortality (24 versus 8.3%; P = 0.0017), and longer ICU (P < 0.0001) and hospital length of stay (LOS) (22 (11 to 40) versus 7 (4 to 18) days; P < 0.0001). Previous use of midazolam (P = 0.009) was more frequent in patients with delirium. On multivariate analysis, delirium was independently associated with increased ICU mortality (OR = 3.14 (1.26 to 7.86); CI, 95%) and hospital mortality (OR = 2.5 (1.1 to 5.7); CI, 95%).

CONCLUSIONS

In this 1-day international study, delirium was frequent and associated with increased mortality and ICU LOS. The main modifiable risk factors associated with the diagnosis of delirium were the use of invasive devices and sedatives (midazolam).

Although geographic variation in semen quality has been reported, this is the first study in the United States to compare semen quality among study centers using standardized methods and strict quality control. We evaluated semen specimens from partners of 512 pregnant women recruited through prenatal clinics in four U.S. cities during 1999-2001; 91% of men provided two specimens. Sperm concentration, semen volume, and motility were determined at the centers, and morphology was assessed at a central laboratory. Study protocols were identical across centers, and quality control was rigorously maintained. Sperm concentration was significantly lower in Columbia, Missouri, than in New York, New York; Minneapolis, Minnesota; and Los Angeles, California. Mean counts were 58.7, 102.9, 98.6, and 80.8 X 10(6)/mL (medians 53.5, 88.5, 81.8, and 64.8 X 10(6)/mL) in Missouri, New York, Minnesota, and California, respectively. The total number of motile sperm was also lower in Missouri than in other centers: 113, 196, 201, and 162 X 10(6) in Missouri, New York, Minnesota, and California, respectively. Semen volume and the percent morphologically normal sperm did not differ appreciably among centers. These between-center differences remained significant in multivariate models that controlled for abstinence time, semen analysis time, age, race, smoking, history of sexually transmitted disease, and recent fever (all p-values < 0.01). Confounding factors and differences in study methods are unlikely to account for the lower semen quality seen in this mid-Missouri population. These data suggest that sperm concentration and motility may be reduced in semirural and agricultural areas relative to more urban and less agriculturally exposed areas.

Several definitions for pancreatic leakage after pancreaticodoudenectomy exist, and the reported range of 2-50% underscores this variation. The goal was to determine if drain data alone was predictive of a leak and validate International Study Group on Pancreatic Fistula (ISGPF) leak criteria. Participating surgeons entered de-identified data into a web-based database designed to collect Whipple-related data. Definitions used were the ISGPF definition,>> or = 3 days, amylase 3x normal; and Sarr's definition,>> or = 5 days, amylase 5x normal,>> 30 ml. We compared how well these two definitions were at detecting a leak and its complications. There were 1,507 cases submitted from 16 international institutions. A pancreaticoduodenectomy (PPPD) was performed in 76.2%. Drain placement occurred in 98.0%. Using the ISGPF definition, the pancreatic leak rate was 26.7 and 14.3% with the Sarr definition. There were more grades A and B leaks detected by the ISGPF definition. Both determined grade C leaks equally. Both definitions correlated with an increased length of stay (LOS), need for percutaneous drains, reoperation, and delayed gastric emptying (DGE). Neither was associated with an increased risk of intensive care unit (ICU) stay or 30-day mortality. The ISGPF was able to capture more patients with clinically relevant leaks than Sarr's criteria; however, the ability to detect a leak by drain data alone is imperfect.

Inflammation and insulin resistance associated with visceral obesity are important risk factors for the development of type 2 diabetes, atherosclerosis, and the metabolic syndrome. The 12/15-lipoxygenase (12/15-LO) enzyme has been linked to inflammatory changes in blood vessels that precede the development of atherosclerosis. The expression and role of 12/15-LO in adipocytes have not been evaluated. We found that 12/15-LO mRNA was dramatically upregulated in white epididymal adipocytes of high-fat fed mice. 12/15-LO was poorly expressed in 3T3-L1 fibroblasts and was upregulated during differentiation into adipocytes. Interestingly, the saturated fatty acid palmitate, a major component of high fat diets, augmented expression of 12/15-LO in vitro. When 3T3-L1 adipocytes were treated with the 12/15-LO products, 12-hydroxyeicosatetranoic acid (12(S)-HETE) and 12-hydroperoxyeicosatetraenoic acid (12(S)-HPETE), expression of proinflammatory cytokine genes, including tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein 1 (MCP-1), interleukin 6 (IL-6), and IL-12p40, was upregulated whereas anti-inflammatory adiponectin gene expression was downregulated. 12/15-LO products also augmented c-Jun N-terminal kinase 1 (JNK-1) phosphorylation, a known negative regulator of insulin signaling. Consistent with impaired insulin signaling, we found that insulin-stimulated 3T3-L1 adipocytes exhibited decreased IRS-1(Tyr) phosphorylation, increased IRS-1(Ser) phosphorylation, and impaired Akt phosphorylation when treated with 12/15-LO product. Taken together, our data suggest that 12/15-LO products create a proinflammatory state and impair insulin signaling in 3T3-L1 adipocytes. Because 12/15-LO expression is upregulated in visceral adipocytes by high-fat feeding in vivo and also by addition of palmitic acid in vitro, we propose that 12/15-LO plays a role in promoting inflammation and insulin resistance associated with obesity.

BACKGROUND

To assess the overuse and underuse of medical procedures, various methods have been developed, but their reproducibility has not been evaluated. This study estimates the reproducibility of one commonly used method.

METHODS

We performed a parallel, three-way replication of the RAND-University of California at Los Angeles appropriateness method as applied to two medical procedures, coronary revascularization and hysterectomy. Three nine-member multidisciplinary panels of experts were composed for each procedure by stratified random sampling from a list of experts nominated by the relevant specialty societies. Each panel independently rated the same set of clinical scenarios in terms of the appropriateness of the relevant procedure on a risk-benefit scale ranging from 1 to 9. Final ratings were used to classify the procedure in each scenario as necessary or not necessary (to evaluate underuse) and inappropriate or not inappropriate (to evaluate overuse). Reproducibility was measured by overall agreement and by the kappa statistic. The criteria for underuse and overuse derived from these ratings were then applied to real populations of patients who had undergone coronary revascularization or hysterectomy.

RESULTS

The rates of agreement among the three coronary-revascularization panels were 95, 94, and 96 percent for inappropriate-use scenarios and 93, 92, and 92 percent for necessary-use scenarios. Agreement among the three hysterectomy panels was 88, 70, and 74 percent for inappropriate-use scenarios. Scenarios involving necessary use of hysterectomy were not assessed. The three-way kappa statistic to detect overuse was 0.52 for coronary revascularization and 0.51 for hysterectomy. The three-way kappa statistic to detect underuse of coronary revascularization was 0.83. Application of individual panels' criteria to real populations of patients resulted in a 100 percent variation in the proportion of cases classified as inappropriate and a 20 percent variation in the proportion of cases classified as necessary.

CONCLUSIONS

The appropriateness method is far from perfect. Appropriateness criteria may be useful in comparing levels of appropriate procedures among populations but should not by themselves be used to direct care for individual patients.

Galectin-1, a beta-galactoside binding protein, is produced by thymic epithelial cells and binds to human thymocytes. We have previously reported that galectin-1 induces the apoptosis of activated T lymphocytes. Because the majority of thymocytes die via apoptosis while still within the thymus, we tested whether galectin-1 could induce the apoptosis of these cells. We now report that in vitro exposure to galectin-1 induced apoptosis of two subsets of CD4(lo) CD8(lo) thymocytes. The phenotypes of susceptible thymocytes were consistent with that of both negatively selected and nonselected cells. Galectin-1-induced apoptosis was enhanced by preexposure of thymocytes to antibody to CD3, suggesting that galectin-1 may be a participant in T-cell- receptor mediated apoptosis. In contrast, pretreatment of thymocytes with dexamethasone had no effect on galectin-1 susceptibility. We noted that 71% of the cells undergoing apoptosis after galectin-1 treatment had a DNA content greater than 2N, indicating that proliferating thymocytes were most sensitive to galectin-1. We propose that galectin-1 plays a role in the apoptosis of both negatively selected and nonselected thymocytes, and that the susceptibility of thymocytes to galectin-1 is regulated, in part, by entry or exit from the cell cycle.

High fat intake is associated with fat mass gain through fatty acid activation of peroxisome proliferator-activated receptors delta and gamma, which promote adipogenesis. We show herein that, compared to a combination of specific agonists to both receptors or to saturated, monounsaturated, and omega-3 polyunsaturated fatty acids, arachidonic acid (C20:4, omega-6) promoted substantially the differentiation of clonal preadipocytes. This effect was blocked by cyclooxygenase inhibitors and mimicked by carbacyclin, suggesting a role for the prostacyclin receptor and activation of the cyclic AMP-dependent pathways that regulate the expression of the CCAAT enhancer binding proteins beta and delta implicated in adipogenesis. During the pregnancy-lactation period, mother mice were fed either a high-fat diet rich in linoleic acid, a precursor of arachidonic acid (LO diet), or the same isocaloric diet enriched in linoleic acid and alpha-linolenic acid (LO/LL diet). Body weight from weaning onwards, fat mass, epididymal fat pad weight, and adipocyte size at 8 weeks of age were higher with LO diet than with LO/LL diet. In contrast, prostacyclin receptor-deficient mice fed either diet were similar in this respect, indicating that the prostacyclin signaling contributes to adipose tissue development. These results raise the issue of the high content of linoleic acid of i) ingested lipids during pregnancy and lactation, and ii) formula milk and infant foods in relation to the epidemic of childhood obesity.

OBJECTIVE

Traumatic brain injury (TBI) is the leading cause of death from blunt trauma, with an estimated cost to society of over dollar 40 billion annually. Evidence-based guidelines for TBI care have been widely discussed, but in-hospital treatment of these patients has been highly variable. The purpose of this study was to determine whether management of TBI patients according to a protocol based on the Brain Trauma Foundation (BTF) guidelines would reduce mortality, length of stay, charges, and disability.

METHODS

In 1995, a protocol following the BTF guidelines was developed by members of the Level I trauma center's interdisciplinary neurotrauma task force. Inclusion criteria for the protocol were blunt head injury, age>> 14 years, and Glasgow Coma Scale score < or = 8. An extensive educational process was conducted to develop compliance among all disciplines for this new management strategy. A historical control group of patients eligible for the protocol was identified by retrospective analysis of trauma registry data for 1991 to 1994. Mortality, intensive care unit days, total hospital days, total charges, Rancho Los Amigos Scores, and Glasgow Outcome Scale scores were compared.

RESULTS

Between 1991 and 2000, over 7,000 blunt TBI patients were managed by the Trauma Service. Of these, 830 met the inclusion criteria for the TBI protocol and lived>> 48 hours. After implementation, initial analysis of the 1995-96 cohort indicated only 50% compliance with the protocol. By 1997, compliance had risen to 88%. Patients were therefore compared as three groups: before the protocol (1991-94, n = 219), during low compliance (1995-96, n = 188), and during high compliance (1997-2000, n = 423). Groups did not differ significantly on Injury Severity Score, head Abbreviated Injury Scale score, or age (p>> 0.05). Admission Glasgow Coma Scale score was slightly higher in the 1991-94 cohort (4.0 vs. 3.5, p = 0.001). From 1991-94 to 1997-2000, intensive care unit stay was reduced by 1.8 days (p = 0.021) and total hospital stay was reduced by 5.4 days (p < 0.001). The charge reduction (calculated in 1997 dollars) per patient for the length of stay decrease was dollar 6,577 in 1995-96 and dollar 8,266 in 1997-2000 (p = 0.002). This represents a total reduction over 6 years of dollar 4.7 million in charges. In addition, the overall mortality rate showed a reduction of 4.0% from 1991-94 to 1997-2000 (17.8% vs. 13.8%), although this was not statistically significant. On the basis of the Glasgow Outcome Scale score, in 1997-2000, 61.5% of the patients had either a "good recovery" or only "moderate disability," compared with 503% in 1995-96 and 43.3% in 1991-94 (p < 0.001). The Rancho Los Amigos Scores showed a similar trend, with 56.6% of the 1997-2000 patients having appropriate responses at 10 to 14 days, compared with only 44.0% of the 1995-96 patients and 43.9% of the 1991-94 patients (p = 0.004).

CONCLUSIONS

Adherence to a protocol based on the BTF guidelines can result in a significant decrease in hospital days and charges for TBI patients who live>> 48 hours. In addition, mortality and outcome may be significantly affected. This analysis suggests that increased efforts to improve adherence to national guidelines may have a significant impact on head injury care outcomes and could dramatically reduce the substantial financial resources that are currently consumed in the acute care phases for this injury.