BACKGROUND

Isolated tears of the subscapularis occur less commonly than those involving the superior and posterior components of the rotator cuff. The purpose of the present study was to evaluate the structural integrity and clinical outcomes after arthroscopic repair of isolated subscapularis tears.

METHODS

A prospective study of seventeen consecutive patients who were managed with an all-arthroscopic repair of the subscapularis tendon was performed. The study group included thirteen men and four women who had an average age of forty-seven years at the time of surgery. The average interval from the onset of symptoms to the time of surgery was twenty-four months. Thirteen tears were traumatic, and four were degenerative. Seven patients had a tear involving the superior third of the tendon, six had a tear involving the superior two-thirds of the tendon, and four had complete separation of the subscapularis from its insertion on the lesser tuberosity. Clinical findings were assessed for all patients preoperatively and postoperatively with use of the Constant and University of California at Los Angeles scoring systems, and all patients had postoperative computed tomographic arthrography studies to evaluate the structural integrity of the repair.

RESULTS

The average duration of follow-up was twenty-nine months. When the preoperative findings were compared with the most recent findings, the average relative Constant score had improved from 58% to 96% (p < 0.05), the average University of California at Los Angeles score had improved from 16 to 32 points (p < 0.05), the average pain score had improved from 5.9 to 13.5 points (p < 0.05), the average forward flexion had improved from 146 degrees to 175 degrees (p < 0.05), the average external rotation had improved from 50 degrees to 60.3 degrees (p < 0.05), the average internal rotation had improved from the level of the sacrum to L1-L2 (p < 0.05), and the average abduction strength had improved from 7.4 to 15.6 points (p < 0.05). The structural integrity of the repair was completely intact in fifteen patients and was partially reruptured in two patients on the basis of computed tomographic arthrography. Progression of fatty infiltration of the subscapularis was not observed in any patient. Subjectively, twelve patients were very satisfied with the result, four were satisfied, and one was not satisfied.

CONCLUSIONS

Arthroscopic repair of an isolated subscapularis tear can yield marked improvements in shoulder function, can significantly reduce pain, and can result in a durable structural repair.

METHODS

Therapeutic Level IV.

Direct isolation of human central nervous system stem cells (CNS-SC) based on cell surface markers yields a highly purified stem cell population that can extensively expand in vitro and exhibit multilineage differentiation potential both in vitro and in vivo. The CNS-SC were isolated from fetal brain tissue using the cell surface markers CD133(+), CD34(-), CD45(-), and CD24(-/lo) (CD133(+) cells). Fluorescence-activated cell sorted (FACS) CD133(+) cells continue to expand exponentially as neurospheres while retaining multipotential differentiation capacity for >10 passages. CD133(-), CD34(-), and CD45(-) sorted cells (approximately 95% of total fetal brain tissue) fail to initiate neurospheres. Neurosphere cells transplanted into neonatal immunodeficient NOD-SCID mice proliferated, migrated, and differentiated in a site-specific manner. However, it has been difficult to evaluate human cell engraftment, because many of the available monoclonal antibodies against neural cells (beta-tubulin III and glial fibrillary acidic protein) are not species specific. To trace the progeny of human cells after transplantation, CD133(+)-derived neurosphere cells were transduced with lentiviral vectors containing enhanced green fluorescent protein (eGFP) expressed downstream of the phosphoglycerate kinase promoter. After transduction, GFP(+) cells were enriched by FACS, expanded, and transplanted into the lateral ventricular space of neonatal immunodeficient NOD-SCID brain. The progeny of transplanted cells were detected by either GFP fluorescence or antibody against GFP. GFP(+) cells were present in the subventricular zone-rostral migrating stream, olfactory bulb, and hippocampus as well as nonneurogenic sites, such as cerebellum, cerebral cortex, and striatum. Antibody against GFP revealed that some of the cells displayed differentiating dendrites and processes with neurons or glia cells. Thus, marking human CNS-SC with reporter genes introduced by lentiviral vectors is a useful tool with which to characterize migration and differentiation of human cells in this mouse transplantation model.

Many peripheral autonomic nerves are neither cholinergic nor adrenergic. Such nerves are widely distributed in the gastrointestinal, urogenital and respiratory tracts, and in blood vessels. The nature of their neurotransmitter is not known. We have previously reported that vasoactive intestinal polypeptide (VIP) is a potent inhibitor of opossum lower oesophageal sphincter (LOS) and that its inhibitory effect is exerted directly on the sphincter muscle. Subsequent studies have confirmed the inhibitory effect of VIP on LOS in other species. Recently, very high tissue levels of VIP have been reported in the LOS and other gastrointestinal sphincters. Furthermore, VIP has been localized to intramural neurones and is released upon electrical stimulation of the vagus nerve. We report here that immunoantagonism of VIP with a high-titre antiserum antagonized inhibitory neuromuscular transmission in the LOS. These findings provide evidence of a role for VIP as an inhibitory neurotransmitter.

BACKGROUND

On a macrosocial level, neighborhood characteristics have been found to be associated with the prevalence of HIV and other bloodborne and sexually transmitted infections. The current study used structural equation modeling to examine the relationship between neighborhood social and physical disorder and high-risk sexual partners.

METHODS

A cohort (N=838) recruited for an HIV prevention study of drug users (2002-2004) in Baltimore, Maryland, was interviewed about their neighborhood characteristics, drug use, depressive symptoms (using the Centers for Epidemiological Studies Depression Scale), and HIV/sexually transmitted infection risk behaviors of exchanging sex for money or drugs, having multiple sexual partners, and having partners who injected drugs or smoked crack cocaine. Data were analyzed in February 2005.

RESULTS

Model fit statistics from Mplus (Muthen & Muthen, Los Angeles CA, 2004) indicated statistically significant direct associations between neighborhood disorder and psychologic distress, neighborhood disorder and sexual risk behaviors, and neighborhood disorder and drug use. There were also significant indirect associations of neighborhood disorder on sexual risk behaviors.

CONCLUSIONS

These results highlight the importance of viewing drug use, chronic stress, depression and hopelessness, and infectious diseases such as HIV and hepatitis C as interlinked epidemics that are fostered by neighborhood social and physical disorder. Neighborhood, network, and community level interventions are needed to address these intertwined public health issues.

OBJECTIVE

To compare the efficacy of fluconazole with amphotericin B plus flucytosine in the treatment of cryptococcal meningitis.

METHODS

Patients were randomly assigned to oral fluconazole, 400 mg/d, for 10 weeks or to amphotericin B, 0.7 mg/kg body weight daily for 1 week, then three times weekly for 9 weeks combined with flucytosine, 150 mg/kg d, in four divided doses.

METHODS

Los Angeles County-University of Southern California Medical Center.

METHODS

Between 15 February and 7 December 1988, 42 patients had evidence of their first episode of cryptococcal meningitis, of whom 21 participated in the trial. All patients enrolled were men with the acquired immunodeficiency syndrome (AIDS) except one woman who was receiving prednisone therapy and was excluded from the final analysis.

RESULTS

Of 14 patients with AIDS assigned to fluconazole, 8 (57%; 95% CI, 29% to 82%) failed; none of the 6 patients with AIDS failed who were assigned to amphotericin B plus flucytosine therapy (0%; CI, 0% to 46%) (Fisher exact test, P = 0.04). The mean duration of positive cerebrospinal fluid cultures was 40.6 +/- 5.4 days in patients receiving fluconazole and 15.6 +/- 6.6 days in patients receiving amphotericin B plus flucytosine (Mann-Whitney test, P = 0.02). Overall, 4 patients assigned to fluconazole therapy died whereas no patient assigned to amphotericin B plus flucytosine therapy died (Fisher exact test, P = 0.27).

CONCLUSIONS

Amphotericin B used in combination with flucytosine has superior mycologic and clinical efficacy compared with fluconazole for the treatment of cryptococcal meningitis in patients with AIDS.

BACKGROUND

Naturally occurring thymus derived regulatory T cells (Tregs) are central in the maintenance of self-tolerance. The transcription factor FOXP3 is crucial for the suppressive activity of Tregs and is considered the most specific marker for this population. However, human non regulatory T cells upregulate FOXP3 transiently upon activation which calls for other means to identify the Treg population. Since epigenetic mechanisms are involved in the establishment of stable gene expression patterns during cell differentiation, we hypothesized that the methylation profile of the FOXP3 promoter would allow the distinction of truly committed Tregs.

RESULTS

Human CD4(+)CD25(hi) Tregs displayed a demethylated FOXP3 promoter (1.4%+/-0.95% SEM methylated) in contrast to CD4(+)CD25(lo) T cells which were partially methylated (27.9%+/-7.1%). Furthermore, stimulated CD4(+)CD25(lo) T cells transiently expressed FOXP3 but remained partially methylated, suggesting promoter methylation as a mechanism for regulation of stable FOXP3 expression and Treg commitment. In addition, transient FOXP3 expressing cells exhibited suppressive abilities that correlate to the methylation status of the FOXP3 promoter. As an alternative to bisulphite sequencing, we present a restriction enzyme based screening method for the identification of committed Tregs and apply this method to evaluate the effect of various culturing conditions. We show that a partial demethylation occurs in long-term cultures after activation, whereas the addition of TGF-beta and/or IL-10 does not induce any additional change in methylation level.

CONCLUSIONS

The unique FOXP3 promoter methylation profile in Tregs suggests that a demethylated pattern is a prerequisite for stable FOXP3 expression and suppressive phenotype. Presently, FOXP3 is used to identify Tregs in several human diseases and there are future implications for adoptive Treg transfer in immunotherapy. In these settings there is a need to distinguish true Tregs from transiently FOXP3(+) activated T cells. The screening method we present allows this distinction and enables the identification of cells suitable for in vitro expansions and clinical use.

Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population that shares certain characteristics including an aberrant myeloid phenotype and the ability to suppress T cells. MDSCs have been predominantly studied in malignant diseases and findings suggest involvement in tumor-associated immune suppression. Chronic lymphocytic leukemia (CLL) is the leukemia with the highest incidence among adults. Immune defects occur already at early disease stages and impact the clinical course. We assessed presence, frequency, association to other immune parameters, and functional properties of circulating CD14(+) cells lacking HLA-DR expression (HLA-DR(lo)) in patients with untreated CLL. These monocytic cells represent one of the best-defined human MDSC subsets. Frequency of CD14(+)HLA-DR(lo) cells was significantly increased in CLL patients. Furthermore, MDSCs suppressed in vitro T-cell activation and induced suppressive regulatory T cells (TRegs). The MDSC-mediated modulation of T cells could be attributed to their increased indoleamine 2,3-dioxygenase (IDO) activity. CLL cells induced IDO(hi) MDSCs from healthy donor monocytes suggesting bidirectional crosstalk between CLL-cells, MDSCs, and TRegs. Overall, we identified a MDSC population that expands in CLL. The exact mechanisms responsible for such accumulation remain to be elucidated and it will be of interest to test whether antagonizing suppressive functions of CLL MDSCs could represent a mean for enhancing immune responses.

OBJECTIVE

To examine the association between health-related quality of life (HRQOL) and visual field (VF) loss in participants with open-angle glaucoma (OAG) in the Los Angeles Latino Eye Study (LALES).

METHODS

Population-based cross-sectional study.

METHODS

Two hundred thirteen participants with OAG and 2821 participants without glaucoma or VF loss.

METHODS

Participants in the LALES-a population-based prevalence study of eye disease in Latinos 40 years and older, residing in Los Angeles, California-underwent a detailed eye examination including an assessment of their VF using the Humphrey Automated Field Analyzer (Swedish interactive thresholding algorithm Standard 24-2). Open-angle glaucoma was determined by clinical examination. Mean deviation scores were used to assess severity of VF loss. Health-related QOL was assessed by the Medical Outcomes Study 12-item Short-Form Health Survey (SF-12) and 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25). Linear regression and analysis of covariance were used to assess the relationship between HRQOL scores and VF loss after adjusting for sociodemographic variables and visual acuity.

METHODS

The 25-item NEI-VFQ and SF-12 scores.

RESULTS

A trend of worse NEI-VFQ-25 scores for most subscales was observed with worse VF loss (using both monocular and calculated binocular data). Open-angle glaucoma participants with VF loss had lower scores than participants with no VF loss. This association was also present in participants who were previously undiagnosed and untreated for OAG (N = 160). Participants with any central VF loss had lower NEI-VFQ-25 scores than those with unilateral or bilateral peripheral VF loss. There was no significant impact of severity or location of VF loss on SF-12 scores.

CONCLUSIONS

Greater severity of VF loss in persons with OAG impacts vision-related QOL. This impact was present in persons who were previously unaware that they had glaucoma. Prevention of VF loss in persons with glaucoma is likely to reduce loss of vision-related QOL.

The production of interleukin (IL)-12 is critical for the development of interferon (IFN)-gamma-dependent resistance to Toxoplasma gondii. Nevertheless, when this response is dysregulated, such as occurs in the absence of IL-10, the uncontrolled inflammation that results can have lethal consequences for the host. Recently, we demonstrated that lipoxin (LX)A(4), an eicosanoid mediator that depends on 5-lipoxygenase (LO) for its biosynthesis, exerts a regulatory role on dendritic cell IL-12 production triggered artificially by a T. gondii extract. We now formally establish the physiological relevance of this pathway in the systemic control of IL-12 production induced by live T. gondii infection and demonstrate its function to be distinct from that of IL-10. Thus, T. gondii-exposed wild-type, but not 5-LO-deficient animals, produced high levels of serum LXA(4) beginning at the onset of chronic infection. Moreover, 5-LO(-/-), in contrast to wild-type mice, succumbed during the same period displaying a marked encephalitis. The increased mortality of the 5-LO(-/-) animals was also associated with significant elevations of IL-12 and IFN-gamma and was completely prevented by the administration of a stable LXA(4) analogue. Together, these findings demonstrate a new pathway involving the induction of host LXs for the in vivo regulation of proinflammatory responses during microbial infection.

Recently, cases have been reported in which a mixed chimeric state of blood cells is established after liver transplantation. Because the established chimerism may have aided in the induction of donor-specific tolerance, the mechanism responsible for this chimerism is of clinical importance. To establish this, we examined cells in adult mouse liver and identified the presence of c-kit+ Sca-1+ Lin(lo/-) cells. These cells were capable of forming in vivo as well as in vitro colonies. Furthermore, the cells could reconstitute bone marrow of lethally irradiated recipient mice for at least 12 months. These data obtained from the mouse study strongly suggest that hematopoietic stem cells residing in the donor liver are responsible for mixed chimerism and maintenance of tolerance after liver transplantation.

After growth of gonococci in the presence of cytidine monophospho-N-acetyl-neuraminic acid (CMP-NANA), their 4.5-kD lipooligosaccharide (LOS) component was increased by approximately 400 daltons, whereas the LOS of strains lacking the 4.5-kD component were unaffected. Expression of mAb-defined epitopes on the 4.5-kD component was decreased on LOS of strains grown in CMP-NANA, and treatment of the LOS with neuraminidase reversed this affect. Gonococci incubated with human PMNs also had decreased expression of the 4.5-kD+ epitopes. A detergent extract of gonococci incorporated radiolabeled NANA in the LOS, suggesting the presence of a sialyltransferase in gonococci. Exogenous sialyltransferases also could use LOS as an acceptor.

METHODS

A retrospective review of patients treated at 2 institutions with anterior lumbar interbody fusion using a minimally invasive lateral retroperitoneal approach, and review of literature.

OBJECTIVE

To analyze the outcomes from historical literature and from a retrospectively compiled database of patients having undergone anterior interbody fusions performed through a lateral approach.

BACKGROUND

A paucity of published literature exists describing outcomes following lateral approach fusion surgery.

METHODS

Patients treated with extreme lateral interbody fusion (XLIF) were identified through retrospective chart review. Treatment variables included operating room (OR) time, estimated blood loss (EBL), length of hospital stay (LOS), complications, and fusion rate. A literature review, using the National Center for Biotechnology Information databases PubMed/MEDLINE and Google Scholar, yielded 14 peer-reviewed articles reporting outcomes scoring, complications, fusion status, long-term follow-up, and radiographic assessments related to XLIF. Published XLIF results were summarized and evaluated with current study data.

RESULTS

A total of 84 XLIF patients were included in the current cohort analysis. OR time, EBL, and length of hospital stay averaged 199 minutes, 155 mL, and 2.6 days, respectively, and perioperative and postoperative complication rates were 2.4% and 6.1%. Mean follow-up was 15.7 months. Sixty-eight patients showed evidence of solid arthrodesis and no subsidence on computed tomography and flexion/extension radiographs. Results were within the ranges of those in the literature. Literature review identified reports of significant improvements in clinical outcomes scores, radiographic measures, and cost effectiveness.

CONCLUSIONS

Current data corroborates and contributes to the existing body of literature describing XLIF outcomes. Procedures are generally performed with short OR times, minimal EBL, and few complications. Patients recover quickly, requiring minimal hospital stay, although transient hip/thigh pain and/or weakness is common. Long-term outcomes are generally favorable, with maintained improvements in patient-reported pain and function scores as well as radiographic parameters, including high rates of fusion.

More Americans try to change their health behaviors through self-help than through all other forms of professionally designed programs. Mutual support groups, involving little or no cost to participants, have a powerful effect on mental and physical health, yet little is known about patterns of support group participation in health care. What kinds of illness experiences prompt patients to seek each other's company? In an effort to observe social comparison processes with real-world relevance, support group participation was measured for 20 disease categories in 4 metropolitan areas (New York, Chicago, Los Angeles, and Dallas) and on 2 on-line forums. Support seeking was highest for diseases viewed as stigmatizing (e.g., AIDS, alcoholism, breast and prostate cancer) and was lowest for less embarrassing but equally devastating disorders, such as heart disease. The authors discuss implications for social comparison theory and its applications in health care.

Staphylococcus aureus clinical isolates obtained from patients who were inmates of the San Francisco County jail system showed an increase in the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) from 29%, in 1997, to 74%, in 2002; 91% of the MRSA isolates carried staphylococcal chromosomal cassette mec (SCCmec) type IV. Pulsed field gel electrophoresis and multilocus sequence typing demonstrated 2 major clonal groups. One of these clonal groups is genetically indistinguishable from the strain responsible for an outbreak of MRSA in the Los Angeles County jail system in 2002.

TL1A is a TNF-like cytokine that binds to the death-domain receptor (DR)3 and provides costimulatory signals to activated lymphocytes. Through this interaction, TL1A induces secretion of IFN-gamma and may, therefore, participate in the development of T helper-1-type effector responses. In this study, we investigated whether interactions between TL1A and DR3 are involved in the pathogenesis of chronic murine ileitis. We demonstrate that alternative splicing of DR3 mRNA takes place during the activation of lymphocytes, which results in up-regulation of the complete/transmembrane (tm) form of DR3. Using two immunogenetically distinct animal models of Crohn's disease, we demonstrate that induction of intestinal inflammation is associated with significant up-regulation of TL1A and tm DR3 in the inflamed mucosa. In addition, within isolated lamina propria mononuclear cells from mice with inflammation, TL1A is primarily expressed on CD11c(high) dendritic cells. We also report that TL1A acts preferentially on memory CD4(+)/CD45RB(lo) murine lymphocytes by significantly inducing their proliferation, whereas it does not affect the proliferation of the naïve CD4(+)/CD45RB(hi) T helper cell subpopulation. Finally, we demonstrate that TL1A synergizes with both the cytokine-dependent IL-12/IL-18 pathway and with low-dose stimulation of the T cell receptor to significantly induce the secretion of IFN-gamma via an IL-18-independent pathway. Our results raise the possibility that interaction(s) between TL1A expressed on antigen-presenting cells and tm DR3 on lymphocytes may be of particular importance for the pathogenesis of chronic inflammatory conditions that depend on IFN-gamma secretion, including inflammatory bowel disease. Blockade of the TL1A/DR3 pathway may, therefore, offer therapeutic opportunities in Crohn's disease.

OBJECTIVE

As minimally invasive approaches gain popularity in spine surgery, clinical outcomes and effectiveness of mini-open transforaminal lumbar interbody fusion (TLIF) compared with traditional open TLIF have yet to be established. The authors retrospectively compared the outcomes of patients who underwent mini-open TLIF with those who underwent open TLIF.

METHODS

Between 2003 and 2006, 42 patients underwent TLIF for degenerative disc disease or spondylolisthesis; 21 patients underwent mini-open TLIF and 21 patients underwent open TLIF. The mean age in each group was 53 years, and there was no statistically significant difference in age between the groups (p = 0.98). Data were collected perioperatively. In addition, complications, length of stay (LOS), fusion rate, and modified Prolo Scale (mPS) scores were recorded at routine intervals.

RESULTS

No patient was lost to follow-up. The mean follow-up was 24 months for the mini-open group and 34 months for the open group. The mean estimated blood loss was 194 ml for the mini-open group and 505 ml for the open group (p < 0.01). The mean LOS was 3 days for the mini-open group and 5.5 days for the open group (p < 0.01). The mean mPS score improved from 11 to 19 in the mini-open group and from 10 to 18 in the open group; there was no statistically significant difference in mPS score improvement between the groups (p = 0.19). In the mini-open group there were 2 cases of transient L-5 sensory loss, 1 case of a misplaced screw that required revision, and 1 case of cage migration that required revision. In the open group there was 1 case of radiculitis as well as 1 case of a misplaced screw that required revision. One patient in the mini-open group developed a pseudarthrosis that required reoperation, and all patients in the open group exhibited fusion.

CONCLUSIONS

Mini-open TLIF is a viable alternative to traditional open TLIF with significantly reduced estimated blood loss and LOS. However, the authors found a higher incidence of hardware-associated complications with the mini-open TLIF.

BACKGROUND

The objective of this survey was to identify factors associated with good sexual outcomes in a large group of survivors of localized prostate carcinoma.

METHODS

A postal survey was sent to 2636 men in the Cleveland Clinic Foundation's Prostate Cancer Registry who either were treated with definitive radiotherapy or underwent prostatectomy for localized prostate carcinoma. The survey asked about demographic items, past and current sexual functioning, partner's sexual function and health, and a number of factors hypothesized to affect sexual satisfaction. Standardized questionnaires included the Sexual Self-Schema Scale-Male Version, the International Index of Erectile Function (IIEF), urinary and bowel symptom scales from the Los Angeles Prostate Cancer Index, and the Short Form Health Survey (SF-36).

RESULTS

The return rate was 49%, yielding a sample of 1236 men at an average of 4.3 years post-treatment. Comparing responders with nonresponders suggested that the sample may have been somewhat biased toward men who were more interested in maintaining sexual function. At the time they were diagnosed with prostate carcinoma, 36% of men had erectile dysfunction (ED). Within the past 6 months, however, 85% of men reported having ED. Only 13% of men were having reliable, firm erections spontaneously, and another 8% of men were having erections with the aid of a medical treatment. Men were as distressed about loss of desire and trouble having satisfying orgasms as they were about ED. Of the 84% of men who reported having a current sexual partner, 66% indicated that she had a sexual problem. Younger age was associated strongly with better sexual outcome (global IIEF score). With demographic factors taken into account, better sexual outcome was related significantly to medical factors, including not having neoadjuvant or current antiandrogen therapy, undergoing bilateral nerve-sparing prostatectomy or brachytherapy, and having better mental and physical health composite scores on the SF-36. Sexual factors that were associated with a better outcome included having normal erections before treatment for prostate carcinoma, choosing a treatment based on the hope that it would preserve sexual function, having more sexual partners in the past year, and having a sexually functional partner.

CONCLUSIONS

The great majority of men who survive prostate carcinoma do not achieve a return to functional sexual activity in the years after treatment. The priorities a man places on sexuality and on having a sexually functional partner are important factors in sexual satisfaction at follow-up, over and above the influence of age and medical factors.

Blacks in the United States have the highest prostate cancer rate in the world and nearly twice that of whites in the United States. The 2:1 black-to-white ratio in prostate cancer rates is already apparent at age 45 years, the age at which the earliest prostate cancer cases occur. This finding suggests that the factor(s) responsible for the difference in rates occurs, or first occurs, early in life. Testosterone has been hypothesized to play a role in the etiology of prostate cancer, because testosterone and its metabolite, dihydrotestosterone, are the principal trophic hormones that regulate growth and function of epithelial prostate tissue. This report gives the results of assays of circulating steroid hormone levels in white and black college students in Los Angeles, CA. Mean testosterone levels in blacks were 19% higher than in whites, and free testosterone levels were 21% higher. Both these differences were statistically significant. Adjustment by analysis of covariance for time of sampling, age, weight, alcohol use, cigarette smoking, and use of prescription drugs somewhat reduced the differences. After these adjustments were made, blacks had a 15% higher testosterone level and a 13% higher free testosterone level. A 15% difference in circulating testosterone levels could readily explain a twofold difference in prostate cancer risk.

T cell exhaustion and loss of memory potential occur during many chronic viral infections and cancer. We investigated when during chronic viral infection virus-specific CD8 T cells lose the potential to form memory. Virus-specific CD8 T cells from established chronic infection were unable to become memory CD8 T cells if removed from infection. However, at earlier stages of chronic infection, these virus-specific CD8 T cells retained the potential to partially or fully revert to a memory differentiation program after transfer to infection-free mice. Conversely, effector CD8 T cells primed during acute infection were not protected from exhaustion if transferred to a chronic infection. We also tested whether memory and exhausted CD8 T cells arose from different subpopulations of effector CD8 T cells and found that only the KLRG1(lo) memory precursor subset gave rise to exhausted CD8 T cells. Together, these studies demonstrate that CD8 T cell exhaustion is a progressive developmental process. Early during chronic infection, the fate of virus-specific CD8 T cells remains plastic, while later, exhausted CD8 T cells become fixed in their differentiation state. Moreover, exhausted CD8 T cells arise from the memory precursor and not the terminally differentiated subset of effector CD8 T cells. These studies have implications for our understanding of senescence versus exhaustion and for therapeutic interventions during chronic infection.

The structural basis for organizational heterogeneity of lipids and proteins underlies fundamental questions about the plasma membrane of eukaryotic cells. A current hypothesis is the participation of liquid ordered (Lo) membrane domains (lipid rafts) in dynamic compartmentalization of membrane function, but it has been difficult to demonstrate the existence of these domains in live cells. Recently, giant plasma membrane vesicles (GPMVs) obtained by chemically induced blebbing of cultured cells were found to phase separate into optically resolvable, coexisting fluid domains containing Lo-like and liquid disordered (Ld)-like phases as identified by fluorescent probes. In the present study, we used these GPMVs to investigate the structural bases for partitioning of selected lipids and proteins between coexisting Lo-like/Ld-like fluid phases in compositionally complex membranes. Our results with lipid probes show that the structure of the polar headgroups, in addition to acyl chain saturation, can significantly affect partitioning. We find that the membrane anchor of proteins and the aggregation state of proteins both significantly influence their distributions between coexisting fluid phases in these biological membranes. Our results demonstrate the value of GPMVs for characterizing the phase preference of proteins and lipid probes in the absence of detergents and other perturbations of membrane structure.

PubMed, EMBASE and conference abstracts were reviewed systematically to determine the clinical and economic burden associated with Clostridium difficile infection (CDI) acquired and treated in European healthcare facilities. Inclusion criteria were: published in the English language between 2000 and 2010, and study population of at least 20 patients with documented CDI acquired/treated in European healthcare facilities. Data collection was completed by three unblinded reviewers using the Cochrane Handbook and PRISMA statement. The primary outcomes were mortality, recurrence, length of hospital stay (LOS) and cost related to CDI. In total, 1138 primary articles and conference abstracts were identified, and this was narrowed to 39 and 30 studies, respectively. Data were available from 14 countries, with 47% of studies from UK institutions. CDI mortality at 30 days ranged from 2% (France) to 42% (UK). Mortality rates more than doubled from 1999 to 2004, and continued to rise until 2007 when reductions were noted in the UK. Recurrent CDI varied from 1% (France) to 36% (Ireland); however, recurrence definitions varied between studies. Median LOS ranged from eight days (Belgium) to 27 days (UK). The incremental cost of CDI was £4577 in Ireland and £8843 in Germany, after standardization to 2010 prices. Country-specific estimates, weighted by sample size, ranged from 2.8% to 29.8% for 30-day mortality and from 16 to 37 days for LOS. CDI burden in Europe was most commonly described using 30-day mortality, recurrence, LOS and cost data. The continued spread of CDI and resultant healthcare burden underscores the need for judicious use of antibiotics.

BACKGROUND

Understanding a speaker's communicative intent in everyday interactions is likely to draw on cues such as facial expression and tone of voice. Prior research has shown that individuals with autism spectrum disorders (ASD) show reduced activity in brain regions that respond selectively to the face and voice. However, there is also evidence that activity in key regions can be increased if task demands allow for explicit processing of emotion.

OBJECTIVE

To examine the neural circuitry underlying impairments in interpreting communicative intentions in ASD using irony comprehension as a test case, and to determine whether explicit instructions to attend to facial expression and tone of voice will elicit more normative patterns of brain activity.

METHODS

Eighteen boys with ASD (aged 7-17 years, full-scale IQ >70) and 18 typically developing (TD) boys underwent functional magnetic resonance imaging at the Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles.

METHODS

Blood oxygenation level-dependent brain activity during the presentation of short scenarios involving irony. Behavioral performance (accuracy and response time) was also recorded.

RESULTS

Reduced activity in the medial prefrontal cortex and right superior temporal gyrus was observed in children with ASD relative to TD children during the perception of potentially ironic vs control scenarios. Importantly, a significant group x condition interaction in the medial prefrontal cortex showed that activity was modulated by explicit instructions to attend to facial expression and tone of voice only in the ASD group. Finally, medial prefrontal cortex activity was inversely related to symptom severity in children with ASD such that children with greater social impairment showed less activity in this region.

CONCLUSIONS

Explicit instructions to attend to facial expression and tone of voice can elicit increased activity in the medial prefrontal cortex, part of a network important for understanding the intentions of others, in children with ASD. These findings suggest a strategy for future intervention research.

PURPOSE Differences in cellular levels of histone modifications have predicted clinical outcome in certain cancers. Here, we studied the prognostic and predictive value of three histone modifications in pancreatic adenocarcinoma. METHODS Tissue microarrays (TMAs) from two pancreatic adenocarcinoma cohorts were examined, including those from a 195-patient cohort from Radiation Therapy Oncology Group trial RTOG 9704, a multicenter, phase III, randomized treatment trial comparing adjuvant gemcitabine with fluorouracil and a 140-patient cohort of patients with stage I or II cancer from University of California, Los Angeles Medical Center. Immunohistochemistry was performed for histone H3 lysine 4 dimethylation (H3K4me2), histone H3 lysine 9 dimethylation (H3K9me2), and histone H3 lysine 18 acetylation (H3K18ac). Positive tumor cell staining for each histone modification was used to classify patients into low- and high-staining groups, which were related to clinicopathologic parameters and clinical outcome measures. Results Low cellular levels of H3K4me2, H3K9me2, or H3K18ac were each significant and independent predictors of poor survival in univariate and multivariate models, and combined low levels of H3K4me2 and/or H3K18ac were the most significant predictor of overall survival (hazard ratio, 2.93; 95% CI, 1.78 to 4.82) in the University of California, Los Angeles cohort. In subgroup analyses, histone levels were predictive of survival specifically for those patients with node-negative cancer or for those patients receiving adjuvant fluorouracil, but not gemcitabine, in RTOG 9704. CONCLUSION Cellular levels of histone modifications define previously unrecognized subsets of patients with pancreatic adenocarcinoma with distinct epigenetic phenotypes and clinical outcomes and represent prognostic and predictive biomarkers that could inform clinical decisions, including the use of fluorouracil chemotherapy.

Epidemiologic studies have shown associations between ambient particulate matter (PM) and adverse health outcomes including increased mortality, emergency room visits, and time lost from school and work. The mechanisms of PM-related health effects are still incompletely understood, but a hypothesis under investigation is that many of the adverse health effects may derive from oxidative stress, initiated by the formation of reactive oxygen species (ROS) within affected cells. While the adverse effects from PM have historically been associated with the airborne concentration of PM and more recently fine-particle PM, we considered it relevant to develop an assay to quantitatively measure the ability of PM to catalyze ROS generation as the initial step in the induction of oxidative stress. This ability of PM could then be related to different sources, chemical composition, and physical and spatial/temporal characteristics in the ambient environment. The measurement of ROS-forming ability in relation to sources and other factors will have potential relevance to control of redox-active PM. If oxidative stress represents a relevant mechanism of toxicity from PM, the measurement of redox activity represents a first step in the elucidation of the subsequent downstream processes. We have developed an assay for PM redox activity, utilizing the reduction of oxygen by dithiothreitol which serves as an electron source. We have found that PM will catalyze the reduction of oxygen and have examined the distribution and chemical characteristics of the redox activity of PM fractions collected in different sites in the Los Angeles Basin. Samples of concentrated coarse, fine, and ultrafine PM, obtained with aerosol concentrators, were studied with regard to their chemical properties and redox activity. Redox activity was highest in the ultrafine fraction, in agreement with results indicating ultrafines were the most potent toward inducing that heme oxygenase expression and depleting intracellular glutathione, which has relevance to induction of oxidative stress. Comparison of the redox activity with chemical composition showed a reasonable correlation of redox activity with elemental carbon (r(2)=0.79), organic carbon (r(2)=0.53), and with benzo[ghi]perylene (r(2)=0.82), consistent with species typically found in mobile emission sources.